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  • 201. Ng, Esther
    et al.
    Salihovic, Samira
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lind, P. Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Mahajan, Anubha
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Axelsson, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ingelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lindgren, Cecilia M
    van Bavel, Bert
    Morris, Andrew P
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Genome-wide association study of plasma levels of polychlorinated biphenyls disclose an association with the CYP2B6 gene in a population-based sample2015In: Environmental Research, ISSN 0013-9351, E-ISSN 1096-0953, Vol. 140, p. 95-101Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Polychlorinated biphenyls (PCBs) are a group of man-made environmental pollutants which accumulate in humans with adverse health effects. To date, very little effort has been devoted to the study of the metabolism of PCBs on a genome-wide level.

    OBJECTIVES: Here, we conducted a genome-wide association study (GWAS) to identify genomic regions involved in the metabolism of PCBs.

    METHODS: Plasma levels of 16 PCBs ascertained in a cohort of elderly individuals from Sweden (n=1016) were measured using gas chromatography-high resolution mass spectrophotometry (GC-HRMS). DNA samples were genotyped on the Infinium Omni Express bead microarray, and imputed up to reference panels from the 1000 Genomes Project. Association testing was performed in a linear regression framework under an additive model.

    RESULTS: Plasma levels of PCB-99 demonstrated genome-wide significant association with single nucleotide polymorphisms (SNPs) mapping to chromosome 19q13.2. The SNP with the strongest association was rs8109848 (p=3.7×10(-13)), mapping to an intronic region of CYP2B6. Moreover, when all PCBs were conditioned on PCB-99, further signals were revealed for PCBs -74, -105 and -118, mapping to the same genomic region. The lead SNPs were rs8109848 (p=3.8×10(-12)) for PCB-118, rs4802104 (p=1.4×10(-9)) for PCB-74 and rs4803413 (p=2.5×10(-9)) for PCB-105, all of which map to CYP2B6.

    CONCLUSIONS: In our study, we found plasma levels of four lower-chlorinated PCBs to be significantly associated with the genetic region mapping to the CYP2B6 locus. These findings show that CYP2B6 is of importance for the metabolism of PCBs in humans, and may help to identify individuals who may be susceptible to PCB toxicity.

  • 202.
    Nielsen, Jonas B.
    et al.
    Univ Michigan, Div Cardiovasc Med, Dept Internal Med, Ann Arbor, MI 48109 USA.;Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA..
    Fritsche, Lars G.
    Norwegian Univ Sci & Technol, Dept Publ Hlth & Gen Practice, HUNT Res Ctr, N-7600 Levanger, Norway.;Univ Michigan, Ctr Stat Genet, Ann Arbor, MI 48109 USA.;Norwegian Univ Sci & Technol, Dept Publ Hlth, KG Jebsen Ctr Genet Epidemiol, N-7491 Trondheim, Norway..
    Zhou, Wei
    Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA.;Univ Michigan, Ctr Stat Genet, Ann Arbor, MI 48109 USA..
    Teslovich, Tanya M.
    Regeneron Genet Ctr, Tarrytown, NY 10591 USA..
    Holmen, Oddgeir L.
    Norwegian Univ Sci & Technol, Dept Publ Hlth & Gen Practice, HUNT Res Ctr, N-7600 Levanger, Norway.;Norwegian Univ Sci & Technol, Dept Publ Hlth, KG Jebsen Ctr Genet Epidemiol, N-7491 Trondheim, Norway.;St Olavs Univ Hosp, Dept Cardiol, N-7030 Trondheim, Norway..
    Gustafsson, Stefan
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Gabrielsen, Maiken E.
    Norwegian Univ Sci & Technol, Dept Publ Hlth & Gen Practice, HUNT Res Ctr, N-7600 Levanger, Norway.;Norwegian Univ Sci & Technol, Dept Publ Hlth, KG Jebsen Ctr Genet Epidemiol, N-7491 Trondheim, Norway..
    Schmidt, Ellen M.
    Univ Michigan, Ctr Stat Genet, Ann Arbor, MI 48109 USA..
    Beaumont, Robin
    Royal Devon & Exeter NHS Fdn Trust, Exeter EX2 5WD, Devon, England.;Univ Exeter, Exeter EX2 5WD, Devon, England..
    Wolford, Brooke N.
    Univ Michigan, Div Cardiovasc Med, Dept Internal Med, Ann Arbor, MI 48109 USA.;Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA..
    Lin, Maoxuan
    Univ Michigan, Div Cardiovasc Med, Dept Internal Med, Ann Arbor, MI 48109 USA.;Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA..
    Brummett, Chad M.
    Univ Michigan, Dept Anesthesiol, Ann Arbor, MI 48109 USA..
    Preuss, Michael H.
    Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA.;Icahn Sch Med Mt Sinai, Genet Obes & Related Metab Traits Program, New York, NY 10029 USA..
    Refsgaard, Lena
    Univ Copenhagen, Rigshosp, Dept Cardiol, Lab Mol Cardiol, DK-2100 Copenhagen, Denmark..
    Bottinger, Erwin P.
    Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA.;Icahn Sch Med Mt Sinai, Mindich Child Hlth Dev Inst, New York, NY 10029 USA..
    Graham, Sarah E.
    Univ Michigan, Div Cardiovasc Med, Dept Internal Med, Ann Arbor, MI 48109 USA..
    Surakka, Ida
    Univ Michigan, Div Cardiovasc Med, Dept Internal Med, Ann Arbor, MI 48109 USA..
    Chu, Yunhan
    Norwegian Univ Sci & Technol, Dept Publ Hlth & Gen Practice, HUNT Res Ctr, N-7600 Levanger, Norway.;Norwegian Univ Sci & Technol, Dept Publ Hlth, KG Jebsen Ctr Genet Epidemiol, N-7491 Trondheim, Norway..
    Skogholt, Anne Heidi
    Norwegian Univ Sci & Technol, Dept Publ Hlth & Gen Practice, HUNT Res Ctr, N-7600 Levanger, Norway.;Norwegian Univ Sci & Technol, Dept Publ Hlth, KG Jebsen Ctr Genet Epidemiol, N-7491 Trondheim, Norway..
    Dalen, Havard
    St Olavs Univ Hosp, Dept Cardiol, N-7030 Trondheim, Norway.;Nord Trondelag Hosp Trust, Levanger Hosp, Dept Med, N-7600 Levanger, Norway.;Norwegian Univ Sci & Technol, Dept Circulat & Med Imaging, N-7491 Trondheim, Norway..
    Boyle, Alan P.
    Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA.;Univ Michigan, Dept Computat Med & Bioinformat, Ann Arbor, MI 48109 USA..
    Oral, Hakan
    Univ Michigan, Div Cardiovasc Med, Dept Internal Med, Ann Arbor, MI 48109 USA..
    Herron, Todd J.
    Univ Michigan, Ctr Arrhythmia Res, Dept Internal Med, Ann Arbor, MI 48109 USA..
    Kitzman, Jacob
    Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA..
    Jalife, Jose
    Univ Michigan, Ctr Arrhythmia Res, Dept Internal Med, Ann Arbor, MI 48109 USA.;Fdn Ctr Nacl Invest Cardiovasc, Madrid 28029, Spain..
    Svendsen, Jesper H.
    Univ Copenhagen, Rigshosp, Dept Cardiol, Lab Mol Cardiol, DK-2100 Copenhagen, Denmark.;Univ Copenhagen, Fac Hlth & Med Sci, DK-2200 Copenhagen, Denmark..
    Olesen, Morten S.
    Univ Copenhagen, Rigshosp, Dept Cardiol, Lab Mol Cardiol, DK-2100 Copenhagen, Denmark.;Univ Copenhagen, Dept Biomed, DK-2200 Copenhagen, Denmark..
    Njolstad, Inger
    UiT Arctic Univ Norway, Fac Hlth Sci, Dept Community Med, N-9019 Tromso, Norway..
    Lochen, Maja-Lisa
    UiT Arctic Univ Norway, Fac Hlth Sci, Dept Community Med, N-9019 Tromso, Norway..
    Baras, Aris
    Regeneron Genet Ctr, Tarrytown, NY 10591 USA..
    Gottesman, Omri
    Regeneron Genet Ctr, Tarrytown, NY 10591 USA..
    Marcketta, Anthony
    Regeneron Genet Ctr, Tarrytown, NY 10591 USA..
    O'Dushlaine, Colm
    Regeneron Genet Ctr, Tarrytown, NY 10591 USA..
    Ritchie, Marylyn D.
    Geisinger Hlth Syst, Danville, PA 17822 USA..
    Wilsgaard, Tom
    UiT Arctic Univ Norway, Fac Hlth Sci, Dept Community Med, N-9019 Tromso, Norway..
    Loos, Ruth J. F.
    Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA.;Icahn Sch Med Mt Sinai, Genet Obes & Related Metab Traits Program, New York, NY 10029 USA..
    Frayling, Timothy M.
    Royal Devon & Exeter NHS Fdn Trust, Exeter EX2 5WD, Devon, England.;Univ Exeter, Exeter EX2 5WD, Devon, England..
    Boehnke, Michael
    Univ Michigan, Ctr Stat Genet, Ann Arbor, MI 48109 USA.;Norwegian Univ Sci & Technol, Dept Publ Hlth, KG Jebsen Ctr Genet Epidemiol, N-7491 Trondheim, Norway..
    Ingelsson, Erik
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Division of Cardiovascular Medicine, Depart- ment of Medicine, Stanford University School of Medicine, Stanford, USA.
    Carey, David J.
    Dewey, Frederick E.
    Regeneron Genet Ctr, Tarrytown, NY 10591 USA..
    Kang, Hyun M.
    Univ Michigan, Ctr Stat Genet, Ann Arbor, MI 48109 USA..
    Abecasis, Goncalo R.
    Univ Michigan, Ctr Stat Genet, Ann Arbor, MI 48109 USA.;Norwegian Univ Sci & Technol, Dept Publ Hlth, KG Jebsen Ctr Genet Epidemiol, N-7491 Trondheim, Norway..
    Hveem, Kristian
    Norwegian Univ Sci & Technol, Dept Publ Hlth & Gen Practice, HUNT Res Ctr, N-7600 Levanger, Norway.;Norwegian Univ Sci & Technol, Dept Publ Hlth, KG Jebsen Ctr Genet Epidemiol, N-7491 Trondheim, Norway.;Nord Trondelag Hosp Trust, Levanger Hosp, Dept Med, N-7600 Levanger, Norway..
    Willer, Cristen J.
    Univ Michigan, Div Cardiovasc Med, Dept Internal Med, Ann Arbor, MI 48109 USA.;Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA.;Univ Michigan, Ctr Stat Genet, Ann Arbor, MI 48109 USA.;Norwegian Univ Sci & Technol, Dept Publ Hlth, KG Jebsen Ctr Genet Epidemiol, N-7491 Trondheim, Norway.;Univ Michigan, Dept Computat Med & Bioinformat, Ann Arbor, MI 48109 USA..
    Genome-wide Study of Atrial Fibrillation Identifies Seven Risk Loci and Highlights Biological Pathways and Regulatory Elements Involved in Cardiac Development2018In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 102, no 1, p. 103-115Article in journal (Refereed)
    Abstract [en]

    Atrial fibrillation (AF) is a common cardiac arrhythmia and a major risk factor for stroke, heart failure, and premature death. The pathogenesis of AF remains poorly understood, which contributes to the current lack of highly effective treatments. To understand the genetic variation and biology underlying AF, we undertook a genome-wide association study (GWAS) of 6,337 AF individuals and 61,607 AF-free individuals from Norway, including replication in an additional 30,679 AF individuals and 278,895 AF-free individuals. Through genotyping and dense imputation mapping from whole-genome sequencing, we tested almost nine million genetic variants across the genome and identified seven risk loci, including two novel loci. One novel locus (lead single-nucleotide variant [SNV] rs12614435; p = 6.76 × 10−18) comprised intronic and several highly correlated missense variants situated in the I-, A-, and M-bands of titin, which is the largest protein in humans and responsible for the passive elasticity of heart and skeletal muscle. The other novel locus (lead SNV rs56202902; p = 1.54 × 10−11) covered a large, gene-dense chromosome 1 region that has previously been linked to cardiac conduction. Pathway and functional enrichment analyses suggested that many AF-associated genetic variants act through a mechanism of impaired muscle cell differentiation and tissue formation during fetal heart development.

  • 203.
    Nikpay, Majid
    et al.
    Univ Ottawa, Inst Heart, Ruddy Canadian Cardiovasc Genet Ctr, Ottawa, ON, Canada..
    Goel, Anuj
    Univ Oxford, Div Cardiovasc Med, Radcliffe Dept Med, Oxford, England.;Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England..
    Won, Hong-Hee
    Broad Inst MIT & Harvard Univ, Cambridge, MA USA.;Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA.;Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA.;Harvard Univ, Sch Med, Dept Med, Boston, MA USA..
    Hall, Leanne M.
    Univ Leicester, Dept Cardiovasc Sci, Leicester, Leics, England..
    Willenborg, Christina
    Univ Lubeck, Inst Integrat & Expt Genom, Lubeck, Germany.;DZHK German Res Ctr Cardiovasc Res, Lubeck, Germany..
    Kanoni, Stavroula
    Queen Mary Univ London, Barts & London Sch Med & Dent, William Harvey Res Inst, London, England..
    Saleheen, Danish
    Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA.;Ctr Noncommunicable Dis, Karachi, Pakistan..
    Kyriakou, Theodosios
    Univ Oxford, Div Cardiovasc Med, Radcliffe Dept Med, Oxford, England.;Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England..
    Nelson, Christopher P.
    Univ Leicester, Dept Cardiovasc Sci, Leicester, Leics, England.;Glenfield Hosp, NIHR, Leicester Cardiovasc Biomed Res Unit, Leicester, Leics, England..
    Hopewell, Jemma C.
    Univ Oxford, Nuffield Dept Populat Hlth, Clin Trial Serv Unit, Oxford, England.;Univ Oxford, Nuffield Dept Populat Hlth, Epidemiol Studies Unit CTSU, Oxford, England..
    Webb, Thomas R.
    Univ Leicester, Dept Cardiovasc Sci, Leicester, Leics, England.;Glenfield Hosp, NIHR, Leicester Cardiovasc Biomed Res Unit, Leicester, Leics, England..
    Zeng, Lingyao
    Tech Univ Munich, Deutsches Herzzentrum Munchen, D-80290 Munich, Germany.;DZHK German Ctr Cardiovasc Res, Munich, Germany..
    Dehghan, Abbas
    Erasmus Univ, Med Ctr, Dept Epidemiol, Rotterdam, Netherlands..
    Alver, Maris
    Univ Tartu, Estonian Genome Ctr, EE-50090 Tartu, Estonia.;Univ Tartu, Inst Mol & Cell Biol, EE-50090 Tartu, Estonia..
    Armasu, Sebastian M.
    Mayo Clin, Dept Hlth Sci Res, Div Biomed Stat & Informat, Rochester, MN USA..
    Auro, Kirsi
    Natl Inst Hlth & Welf, Dept Hlth, Helsinki, Finland.;Univ Helsinki, Inst Mol Med Finland FIMM, Helsinki, Finland.;Univ Helsinki, Diabet & Obes Res Program, Helsinki, Finland..
    Bjonnes, Andrew
    Broad Inst MIT & Harvard Univ, Cambridge, MA USA.;Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA..
    Chasman, Daniel I.
    Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02115 USA.;Harvard Univ, Sch Med, Boston, MA USA..
    Chen, Shufeng
    Chinese Acad Med Sci, Natl Ctr Cardiovasc Dis, Fuwai Hosp, State Key Lab Cardiovasc Dis, Beijing 100730, Peoples R China.;Peking Union Med Coll, Beijing 100021, Peoples R China..
    Ford, Ian
    Univ Glasgow, Robertson Ctr Biostat, Glasgow, Lanark, Scotland..
    Franceschini, Nora
    Univ N Carolina, Dept Epidemiol, Gillings Sch Global Publ Hlth, Chapel Hill, NC USA..
    Gieger, Christian
    DZHK German Ctr Cardiovasc Res, Munich, Germany.;German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol 2, Neuherberg, Germany.;German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Res Unit Mol Epidemiol, Neuherberg, Germany..
    Grace, Christopher
    Univ Oxford, Div Cardiovasc Med, Radcliffe Dept Med, Oxford, England.;Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England..
    Gustafsson, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Huang, Jie
    Wellcome Trust Sanger Inst, Hinxton, England..
    Hwang, Shih-Jen
    NHLBI, Framingham Heart Study, Framingham, MA USA.;Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA..
    Kim, Yun Kyoung
    Korea Natl Inst Hlth, Ctr Genome Sci, Chungcheongbuk Do, South Korea..
    Kleber, Marcus E.
    Heidelberg Univ, Med Fac Mannheim, Vth Dept Med Nephrol Hypertensiol Endocrinol Diab, Mannheim, Germany..
    Lau, King Wai
    Univ Oxford, Nuffield Dept Populat Hlth, Clin Trial Serv Unit, Oxford, England.;Univ Oxford, Nuffield Dept Populat Hlth, Epidemiol Studies Unit CTSU, Oxford, England..
    Lu, Xiangfeng
    Chinese Acad Med Sci, Natl Ctr Cardiovasc Dis, Fuwai Hosp, State Key Lab Cardiovasc Dis, Beijing 100730, Peoples R China.;Peking Union Med Coll, Beijing 100021, Peoples R China..
    Lu, Yingchang
    Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA.;Icahn Sch Med Mt Sinai, Genet Obes & Related Metab Traits Program, New York, NY 10029 USA..
    Lyytikainen, Leo-Pekka
    Fimlab Labs, Dept Clin Chem, Tampere, Finland.;Univ Tampere, Sch Med, Dept Clin Chem, FIN-33101 Tampere, Finland..
    Mihailov, Evelin
    Univ Tartu, Estonian Genome Ctr, EE-50090 Tartu, Estonia..
    Morrison, Alanna C.
    Univ Texas Hlth Sci Ctr Houston, Human Genet Ctr, Sch Publ Hlth, Houston, TX 77030 USA..
    Pervjakova, Natalia
    Univ Tartu, Estonian Genome Ctr, EE-50090 Tartu, Estonia.;Natl Inst Hlth & Welf, Dept Hlth, Helsinki, Finland.;Univ Helsinki, Inst Mol Med Finland FIMM, Helsinki, Finland.;Univ Helsinki, Diabet & Obes Res Program, Helsinki, Finland..
    Qu, Liming
    Univ Penn, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA..
    Rose, Lynda M.
    Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02115 USA..
    Salfati, Elias
    Stanford Univ, Dept Med, Div Cardiovasc Med, Stanford, CA 94305 USA..
    Saxena, Richa
    Broad Inst MIT & Harvard Univ, Cambridge, MA USA.;Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA.;Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Anesthesia Crit Care & Pain Med, Boston, MA USA..
    Scholz, Markus
    Univ Leipzig, Fac Med, Inst Med Informat Stat & Epidemiol, D-04109 Leipzig, Germany.;LIFE Res Ctr Civilizat Dis, Leipzig, Germany..
    Smith, Albert V.
    Iceland Heart Assoc, Kopavogur, Iceland.;Univ Iceland, Fac Med, Reykjavik, Iceland..
    Tikkanen, Emmi
    Univ Helsinki, Inst Mol Med Finland FIMM, Helsinki, Finland.;Univ Helsinki, Dept Publ Hlth, Helsinki, Finland..
    Uitterlinden, Andre
    Erasmus Univ, Med Ctr, Dept Epidemiol, Rotterdam, Netherlands..
    Yang, Xueli
    Chinese Acad Med Sci, Natl Ctr Cardiovasc Dis, Fuwai Hosp, State Key Lab Cardiovasc Dis, Beijing 100730, Peoples R China.;Peking Union Med Coll, Beijing 100021, Peoples R China..
    Zhang, Weihua
    Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Biostat, London, England.;Ealing Hosp Natl Hlth Serv NHS Trust, Dept Cardiol, Southall, Middx, England..
    Zhao, Wei
    Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA..
    de Andrade, Mariza
    Mayo Clin, Dept Hlth Sci Res, Div Biomed Stat & Informat, Rochester, MN USA..
    de Vries, Paul S.
    Erasmus Univ, Med Ctr, Dept Epidemiol, Rotterdam, Netherlands..
    van Zuydam, Natalie R.
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Dundee, Med Res Inst, Dundee, Scotland..
    Anand, Sonia S.
    McMaster Univ, Dept Med, Populat Hlth Res Inst, Hamilton Hlth Sci, Hamilton, ON, Canada..
    Bertram, Lars
    Univ Lubeck, Inst Neurogenet & Integrat, Platform Genome Analyt, Lubeck, Germany.;Univ Lubeck, Inst Expt Gen, Platform Genome Analyt, Lubeck, Germany.;Univ London Imperial Coll Sci Technol & Med, Fac Med, Sch Publ Hlth, Neuroepidemiol & Ageing Res Unit, London, England..
    Beutner, Frank
    LIFE Res Ctr Civilizat Dis, Leipzig, Germany.;Univ Leipzig, Heart Ctr Leipzig, Cardiol, D-04109 Leipzig, Germany..
    Dedoussis, George
    Harokopio Univ, Dept Dietet Nutr, Athens, Greece..
    Frossard, Philippe
    Ctr Noncommunicable Dis, Karachi, Pakistan..
    Gauguier, Dominique
    INSERM, Ctr Rech Cordeliers, UMRS 1138, Paris, France..
    Goodall, Alison H.
    Glenfield Hosp, NIHR, Leicester Cardiovasc Biomed Res Unit, Leicester, Leics, England.;Univ Leicester, Glenfield Hosp, Dept Cardiovasc Sci, Leicester, Leics, England..
    Gottesman, Omri
    Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA..
    Haber, Marc
    Lebanese Amer Univ, Sch Med, Beirut, Lebanon..
    Han, Bok-Ghee
    Korea Natl Inst Hlth, Ctr Genome Sci, Chungcheongbuk Do, South Korea..
    Huang, Jianfeng
    Peking Union Med Coll, Beijing 100021, Peoples R China.;Chinese Acad Med Sci, Natl Ctr Cardiovasc Dis, Fuwai Hosp, Hypertens Div, Beijing 100730, Peoples R China..
    Jalilzadeh, Shapour
    Univ Oxford, Div Cardiovasc Med, Radcliffe Dept Med, Oxford, England.;Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England..
    Kessler, Thorsten
    Tech Univ Munich, Deutsches Herzzentrum Munchen, D-80290 Munich, Germany.;Klinikum Rechts Der Isar, Munich, Germany..
    Koenig, Inke R.
    DZHK German Res Ctr Cardiovasc Res, Lubeck, Germany.;Univ Lubeck, Inst Med Biometrie & Stat, Lubeck, Germany..
    Lannfelt, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Lieb, Wolfgang
    Univ Kiel, Inst Epidemiol, Kiel, Germany..
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Lindgren, Cecilia M.
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.;Broad Inst MIT & Harvard Univ, Cambridge, MA USA..
    Lokki, Marja-Liisa
    Univ Helsinki, Haartman Inst, Transplantat Lab, Helsinki, Finland..
    Magnusson, Patrik K.
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Mallick, Nadeem H.
    Punjab Inst Cardiol, Lahore, Pakistan..
    Mehra, Narinder
    All India Inst Med Sci, New Delhi, India..
    Meitinger, Thomas
    DZHK German Ctr Cardiovasc Res, Munich, Germany.;German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Humangenet, Neuherberg, Germany.;Tech Univ Munich, Inst Human Genet, D-80290 Munich, Germany..
    Memon, Fazal-ur-Rehman
    Red Crescent Inst Cardiol, Hyderabad, Andhra Pradesh, Pakistan..
    Morris, Andrew P.
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Liverpool, Dept Biostat, Liverpool L69 3BX, Merseyside, England..
    Nieminen, Markku S.
    Univ Helsinki, Cent Hosp, Dept Med, Dept Cardiol, Helsinki, Finland..
    Pedersen, Nancy L.
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Peters, Annette
    DZHK German Ctr Cardiovasc Res, Munich, Germany.;German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol 2, Neuherberg, Germany..
    Rallidis, Loukianos S.
    Univ Athens, Sch Med, Attikon Hosp, Dept Cardiol 2, GR-11527 Athens, Greece..
    Rasheed, Asif
    Ctr Noncommunicable Dis, Karachi, Pakistan.;Red Crescent Inst Cardiol, Hyderabad, Andhra Pradesh, Pakistan..
    Samuel, Maria
    Ctr Noncommunicable Dis, Karachi, Pakistan..
    Shah, Svati H.
    Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA..
    Sinisalo, Juha
    Univ Helsinki, Cent Hosp, Dept Med, Dept Cardiol, Helsinki, Finland..
    Stirrups, Kathleen E.
    Queen Mary Univ London, Barts & London Sch Med & Dent, William Harvey Res Inst, London, England.;Univ Cambridge, Dept Haematol, Cambridge, England..
    Trompet, Stella
    Leiden Univ, Med Ctr, Dept Cardiol, Leiden, Netherlands.;Leiden Univ, Med Ctr, Dept Gerontol & Geriatr, Leiden, Netherlands..
    Wang, Laiyuan
    Chinese Acad Med Sci, Natl Ctr Cardiovasc Dis, Fuwai Hosp, State Key Lab Cardiovasc Dis, Beijing 100730, Peoples R China.;Peking Union Med Coll, Beijing 100021, Peoples R China.;Natl Human Genome Ctr Beijing, Beijing, Peoples R China..
    Zaman, Khan S.
    Natl Inst Cardiovasc Dis, Karachi, Pakistan..
    Ardissino, Diego
    Univ Parma, Azienda Osped, Div Cardiol, I-43100 Parma, Italy.;Assoc Studio Trombosi Cardiol, Pavia, Italy..
    Boerwinkle, Eric
    Univ Texas Hlth Sci Ctr Houston, Human Genet Ctr, Sch Publ Hlth, Houston, TX 77030 USA.;Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA..
    Borecki, Ingrid B.
    Washington Univ, Sch Med, Dept Genet, St Louis, MO 63110 USA..
    Bottinger, Erwin P.
    Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA..
    Buring, Julie E.
    Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02115 USA..
    Chambers, John C.
    Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Biostat, London, England.;Ealing Hosp Natl Hlth Serv NHS Trust, Dept Cardiol, Southall, Middx, England.;Imperial Coll Healthcare NHS Trust, London, England..
    Collins, Rory
    Univ Oxford, Nuffield Dept Populat Hlth, Clin Trial Serv Unit, Oxford, England.;Univ Oxford, Nuffield Dept Populat Hlth, Epidemiol Studies Unit CTSU, Oxford, England..
    Cupples, L. Adrienne
    NHLBI, Framingham Heart Study, Framingham, MA USA.;Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA..
    Danesh, John
    Wellcome Trust Sanger Inst, Hinxton, England.;Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England..
    Demuth, Ilja
    Berlin Aging Study 2, Berlin, Germany.;Charite, Res Grp Geriatr, D-13353 Berlin, Germany.;Charite, Inst Med & Human Genet, D-13353 Berlin, Germany..
    Elosua, Roberto
    Inst Hosp Mar Invest Med IMIM, Grp Epidemiol & Genet Cardiovasc, Barcelona, Spain..
    Epstein, Stephen E.
    MedStar Washington Hosp Ctr, MedStar Heart & Vasc Inst, Washington, DC USA..
    Esko, Tonu
    Broad Inst MIT & Harvard Univ, Cambridge, MA USA.;Univ Tartu, Estonian Genome Ctr, EE-50090 Tartu, Estonia.;Boston Childrens Hosp, Div Endocrinol & Basic & Translat Obes Res, Boston, MA USA.;Harvard Univ, Sch Med, Dept Genet, Boston, MA USA..
    Feitosa, Mary F.
    Washington Univ, Sch Med, Dept Genet, St Louis, MO 63110 USA..
    Franco, Oscar H.
    Erasmus Univ, Med Ctr, Dept Epidemiol, Rotterdam, Netherlands..
    Franzosi, Maria Grazia
    IRCCS Ist Ric Farmacol Mario Negri, Dept Cardiovasc Res, Milan, Italy..
    Granger, Christopher B.
    Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA..
    Gu, Dongfeng
    Chinese Acad Med Sci, Natl Ctr Cardiovasc Dis, Fuwai Hosp, State Key Lab Cardiovasc Dis, Beijing 100730, Peoples R China.;Peking Union Med Coll, Beijing 100021, Peoples R China..
    Gudnason, Vilmundur
    Iceland Heart Assoc, Kopavogur, Iceland.;Univ Iceland, Fac Med, Reykjavik, Iceland..
    Hall, Alistair S.
    Univ Leeds, Leeds Inst Genet Hlth & Therapeut, Leeds, W Yorkshire, England..
    Hamsten, Anders
    Karolinska Inst, Dept Med Solna, Atherosclerosis Res Unit, Cardiovasc Genet & Genom Grp, Stockholm, Sweden..
    Harris, Tamara B.
    NIA, Lab Epidemiol Demog & Biometry, US Natl Inst Hlth, Bethesda, MD 20892 USA..
    Hazen, Stanley L.
    Cleveland Clin, Dept Cellular & Mol Med, Cleveland, OH 44106 USA..
    Hengstenberg, Christian
    Tech Univ Munich, Deutsches Herzzentrum Munchen, D-80290 Munich, Germany.;DZHK German Ctr Cardiovasc Res, Munich, Germany..
    Hofman, Albert
    Erasmus Univ, Med Ctr, Dept Epidemiol, Rotterdam, Netherlands..
    Ingelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.;Stanford Univ, Dept Med, Div Cardiovasc Med, Stanford, CA 94305 USA..
    Iribarren, Carlos
    Kaiser Permanente Div Res, Oakland, CA USA..
    Jukema, J. Wouter
    Leiden Univ, Med Ctr, Dept Cardiol, Leiden, Netherlands.;Durrer Ctr Cardiogenet Res, Amsterdam, Netherlands.;Interunivers Cardiol Inst Netherlands, Utrecht, Netherlands..
    Karhunen, Pekka J.
    Fimlab Labs, Dept Clin Chem, Tampere, Finland.;Univ Tampere, Sch Med, Dept Forens Med, FIN-33101 Tampere, Finland..
    Kim, Bong-Jo
    Korea Natl Inst Hlth, Ctr Genome Sci, Chungcheongbuk Do, South Korea..
    Kooner, Jaspal S.
    Ealing Hosp Natl Hlth Serv NHS Trust, Dept Cardiol, Southall, Middx, England.;Imperial Coll Healthcare NHS Trust, London, England.;Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, Cardiovasc Sci, London, England..
    Kullo, Iftikhar J.
    Mayo Clin, Dept Med, Cardiovasc Dis, Rochester, MN USA..
    Lehtimaki, Terho
    Fimlab Labs, Dept Clin Chem, Tampere, Finland.;Univ Tampere, Sch Med, Dept Clin Chem, FIN-33101 Tampere, Finland..
    Loos, Ruth J. F.
    Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA.;Icahn Sch Med Mt Sinai, Genet Obes & Related Metab Traits Program, New York, NY 10029 USA.;Icahn Sch Med Mt Sinai, Mindich Child Hlth & Dev Inst, New York, NY 10029 USA..
    Melander, Olle
    Lund Univ, Univ Hosp Malmo, Dept Clin Sci Hypertens & Cardiovasc Dis, Malmo, Sweden..
    Metspalu, Andres
    Univ Tartu, Estonian Genome Ctr, EE-50090 Tartu, Estonia.;Univ Tartu, Inst Mol & Cell Biol, EE-50090 Tartu, Estonia..
    Maerz, Winfried
    Heidelberg Univ, Med Fac Mannheim, Vth Dept Med Nephrol Hypertensiol Endocrinol Diab, Mannheim, Germany.;Synlab Acad, Synlab Serv, Mannheim, Germany.;Med Univ Graz, Clin Inst Med & Chem Lab Diagnost, Graz, Austria..
    Palmer, Colin N.
    Univ Dundee, Med Res Inst, Dundee, Scotland..
    Perola, Markus
    Univ Tartu, Estonian Genome Ctr, EE-50090 Tartu, Estonia.;Natl Inst Hlth & Welf, Dept Hlth, Helsinki, Finland.;Univ Helsinki, Inst Mol Med Finland FIMM, Helsinki, Finland.;Univ Helsinki, Diabet & Obes Res Program, Helsinki, Finland..
    Quertermous, Thomas
    Stanford Univ, Dept Med, Div Cardiovasc Med, Stanford, CA 94305 USA.;Stanford Univ, Stanford Cardiovasc Inst, Stanford, CA 94305 USA..
    Rader, Daniel J.
    Univ Penn, Perelman Sch Med, Dept Genet, Philadelphia, PA 19104 USA.;Univ Penn, Perelman Sch Med, Cardiovasc Inst, Philadelphia, PA 19104 USA..
    Ridker, Paul M.
    Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02115 USA.;Harvard Univ, Sch Med, Boston, MA USA..
    Ripatti, Samuli
    Univ Helsinki, Inst Mol Med Finland FIMM, Helsinki, Finland.;Wellcome Trust Sanger Inst, Hinxton, England.;Univ Helsinki, Dept Publ Hlth, Helsinki, Finland..
    Roberts, Robert
    Univ Ottawa, Inst Heart, Ottawa, ON, Canada..
    Salomaa, Veikko
    Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland..
    Sanghera, Dharambir K.
    Univ Oklahoma, Hlth Sci Ctr, Dept Pediat, Coll Med, Oklahoma City, OK 73190 USA.;Univ Oklahoma, Hlth Sci Ctr, Coll Pharm, Dept Pharmaceut Sci, Oklahoma City, OK 73190 USA.;Oklahoma Ctr Neurosci, Oklahoma City, OK USA..
    Schwartz, Stephen M.
    Fred Hutchinson Canc Res Ctr, Publ Hlth Sci Div, Seattle, WA 98104 USA.;Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA..
    Seedorf, Udo
    Univ Med Ctr Hamburg Eppendorf, Ctr Dent & Oral Med, Dept Prosthet Dent, Hamburg, Germany..
    Stewart, Alexandre F.
    Univ Ottawa, Inst Heart, Ruddy Canadian Cardiovasc Genet Ctr, Ottawa, ON, Canada..
    Stott, David J.
    Univ Glasgow, Fac Med, Inst Cardiovasc & Med Sci, Glasgow, Lanark, Scotland..
    Thiery, Joachim
    LIFE Res Ctr Civilizat Dis, Leipzig, Germany.;Univ Hosp Leipzig, Fac Med, Inst Lab Med Clin Chem & Mol Diagnost, Leipzig, Germany..
    Zalloua, Pierre A.
    Lebanese Amer Univ, Sch Med, Beirut, Lebanon.;Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA..
    O'Donnell, Christopher J.
    NHLBI, Framingham Heart Study, Framingham, MA USA.;NHLBI, Div Intramural Res, Bethesda, MD 20892 USA.;Massachusetts Gen Hosp, Cardiol Div, Boston, MA 02114 USA..
    Reilly, Muredach P.
    Assimes, Themistocles L.
    Stanford Univ, Dept Med, Div Cardiovasc Med, Stanford, CA 94305 USA.;Stanford Univ, Stanford Cardiovasc Inst, Stanford, CA 94305 USA..
    Thompson, John R.
    Univ Leicester, Dept Hlth Sci, Leicester, Leics, England..
    Erdmann, Jeanette
    Univ Lubeck, Inst Integrat & Expt Genom, Lubeck, Germany.;DZHK German Res Ctr Cardiovasc Res, Lubeck, Germany..
    Clarke, Robert
    Univ Oxford, Nuffield Dept Populat Hlth, Clin Trial Serv Unit, Oxford, England.;Univ Oxford, Nuffield Dept Populat Hlth, Epidemiol Studies Unit CTSU, Oxford, England..
    Watkins, Hugh
    Univ Oxford, Div Cardiovasc Med, Radcliffe Dept Med, Oxford, England.;Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England..
    Kathiresan, Sekar
    Broad Inst MIT & Harvard Univ, Cambridge, MA USA.;Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA.;Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA.;Harvard Univ, Sch Med, Dept Med, Boston, MA USA..
    McPherson, Ruth
    Univ Ottawa, Inst Heart, Ruddy Canadian Cardiovasc Genet Ctr, Ottawa, ON, Canada..
    Deloukas, Panos
    Queen Mary Univ London, Barts & London Sch Med & Dent, William Harvey Res Inst, London, England.;King Abdulaziz Univ, Princess Al Jawhara Al Brahim Ctr Excellence Res, Jeddah 21413, Saudi Arabia..
    Schunkert, Heribert
    Tech Univ Munich, Deutsches Herzzentrum Munchen, D-80290 Munich, Germany.;DZHK German Ctr Cardiovasc Res, Munich, Germany..
    Samani, Nilesh J.
    Univ Leicester, Dept Cardiovasc Sci, Leicester, Leics, England.;Glenfield Hosp, NIHR, Leicester Cardiovasc Biomed Res Unit, Leicester, Leics, England..
    Farrall, Martin
    Univ Oxford, Div Cardiovasc Med, Radcliffe Dept Med, Oxford, England.;Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England..
    A comprehensive 1000 Genomes-based genome-wide association meta-analysis of coronary artery disease2015In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 47, no 10, p. 1121-1130Article in journal (Refereed)
    Abstract [en]

    Existing knowledge of genetic variants affecting risk of coronary artery disease (CAD) is largely based on genome-wide association study (GWAS) analysis of common SNPs. Leveraging phased haplotypes from the 1000 Genomes Project, we report a GWAS meta-analysis of similar to 185,000 CAD cases and controls, interrogating 6.7 million common (minor allele frequency (MAF) > 0.05) and 2.7 million low-frequency (0.005 < MAF < 0.05) variants. In addition to confirming most known CAD-associated loci, we identified ten new loci (eight additive and two recessive) that contain candidate causal genes newly implicating biological processes in vessel walls. We observed intralocus allelic heterogeneity but little evidence of low-frequency variants with larger effects and no evidence of synthetic association. Our analysis provides a comprehensive survey of the fine genetic architecture of CAD, showing that genetic susceptibility to this common disease is largely determined by common SNPs of small effect size.

  • 204.
    Nolte, Ilja M.
    et al.
    Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, POB 30001, NL-9700 RB Groningen, Netherlands..
    Munoz, M. Loretto
    Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, POB 30001, NL-9700 RB Groningen, Netherlands..
    Tragante, Vinicius
    Univ Med Ctr Utrecht, Div Heart & Lungs, Dept Cardiol, Heidelberglaan 100, NL-3584 CX Utrecht, Netherlands..
    Amare, Azmeraw T.
    Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, POB 30001, NL-9700 RB Groningen, Netherlands.;Univ Adelaide, Sch Med, Dept Epidemiol, Adelaide, SA 5005, Australia.;Bahir Dar Univ, Coll Med & Hlth Sci, Bahir Dar 6000, Ethiopia..
    Jansen, Rick
    Vrije Univ Amsterdam, Med Ctr, EMGO Inst Hlth & Care Res & Neurosci, Dept Psychiat,GGZ inGeest, Campus Amsterdam, NL-1081 BT Amsterdam, Netherlands..
    Vaez, Ahmad
    Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, POB 30001, NL-9700 RB Groningen, Netherlands.;Isfahan Univ Med Sci, Sch Med, Esfahan 8174673461, Iran..
    von der Heyde, Benedikt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Avery, Christy L.
    Univ N Carolina, Gillings Sch Global Publ Hlth, Dept Epidemiol, Chapel Hill, NC 27599 USA..
    Bis, Joshua C.
    Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA 98104 USA..
    Dierckx, Bram
    Dept Child & Adolescent Psychiat, Dept Child & Adolescent Psychiat Psychol, POB 2060, NL-3000 CB Rotterdam, Netherlands.;Erasmus MC, Generat Study Grp R, POB 2060, NL-3000 CB0 Rotterdam, Netherlands..
    van Dongen, Jenny
    Vrije Univ Amsterdam, Dept Biol Psychol Behav & Movement Sci, NL-1081 BT Amsterdam, Netherlands..
    Gogarten, Stephanie M.
    Univ Washington, Sch Publ Hlth, Dept Biostat, Seattle, WA 98195 USA..
    Goyette, Philippe
    Montreal Heart Inst, Montreal, PQ H1T IC8, Canada..
    Hernesniemi, Jussi
    Fimlab Labs, Dept Clin Chem, Tampere 33520, Finland.;Univ Tampere, Dept Clin Chem, Sch Med, Tampere 33014, Finland.;Tampere Univ Hosp, Heart Hosp, Dept Cardiol, Tampere 33521, Finland..
    Huikari, Ville
    Univ Oulu, Ctr Life Course Hlth Res, Oulu 90014, Finland..
    Hwang, Shih-Jen
    Framingham Heart Dis Epidemiol Study, Framingham, MA 01702 USA.;NHLBI, Populat Sci Branch, NIH, Bethesda, MD 20892 USA..
    Jaju, Deepali
    Sultan Qaboos Univ Hosp, Dept Clin Physiol, Muscat 123, Oman..
    Kerr, Kathleen F.
    Univ Washington, Sch Publ Hlth, Dept Biostat, Seattle, WA 98195 USA..
    Kluttig, Alexander
    Martin Luther Univ Halle Wittenberg, Inst Med Epidemiol Biostat & Informat, D-06097 Halle, Germany..
    Krijthe, Bouwe P.
    Erasmus MC, Univ Med Ctr Rotterdam, Dept Epidemiol, POB 2060, NL-3000 CB Rotterdam, Netherlands..
    Kumar, Jitender
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    van der Laan, Sander W.
    Univ Med Ctr Utrecht, Dept Heart & Lung, Lab Expt Cardiol, Heidelberglaan 100, NL-3584 CX Utrecht, Netherlands..
    Lyytikainen, Leo-Pekka
    Fimlab Labs, Dept Clin Chem, Tampere 33520, Finland.;Univ Tampere, Dept Clin Chem, Sch Med, Tampere 33014, Finland..
    Maihofer, Adam X.
    Univ Calif San Diego, Dept Psychiat, San Diego, CA 92093 USA.;VA San Diego Healthcare Syst, Ctr Stress & Mental Hlth CESAMH, San Diego, CA 92161 USA..
    Minassian, Arpi
    Univ Calif San Diego, Dept Psychiat, San Diego, CA 92093 USA.;VA San Diego Healthcare Syst, Ctr Stress & Mental Hlth CESAMH, San Diego, CA 92161 USA..
    van der Most, Peter J.
    Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, POB 30001, NL-9700 RB Groningen, Netherlands..
    Mueller-Nurasyid, Martina
    Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Genet Epidemiol, D-85764 Neuherberg, Germany.;Ludwig Maximilians Univ Munchen, Dept Med, Univ Hosp Munich, D-80539 Munich, Germany.;Munich Heart Alliance, DZHK German Ctr Cardiovasc Res, Partner Site, D-80336 Munich, Germany..
    Nivard, Michel
    Vrije Univ Amsterdam, Dept Biol Psychol Behav & Movement Sci, NL-1081 BT Amsterdam, Netherlands.;Vrije Univ Amsterdam, EMGO Inst Hlth & Care Res, NL-1081 HV Amsterdam, Netherlands.;Vrije Univ Amsterdam, Med Ctr, NL-1081 HV Amsterdam, Netherlands..
    Salvi, Erika
    Univ Milan, Dept Hlth Sci, I-20122 Milan, Italy..
    Stewart, James D.
    Univ N Carolina, Gillings Sch Global Publ Hlth, Dept Epidemiol, Chapel Hill, NC 27599 USA.;Univ N Carolina, Carolina Populat Ctr, Chapel Hill, NC 27599 USA..
    Thayer, Julian F.
    Ohio State Univ, Dept Psychol, 1835 Neil Ave, Columbus, OH 43210 USA..
    Verweij, Niek
    Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, POB 30001, NL-9700 RB Groningen, Netherlands..
    Wong, Andrew
    UCL, MRC Unit Lifelong Hlth & Ageing, 33 Bedford Pl, London WC1B 5JU, England..
    Zabaneh, Delilah
    Kings Coll London, Inst Psychiat Psychol & Neurosci, De Crespigny Pk, London SE5 8AF, England.;UCL, Genet Inst, London WC1E 6BT, England..
    Zafarmand, Mohammad H.
    Univ Amsterdam, Acad Med Ctr, Dept Publ Hlth, NL-1105 AZ Amsterdam, Netherlands.;Univ Amsterdam, Acad Med Ctr, Dept Obstet & Gynaecol, NL-1105 AZ Amsterdam, Netherlands..
    Abdellaoui, Abdel
    Vrije Univ Amsterdam, Dept Biol Psychol Behav & Movement Sci, NL-1081 BT Amsterdam, Netherlands.;Vrije Univ Amsterdam, EMGO Inst Hlth & Care Res, NL-1081 HV Amsterdam, Netherlands.;Vrije Univ Amsterdam, Med Ctr, NL-1081 HV Amsterdam, Netherlands..
    Albarwani, Sulayma
    Sultan Qaboos Univ, Coll Med & Hlth Sci, Dept Physiol, Muscat Al Khoudh 123, Oman..
    Albert, Christine
    Harvard Med Sch, Brigham & Womens Hosp, Boston, MA 02115 USA..
    Alonso, Alvaro
    Emory Univ, Rollins Sch Publ Hlth, Dept Epidemiol, Atlanta, GA 30322 USA..
    Ashar, Foram
    Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD 21205 USA..
    Auvinen, Juha
    Univ Oulu, Ctr Life Course Hlth Res, Oulu 90014, Finland.;Oulu Univ Hosp, Unit Primary Hlth Care, Oulu 90220, Finland..
    Axelsson, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Baker, Dewleen G.
    Univ Calif San Diego, Dept Psychiat, San Diego, CA 92093 USA.;VA San Diego Healthcare Syst, Ctr Stress & Mental Hlth CESAMH, San Diego, CA 92161 USA..
    de Bakker, Paul I. W.
    Univ Med Ctr Utrecht, Dept Genet, Ctr Mol Med, NL-3584 CX Utrecht, Netherlands.;Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, Dept Epidemiol, NL-3584 CX Utrecht, Netherlands..
    Barcella, Matteo
    Univ Milan, Dept Hlth Sci, I-20122 Milan, Italy..
    Bayoumi, Riad
    Mohammed Bin Rashid Univ, Coll Med, Dubai Healthcare City, POB 505055, Dubai, U Arab Emirates..
    Bieringa, Rob J.
    Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, POB 30001, NL-9700 RB Groningen, Netherlands..
    Boomsma, Dorret
    Vrije Univ Amsterdam, Dept Biol Psychol Behav & Movement Sci, NL-1081 BT Amsterdam, Netherlands.;Vrije Univ Amsterdam, EMGO Inst Hlth & Care Res, NL-1081 HV Amsterdam, Netherlands.;Vrije Univ Amsterdam, Med Ctr, NL-1081 HV Amsterdam, Netherlands..
    Boucher, Gabrielle
    Montreal Heart Inst, Montreal, PQ H1T IC8, Canada..
    Britton, Annie R.
    UCL, Dept Epidemiol & Publ Hlth, London WC1E 6BT, England..
    Christophersen, Ingrid E.
    Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA.;Broad Inst Harvard, Program Med & Populat Genet, Cambridge, MA 02114 USA.;MIT, Cambridge, MA 02114 USA.;Baerum Hosp, Vestre Viken Hosp Trust, Dept Med Res, N-1346 Rud, Norway..
    Dietrich, Andrea
    Univ Groningen, Univ Med Ctr Groningen, Dept Child & Adolescent Psychiat, POB 30001, NL-9700 RB Groningen, Netherlands..
    Ehret, George B.
    Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Ctr Complex Dis Genom, Baltimore, MD 21205 USA.;Geneva Univ Hosp, Dept Specialties Internal Med, Cardiol, CH-1211 Geneva, Switzerland..
    Ellinor, Patrick T.
    Broad Inst Harvard, Program Med & Populat Genet, Cambridge, MA 02114 USA.;MIT, Cambridge, MA 02114 USA.;Massachusetts Gen Hosp, Cardiac Arrhythmia Serv, Boston, MA 02114 USA.;Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA..
    Eskola, Markku
    Tampere Univ Hosp, Heart Hosp, Dept Cardiol, Tampere 33521, Finland.;Univ Tampere, Sch Med, Dept Cardiol, Tampere 33014, Finland..
    Felix, Janine F.
    Erasmus MC, Univ Med Ctr Rotterdam, Dept Epidemiol, POB 2060, NL-3000 CB Rotterdam, Netherlands..
    Floras, John S.
    Univ Toronto, Univ Hlth Network, Toronto, ON, Canada.;Univ Toronto, Mt Sinai Hosp, Div Cardiol, Dept Med, Toronto, ON, Canada.;Univ Hlth Network, Toronto Gen Res Inst, Toronto, ON M5G 2C4, Canada..
    Franco, Oscar H.
    Erasmus MC, Univ Med Ctr Rotterdam, Dept Epidemiol, POB 2060, NL-3000 CB Rotterdam, Netherlands..
    Friberg, Peter
    Univ Gothenburg, Sahlgrenska Univ Hosp, Inst Med, Dept Mol & Clin Med, SE-41345 Gothenburg, Sweden..
    Gademan, Maaike G. J.
    Univ Amsterdam, Acad Med Ctr, Dept Publ Hlth, NL-1105 AZ Amsterdam, Netherlands..
    Geyer, Mark A.
    Univ Calif San Diego, Dept Psychiat, San Diego, CA 92093 USA..
    Giedraitis, Vilmantas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Hartman, Catharina A.
    Univ Groningen, Univ Med Ctr Groningen, Interdisciplinary Ctr Psychopathol & Emot Regulat, Dept Psychiat, POB 30001, NL-9700 RB Groningen, Netherlands..
    Hemerich, Daiane
    Univ Med Ctr Utrecht, Div Heart & Lungs, Dept Cardiol, Heidelberglaan 100, NL-3584 CX Utrecht, Netherlands.;Minist Educ Brazil, CAPES Fdn, BR-70040020 Brasilia, DF, Brazil..
    Hofman, Albert
    Erasmus MC, Univ Med Ctr Rotterdam, Dept Epidemiol, POB 2060, NL-3000 CB Rotterdam, Netherlands..
    Hottenga, Jouke-Jan
    Vrije Univ Amsterdam, Dept Biol Psychol Behav & Movement Sci, NL-1081 BT Amsterdam, Netherlands.;Vrije Univ Amsterdam, EMGO Inst Hlth & Care Res, NL-1081 HV Amsterdam, Netherlands.;Vrije Univ Amsterdam, Med Ctr, NL-1081 HV Amsterdam, Netherlands..
    Huikuri, Heikki
    Oulu Univ Hosp, Med Res Ctr, Res Unit Internal Med, Oulu 90220, Finland.;Univ Oulu, SF-90220 Oulu, Finland..
    Hutri-Kahonen, Nina
    Tampere Univ Hosp, Dept Pediat, Tampere 33521, Finland.;Univ Tampere, Sch Med, Dept Pediat, Tampere 33014, Finland..
    Jouven, Xavier
    Paris Descartes Univ, INSERM, U970, F-75006 Paris, France..
    Junttila, Juhani
    Oulu Univ Hosp, Med Res Ctr, Res Unit Internal Med, Oulu 90220, Finland.;Univ Oulu, SF-90220 Oulu, Finland..
    Juonala, Markus
    Univ Turku, Dept Med, Turku 20520, Finland.;Turku Univ Hosp, Div Med, Turku 20521, Finland..
    Kiviniemi, Antti M.
    Oulu Univ Hosp, Med Res Ctr, Res Unit Internal Med, Oulu 90220, Finland.;Univ Oulu, SF-90220 Oulu, Finland..
    Kors, Jan A.
    Erasmus MC, Dept Med Informat, NL-3015 CE Rotterdam, Netherlands..
    Kumari, Meena
    UCL, Dept Epidemiol & Publ Hlth, London WC1E 6BT, England.;Essex Univ, ISER, Colchester CO4 3SQ, Essex, England..
    Kuznetsova, Tatiana
    Univ Leuven, KU Leuven Dept Cardiovasc Sci, Studies Coordinating Ctr, Res Unit Hypertens & Cardiovasc Epidemiol, B-3000 Leuven, Belgium..
    Laurie, Cathy C.
    Univ Washington, Sch Publ Hlth, Dept Biostat, Seattle, WA 98195 USA..
    Lefrandt, Joop D.
    Univ Groningen, Univ Med Ctr Groningen, Dept Internal Med, Div Vasc Med, POB 30001, NL-9700 RB Groningen, Netherlands..
    Li, Yong
    Univ Freiburg, Fac Med, Med Center, Div Genet Epidemiol,Inst Med Biometry & Stat, D-79110 Freiburg, Germany..
    Li, Yun
    Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA.;Univ N Carolina, Dept Biostat, Chapel Hill, NC 27599 USA.;Univ N Carolina, Dept Comp Sci, Chapel Hill, NC 27599 USA..
    Liao, Duanping
    Penn State Univ, Coll Med, Dept Publ Hlth Sci, Div Epidemiol, Hershey, PA 17033 USA..
    Limacher, Marian C.
    Univ Florida, Coll Med, Div Cardiovasc Med, Gainesville, FL 32611 USA..
    Lin, Henry J.
    Harbor UCLA Med Ctr, Dept Pediat, Los Angeles Biomed Res Inst Harbor, Inst Translat Genom & Populat Sci, Torrance, CA 90502 USA.;Harbor UCLA Med Ctr, Dept Pediat, Div Med Genet, Torrance, CA 90502 USA..
    Lindgren, Cecilia M.
    Univ Oxford, Big Data Inst, Li Ka Shing Ctr Hlth Informat & Discovery, Oxford OX3 7BN, England.;Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England..
    Lubitz, Steven A.
    Broad Inst Harvard, Program Med & Populat Genet, Cambridge, MA 02114 USA.;MIT, Cambridge, MA 02114 USA.;Massachusetts Gen Hosp, Cardiac Arrhythmia Serv, Boston, MA 02114 USA.;Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA..
    Mahajan, Anubha
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England..
    McKnight, Barbara
    Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA 98104 USA.;Univ Washington, Sch Publ Hlth, Dept Biostat, Seattle, WA 98195 USA.;Fred Hutchinson Canc Res Ctr, Publ Hlth Sci Div, Seattle, WA 98109 USA..
    zu Schwabedissen, Henriette Meyer
    Univ Basel, Dept Pharmaceut Sci, Biopharm, CH-4056 Basel, Switzerland..
    Milaneschi, Yuri
    Vrije Univ Amsterdam, Med Ctr, EMGO Inst Hlth & Care Res & Neurosci, Dept Psychiat,GGZ inGeest, Campus Amsterdam, NL-1081 BT Amsterdam, Netherlands..
    Mononen, Nina
    Fimlab Labs, Dept Clin Chem, Tampere 33520, Finland.;Univ Tampere, Dept Clin Chem, Sch Med, Tampere 33014, Finland..
    Morris, Andrew P.
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England.;Univ Liverpool, Dept Biostat, Liverpool L69 3GL, Merseyside, England..
    Nalls, Mike A.
    NIA, Lab Neurogenet, NIH, Bethesda, MD 20892 USA..
    Navis, Gerjan
    Univ Groningen, Univ Med Ctr Groningen, Dept Internal Med, Div Nephrol, POB 30001, NL-9700 RB Groningen, Netherlands..
    Neijts, Melanie
    Vrije Univ Amsterdam, Dept Biol Psychol Behav & Movement Sci, NL-1081 BT Amsterdam, Netherlands.;Vrije Univ Amsterdam, EMGO Inst Hlth & Care Res, NL-1081 HV Amsterdam, Netherlands.;Vrije Univ Amsterdam, Med Ctr, NL-1081 HV Amsterdam, Netherlands..
    Nikus, Kjell
    Tampere Univ Hosp, Heart Hosp, Dept Cardiol, Tampere 33521, Finland.;Univ Tampere, Sch Med, Dept Cardiol, Tampere 33014, Finland..
    North, Kari E.
    Univ N Carolina, Gillings Sch Global Publ Hlth, Dept Epidemiol, Chapel Hill, NC 27599 USA.;Univ N Carolina, Carolina Ctr Genome Sci, Chapel Hill, NC 27599 USA..
    O'Connor, Daniel T.
    Univ Calif San Diego, Dept Med, San Diego, CA 92093 USA..
    Ormel, Johan
    Univ Groningen, Univ Med Ctr Groningen, Interdisciplinary Ctr Psychopathol & Emot Regulat, Dept Psychiat, POB 30001, NL-9700 RB Groningen, Netherlands..
    Perz, Siegfried
    Helmholtz Zentrum Munchen, Inst Epidemiol 2, German Res Ctr Environm Hlth, D-85764 Neuherberg, Germany..
    Peters, Annette
    Munich Heart Alliance, DZHK German Ctr Cardiovasc Res, Partner Site, D-80336 Munich, Germany.;Helmholtz Zentrum Munchen, Inst Epidemiol 2, German Res Ctr Environm Hlth, D-85764 Neuherberg, Germany.;German Ctr Diabet Res, D-85764 Neuherberg, Germany..
    Psaty, Bruce M.
    Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA 98104 USA.;Univ Washington, Dept Epidemiol & Hlth Serv, Seattle, WA 98195 USA.;Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA 98101 USA..
    Raitakari, Olli T.
    Turku Univ Hosp, Dept Clin Physiol & Nucl Med, Turku 20521, Finland.;Univ Turku, Res Ctr Appl & Prevent Cardiovasc Med, Turku 20520, Finland..
    Risbrough, Victoria B.
    Univ Calif San Diego, Dept Psychiat, San Diego, CA 92093 USA.;VA San Diego Healthcare Syst, Ctr Stress & Mental Hlth CESAMH, San Diego, CA 92161 USA..
    Sinner, Moritz F.
    Ludwig Maximilians Univ Munchen, Dept Med, Univ Hosp Munich, D-80539 Munich, Germany.;Munich Heart Alliance, DZHK German Ctr Cardiovasc Res, Partner Site, D-80336 Munich, Germany..
    Siscovick, David
    New York Acad Med, New York, NY 10029 USA..
    Smit, Johannes H.
    Vrije Univ Amsterdam, Med Ctr, EMGO Inst Hlth & Care Res & Neurosci, Dept Psychiat,GGZ inGeest, Campus Amsterdam, NL-1081 BT Amsterdam, Netherlands..
    Smith, Nicholas L.
    Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA 98101 USA.;Univ Washington, Sch Publ Hlth, Dept Epidemiol, Seattle, WA 98195 USA.;Vet Affairs Off Res & Dev, Seattle Epidemiol Res & Informat Ctr, Seattle, WA 98108 USA..
    Soliman, Elsayed Z.
    Wake Forest Sch Med, Div Publ Hlth Sci, Epidemiol Cardiol Res Ctr EPICARE, Winston Salem, NC 27157 USA..
    Sotoodehnia, Nona
    Univ Washington, Dept Med & Epidemiol, Div Cardiol, Cardiovasc Hlth Res Unit, Seattle, WA 98101 USA..
    Staessen, Jan A.
    Univ Leuven, KU Leuven Dept Cardiovasc Sci, Studies Coordinating Ctr, Res Unit Hypertens & Cardiovasc Epidemiol, B-3000 Leuven, Belgium..
    Stein, Phyllis K.
    Washington Univ, Heart Rate Variabil Lab, Sch Med, St Louis, MO 63108 USA..
    Stilp, Adrienne M.
    Univ Washington, Sch Publ Hlth, Dept Biostat, Seattle, WA 98195 USA..
    Stolarz-Skrzypek, Katarzyna
    Jagiellonian Univ, Med Coll, Dept Cardiol Intervent Electrocardi & Hypertens 1, PL-31008 Krakow, Poland..
    Strauch, Konstantin
    Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Genet Epidemiol, D-85764 Neuherberg, Germany.;Ludwig Maximilians Univ Munchen, Chair Genet Epidemiol, Inst Med Informat Biometry & Epidemiol, D-81377 Munich, Germany..
    Sundstrom, Johan
    Uppsala Univ, Dept Med Sci Cardiovasc Epidemiol, S-75185 Uppsala, Sweden..
    Swenne, Cees A.
    Leiden Univ, Med Ctr, Dept Cardiol, NL-2300 RC Leiden, Netherlands..
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Tardif, Jean-Claude
    Montreal Heart Inst, Montreal, PQ H1T IC8, Canada.;Univ Montreal, Montreal, PQ H3T IJ4, Canada..
    Taylor, Kent D.
    Harbor UCLA Med Ctr, Los Angeles Biomed Res Inst, Dept Pediat & Med, Inst Translat Genom & Populat Sci, Torrance, CA 90509 USA..
    Teumer, Alexander
    Univ Med Greifswald, Inst Community Med, D-17475 Greifswald, Germany..
    Thornton, Timothy A.
    Univ Washington, Sch Publ Hlth, Dept Biostat, Seattle, WA 98195 USA..
    Tinker, Lesley E.
    Fred Hutchinson Canc Res Ctr, Publ Hlth Sci Div, Seattle, WA 98109 USA..
    Uitterlinden, Andre G.
    Erasmus MC, Univ Med Ctr Rotterdam, Dept Epidemiol, POB 2060, NL-3000 CB Rotterdam, Netherlands.;Erasmus Univ, Med Ctr, Dept Internal Med, NL-3015 CE Rotterdam, Netherlands.;Netherlands Consortium Hlth Aging, Netherlands Genom Initiat, NL-2300 RC Leiden, Netherlands..
    van Setten, Jessica
    Univ Med Ctr Utrecht, Div Heart & Lungs, Dept Cardiol, Heidelberglaan 100, NL-3584 CX Utrecht, Netherlands..
    Voss, Andreas
    IGHT Jena Ernst Abbe Hsch, Inst Innovat Hlth Technol, D-07745 Jena, Germany..
    Waldenberger, Melanie
    Dept Child & Adolescent Psychiat, Dept Child & Adolescent Psychiat Psychol, POB 2060, NL-3000 CB Rotterdam, Netherlands.;Helmholtz Zentrum Munchen, Inst Epidemiol 2, German Res Ctr Environm Hlth, D-85764 Neuherberg, Germany.;Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Res Unit Mol Epidemiol, D-85764 Neuherberg, Germany..
    Wilhelmsen, Kirk C.
    Univ N Carolina, Dept Genet & Neurol, Chapel Hill, NC 27599 USA.;Renaissance Comp Inst, Chapel Hill, NC 27599 USA..
    Willemsen, Gonneke
    Vrije Univ Amsterdam, Dept Biol Psychol Behav & Movement Sci, NL-1081 BT Amsterdam, Netherlands.;Vrije Univ Amsterdam, EMGO Inst Hlth & Care Res, NL-1081 HV Amsterdam, Netherlands.;Vrije Univ Amsterdam, Med Ctr, NL-1081 HV Amsterdam, Netherlands..
    Wong, Quenna
    Univ Washington, Sch Publ Hlth, Dept Biostat, Seattle, WA 98195 USA..
    Zhang, Zhu-Ming
    Wake Forest Sch Med, Div Publ Hlth Sci, Epidemiol Cardiol Res Ctr EPICARE, Winston Salem, NC 27157 USA.;Wake Forest Sch Med, Div Publ Hlth Sci, Dept Epidemiol & Prevent, Winston Salem, NC 27157 USA..
    Zonderman, Alan B.
    NIA, Lab Epidemiol & Populat Sci, NIH, Baltimore, MD 21224 USA..
    Cusi, Daniele
    Italian Natl Res Council, CNR, Inst Biomed Technol, I-20090 Milan, Italy.;KOS Genet SRL, I-20091 Milan, Italy..
    Evans, Michele K.
    NIA, Lab Epidemiol & Populat Sci, NIH, Baltimore, MD 21224 USA..
    Greiser, Halina K.
    German Canc Res Ctr, Div Canc Epidemiol, D-69210 Heidelberg, Germany..
    van der Harst, Pim
    Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, POB 30001, NL-9700 RB Groningen, Netherlands..
    Hassan, Mohammad
    Sultan Qaboos Univ, Coll Med & Hlth Sci, Dept Physiol, Muscat Al Khoudh 123, Oman..
    Ingelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Stanford Univ, Sch Med, Div Cardiovasc Med, Dept Med, Stanford, CA 94305 USA..
    Jarvelin, Marjo-Riitta
    Univ Oulu, Ctr Life Course Hlth Res, Oulu 90014, Finland.;Oulu Univ Hosp, Unit Primary Hlth Care, Oulu 90220, Finland.;Imperial Coll London, Fac Med, Sch Publ Hlth, Dept Epidemiol & Biostat, St Marys Campus, London, England.;Univ Oulu, Bioctr Oulu, Oulu 90014, Finland..
    Kaab, Stefan
    Ludwig Maximilians Univ Munchen, Dept Med, Univ Hosp Munich, D-80539 Munich, Germany.;Munich Heart Alliance, DZHK German Ctr Cardiovasc Res, Partner Site, D-80336 Munich, Germany..
    Kahonen, Mika
    Tampere Univ Hosp, Dept Clin Physiol, Tampere 33521, Finland.;Univ Tampere, Sch Med, Dept Clin Physiol, Tampere 33014, Finland..
    Kivimaki, Mika
    UCL, Dept Epidemiol & Publ Hlth, London WC1E 6BT, England..
    Kooperberg, Charles
    Fred Hutchinson Canc Res Ctr, Publ Hlth Sci Div, Seattle, WA 98109 USA..
    Kuh, Diana
    UCL, MRC Unit Lifelong Hlth & Ageing, 33 Bedford Pl, London WC1B 5JU, England..
    Lehtimaki, Terho
    Fimlab Labs, Dept Clin Chem, Tampere 33520, Finland.;Univ Tampere, Dept Clin Chem, Sch Med, Tampere 33014, Finland..
    Lind, Lars
    Uppsala Univ, Dept Med Sci Cardiovasc Epidemiol, S-75185 Uppsala, Sweden..
    Nievergelt, Caroline M.
    Univ Calif San Diego, Dept Psychiat, San Diego, CA 92093 USA.;VA San Diego Healthcare Syst, Ctr Stress & Mental Hlth CESAMH, San Diego, CA 92161 USA..
    O'Donnell, Chris J.
    Framingham Heart Dis Epidemiol Study, Framingham, MA 01702 USA.;NHLBI, Populat Sci Branch, NIH, Bethesda, MD 20892 USA.;Boston Vet Adm Healthcare Boston, Cardiol Sect, Boston, MD 02132 USA..
    Oldehinkel, Albertine J.
    Univ Groningen, Univ Med Ctr Groningen, Interdisciplinary Ctr Psychopathol & Emot Regulat, Dept Psychiat, POB 30001, NL-9700 RB Groningen, Netherlands..
    Penninx, Brenda
    Vrije Univ Amsterdam, Med Ctr, EMGO Inst Hlth & Care Res & Neurosci, Dept Psychiat,GGZ inGeest, Campus Amsterdam, NL-1081 BT Amsterdam, Netherlands..
    Reiner, Alexander P.
    Fred Hutchinson Canc Res Ctr, Publ Hlth Sci Div, Seattle, WA 98109 USA.;Univ Washington, Sch Publ Hlth, Dept Epidemiol, Seattle, WA 98195 USA..
    Riese, Harriette
    Univ Groningen, Univ Med Ctr Groningen, Interdisciplinary Ctr Psychopathol & Emot Regulat, Dept Psychiat, POB 30001, NL-9700 RB Groningen, Netherlands..
    van Roon, Arie M.
    Univ Groningen, Univ Med Ctr Groningen, Dept Internal Med, Div Vasc Med, POB 30001, NL-9700 RB Groningen, Netherlands..
    Rioux, John D.
    Montreal Heart Inst, Montreal, PQ H1T IC8, Canada.;Univ Montreal, Montreal, PQ H3T IJ4, Canada..
    Rotter, Jerome I.
    Harbor UCLA Med Ctr, Los Angeles Biomed Res Inst, Dept Pediat & Med, Inst Translat Genom & Populat Sci, Torrance, CA 90509 USA..
    Sofer, Tamar
    Univ Washington, Sch Publ Hlth, Dept Biostat, Seattle, WA 98195 USA..
    Stricker, Bruno H.
    Erasmus MC, Univ Med Ctr Rotterdam, Dept Epidemiol, POB 2060, NL-3000 CB Rotterdam, Netherlands.;Inspectorate Hlth Care, NL-2511 VX The Hague, Netherlands..
    Tiemeier, Henning
    Dept Child & Adolescent Psychiat, Dept Child & Adolescent Psychiat Psychol, POB 2060, NL-3000 CB Rotterdam, Netherlands.;Erasmus MC, Univ Med Ctr Rotterdam, Dept Epidemiol, POB 2060, NL-3000 CB Rotterdam, Netherlands..
    Vrijkotte, Tanja G. M.
    Univ Amsterdam, Acad Med Ctr, Dept Publ Hlth, NL-1105 AZ Amsterdam, Netherlands..
    Asselbergs, Folkert W.
    Univ Med Ctr Utrecht, Div Heart & Lungs, Dept Cardiol, Heidelberglaan 100, NL-3584 CX Utrecht, Netherlands.;UCL, Inst Cardiovasc Sci, 222 Euston Rd, London NW1 2DA, England.;ICIN Netherlands Heart Inst, Durrer Ctr Cardiogenet Res, NL-3501 DG Utrecht, Netherlands..
    Brundel, Bianca J. J. M.
    Vrije Univ Amsterdam, Inst Cardiovasc Res, Dept Physiol, Med Ctr, De Boelelaan 1118, NL-1081 HV Amsterdam, Netherlands..
    Heckbert, Susan R.
    Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA 98104 USA.;Univ Washington, Sch Publ Hlth, Dept Epidemiol, Seattle, WA 98195 USA..
    Whitsel, Eric A.
    Univ N Carolina, Gillings Sch Global Publ Hlth, Dept Epidemiol, Chapel Hill, NC 27599 USA.;Univ N Carolina, Dept Med, Chapel Hill, NC 27599 USA..
    den Hoed, Marcel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Snieder, Harold
    Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, POB 30001, NL-9700 RB Groningen, Netherlands..
    de Geus, Eco J. C.
    Vrije Univ Amsterdam, Dept Biol Psychol Behav & Movement Sci, NL-1081 BT Amsterdam, Netherlands.;Vrije Univ Amsterdam, EMGO Inst Hlth & Care Res, NL-1081 HV Amsterdam, Netherlands.;Vrije Univ Amsterdam, Med Ctr, NL-1081 HV Amsterdam, Netherlands..
    Genetic loci associated with heart rate variability and their effects on cardiac disease risk2017In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 8, article id 15805Article in journal (Refereed)
    Abstract [en]

    Reduced cardiac vagal control reflected in low heart rate variability (HRV) is associated with greater risks for cardiac morbidity and mortality. In two-stage meta-analyses of genome-wide association studies for three HRV traits in up to 53,174 individuals of European ancestry, we detect 17 genome-wide significant SNPs in eight loci. HRV SNPs tag non-synonymous SNPs (in NDUFA11 and KIAA1755), expression quantitative trait loci (eQTLs) (influencing GNG11, RGS6 and NEO1), or are located in genes preferentially expressed in the sinoatrial node (GNG11, RGS6 and HCN4). Genetic risk scores account for 0.9 to 2.6% of the HRV variance. Significant genetic correlation is found for HRV with heart rate (-0.74 < r(g) < -0.55) and blood pressure (-0.35 < r(g) < -0.20). These findings provide clinically relevant biological insight into heritable variation in vagal heart rhythm regulation, with a key role for genetic variants (GNG11, RGS6) that influence G-protein heterotrimer action in GIRK-channel induced pacemaker membrane hyperpolarization.

  • 205.
    Nowak, C.
    et al.
    Karolinska Inst, Dept Neurobiol Care Sci & Soc NVS, Huddinge, Sweden.
    Carlsson, A. C.
    Karolinska Inst, Dept Neurobiol Care Sci & Soc NVS, Huddinge, Sweden.
    Östgren, C. J.
    Linkoping Univ, Linkoping, Sweden.
    Nyström, F. H.
    Linkoping Univ, Linkoping, Sweden.
    Alam, M.
    Dalarna Univ, Falun, Sweden.
    Feldreich, T. R.
    Dalarna Univ, Falun, Sweden.
    Sundström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Roig, J. J. Carrero
    Karolinska Inst, Solna, Sweden.
    Leppert, Jerzy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland.
    Hedberg, Pär O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland.
    Cordeiro, A. C.
    Dante Pazzanese Inst Cardiol, Sao Paulo, Brazil.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Ingelsson, E.
    Stanford Univ, Sch Med, Stanford, CA 94305 USA.
    Fall, Tove
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Arnlöv, J.
    Karolinska Inst, Dept Neurobiol Care Sci & Soc NVS, Huddinge, Sweden;Dalarna Univ, Falun, Sweden.
    Multiplex proteomics for prediction of major cardiovascular events in type 2 diabetes2018In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 61, p. S65-S65Article in journal (Other academic)
  • 206.
    Nowak, Christoph
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Insulin Resistance: Causes, biomarkers and consequences2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The worldwide increasing number of persons affected by largely preventable diseases like diabetes demands better prevention and treatment. Insulin is required for effective utilisation of circulating nutrients. Impaired responsiveness to insulin (insulin resistance, IR) is a hallmark of type 2 diabetes and independently raises the risk of heart attack and stroke. The pathophysiology of IR is incompletely understood. High-throughput measurement of large numbers of circulating biomarkers may provide new insights beyond established risk factors.

    The aims of this thesis were to (i) use proteomics, metabolomics and genomics methods in large community samples to identify biomarkers of IR; (ii) assess biomarkers for risk prediction and insights into aetiology and consequences of IR; and (iii) use Mendelian randomisation analysis to assess causality.

    In Study I, analysis of 80 circulating proteins in 70-to-77-year-old Swedes identified cathepsin D as a biomarker for IR and highlighted a tentative causal effect of IR on raised plasma tissue plasminogen activator levels. In Study II, nontargeted fasting plasma metabolomics was used to discover 52 metabolites associated with glycaemic traits in non-diabetic 70-year-old men. Replication in independent samples of several thousand persons provided evidence for a causal effect of IR on reduced plasma oleic acid and palmitoleic acid levels. In Study III, nontargeted metabolomics in plasma samples obtained at three time points during an oral glucose challenge in 70-year-old men identified associations between a physiologic measure of IR and concentration changes in medium-chain acylcarnitines, monounsaturated fatty acids, bile acids and lysophosphatidylethanolamines. Study IV provided evidence in two large longitudinal cohorts for causal effects of type 2 diabetes and impaired insulin secretion on raised coronary artery disease risk.

    In conclusion, the Studies in this thesis provide new insights into the pathophysiology and adverse health consequences of IR and illustrate the value of combining traditional epidemiologic designs with recent molecular techniques and bioinformatics methods. The results provide limited evidence for the role of circulating proteins and small molecules in IR and require replication in separate studies and validation in experimental designs.

  • 207.
    Nowak, Christoph
    et al.
    Karolinska Inst, Div Family Med & Primary Care, Dept Neurobiol Care Sci & Soc NVS, Alfred Nobels Alle 23, SE-14183 Huddinge, Sweden.
    Carlsson, Axel C
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Karolinska Inst, Div Family Med & Primary Care, Dept Neurobiol Care Sci & Soc NVS, Alfred Nobels Alle 23, SE-14183 Huddinge, Sweden.
    Östgren, Carl Johan
    Linkoping Univ, Dept Med & Hlth Sci, Linkoping, Sweden.
    Nyström, Fredrik H.
    Linkoping Univ, Dept Med & Hlth Sci, Linkoping, Sweden.
    Alam, Moudud
    Dalarna Univ, Sch Technol & Business Studies Stat, Falun, Sweden.
    Feldreich, Tobias
    Dalarna Univ, Sch Hlth & Social Studies, Falun, Sweden.
    Sundström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Carrero, Juan-Jesus
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden.
    Leppert, Jerzy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland.
    Hedberg, Pär
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland.
    Henriksen, Egil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland.
    Cordeiro, Antonio C.
    Dante Pazzanese Inst Cardiol, Dept Hypertens & Nephrol, Sao Paulo, Brazil.
    Giedraitis, Vilmantas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Ingelsson, Erik
    Stanford Univ, Sch Med, Div Cardiovasc Med, Dept Med, Stanford, CA 94305 USA.
    Fall, Tove
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Ärnlöv, Johan
    Karolinska Inst, Div Family Med & Primary Care, Dept Neurobiol Care Sci & Soc NVS, Alfred Nobels Alle 23, SE-14183 Huddinge, Sweden;Dalarna Univ, Sch Hlth & Social Studies, Falun, Sweden.
    Multiplex proteomics for prediction of major cardiovascular events in type 2 diabetes2018In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 61, no 8, p. 1748-1757Article in journal (Refereed)
    Abstract [en]

    Aims/hypothesis Multiplex proteomics could improve understanding and risk prediction of major adverse cardiovascular events (MACE) in type 2 diabetes. This study assessed 80 cardiovascular and inflammatory proteins for biomarker discovery and prediction of MACE in type 2 diabetes. Methods We combined data from six prospective epidemiological studies of 30-77-year-old individuals with type 2 diabetes in whom 80 circulating proteins were measured by proximity extension assay. Multivariable-adjusted Cox regression was used in a discovery/replication design to identify biomarkers for incident MACE. We used gradient-boosted machine learning and lasso regularised Cox regression in a random 75% training subsample to assess whether adding proteins to risk factors included in the Swedish National Diabetes Register risk model would improve the prediction of MACE in the separate 25% test subsample. Results Of 1211 adults with type 2 diabetes (32% women), 211 experienced a MACE over a mean (+/- SD) of 6.4 +/- 2.3 years. We replicated associations (< 5% false discovery rate) between risk of MACE and eight proteins: matrix metalloproteinase (MMP)-12, IL-27 subunit alpha (IL-27a), kidney injury molecule (KIM)-1, fibroblast growth factor (FGF)-23, protein S100-A12, TNF receptor (TNFR)-1, TNFR-2 and TNF-related apoptosis-inducing ligand receptor (TRAIL-R)2. Addition of the 80-protein assay to established risk factors improved discrimination in the separate test sample from 0.686 (95% CI 0.682, 0.689) to 0.748 (95% CI 0.746, 0.751). A sparse model of 20 added proteins achieved a C statistic of 0.747 (95% CI 0.653, 0.842) in the test sample. Conclusions/interpretation We identified eight protein biomarkers, four of which are novel, for risk of MACE in community residents with type 2 diabetes, and found improved risk prediction by combining multiplex proteomics with an established risk model. Multiprotein arrays could be useful in identifying individuals with type 2 diabetes who are at highest risk of a cardiovascular event.

  • 208.
    Nowak, Christoph
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Dept Neurobiol Care Sci & Soc, Huddinge, Sweden.
    Hetty, Susanne
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Salihovic, Samira
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Castillejo-Lopez, Casimiro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ganna, Andrea
    Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA;Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA 02142 USA;Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Cambridge, MA 02142 USA;Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden.
    Cook, Naomi L.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Broeckling, Corey D.
    Colorado State Univ, Prote & Metabol Facil, Ft Collins, CO 80523 USA.
    Prenni, Jessica E.
    Colorado State Univ, Prote & Metabol Facil, Ft Collins, CO 80523 USA.
    Shen, Xia
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden;Univ Edinburgh, Usher Inst Populat Hlth Sci & Informat, Ctr Global Hlth Res, Edinburgh, Midlothian, Scotland.
    Giedraitis, Vilmantas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Ärnlöv, Johan
    Dalarna Univ, Sch Hlth & Social Studies, Falun, Sweden;Karolinska Inst, Dept Neurobiol Care Sci & Soc, Huddinge, Sweden.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Berne, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Sundström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Fall, Tove
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Ingelsson, Erik
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Stanford Univ, Dept Med, Sch Med, Div Cardiovasc Med, Stanford, CA 94305 USA;Stanford Univ, Stanford Cardiovasc Inst, Stanford, CA 94305 USA.
    Glucose challenge metabolomics implicates medium-chain acylcarnitines in insulin resistance2018In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 8691Article in journal (Refereed)
    Abstract [en]

    Insulin resistance (IR) predisposes to type 2 diabetes and cardiovascular disease but its causes are incompletely understood. Metabolic challenges like the oral glucose tolerance test (OGTT) can reveal pathogenic mechanisms. We aimed to discover associations of IR with metabolite trajectories during OGTT. In 470 non-diabetic men (age 70.6 +/- 0.6 years), plasma samples obtained at 0, 30 and 120 minutes during an OGTT were analyzed by untargeted liquid chromatography-mass spectrometry metabolomics. IR was assessed with the hyperinsulinemic-euglycemic clamp method. We applied age-adjusted linear regression to identify metabolites whose concentration change was related to IR. Nine trajectories, including monounsaturated fatty acids, lysophosphatidylethanolamines and a bile acid, were significantly associated with IR, with the strongest associations observed for medium-chain acylcarnitines C10 and C12, and no associations with L-carnitine or C2-, C8-, C14- or C16-carnitine. Concentrations of C10-and C12-carnitine decreased during OGTT with a blunted decline in participants with worse insulin resistance. Associations persisted after adjustment for obesity, fasting insulin and fasting glucose. In mouse 3T3-L1 adipocytes exposed to different acylcarnitines, we observed blunted insulin-stimulated glucose uptake after treatment with C10-or C12-carnitine. In conclusion, our results identify medium-chain acylcarnitines as possible contributors to IR.

  • 209.
    Nowak, Christoph
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Ingelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Fall, Tove
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Use of type 2 diabetes risk scores in clinical practice: a call for action2015In: LANCET DIABETES & ENDOCRINOLOGY, ISSN 2213-8587, Vol. 3, no 3, p. 166-167Article in journal (Other academic)
  • 210.
    Nowak, Christoph
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Salihovic, Samira
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ganna, Andrea
    Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA.;Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA USA.;Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Cambridge, MA USA.;Karolinska Inst, Dept Med Epidemiol & Biostat MEB, Stockholm, Sweden..
    Brandmaier, Stefan
    Helmholtz Zentrum Munchen, Res Unit Mol Epidemiol, Munich, Germany.;Helmholtz Zentrum Munchen, Inst Epidemiol 2, Munich, Germany..
    Tukiainen, Taru
    Univ Helsinki, FIMM, Helsinki, Finland..
    Broeckling, Corey D.
    Colorado State Univ, Prote & Metabol Facil, Ft Collins, CO 80523 USA..
    Magnusson, Patrik K.
    Karolinska Inst, Dept Med Epidemiol & Biostat MEB, Stockholm, Sweden..
    Prenni, Jessica E.
    Colorado State Univ, Prote & Metabol Facil, Ft Collins, CO 80523 USA..
    Wang-Sattler, Rui
    Helmholtz Zentrum Munchen, Res Unit Mol Epidemiol, Munich, Germany.;Helmholtz Zentrum Munchen, Inst Epidemiol 2, Munich, Germany.;German Ctr Diabet Res DZD, Munich, Germany..
    Peters, Annette
    Helmholtz Zentrum Munchen, Inst Epidemiol 2, Munich, Germany.;German Ctr Diabet Res DZD, Munich, Germany.;Harvard Sch Publ Hlth, Dept Environm Hlth, Boston, MA USA..
    Strauch, Konstantin
    German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Genet Epidemiol, Neuherberg, Germany.;Univ Munich, Chair Genet Epidemiol, Inst Med Informat Biometry & Epidemiol, Munich, Germany..
    Meitinger, Thomas
    Helmholtz Zentrum Munchen, Inst Human Genet, Neuherberg, Germany.;Tech Univ Munich, Inst Human Genet, Munich, Germany..
    Giedraitis, Vilmantas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Ärnlöv, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology. Dalarna Univ, Sch Hlth & Social Studies, Falun, Sweden..
    Berne, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Gieger, Christian
    Helmholtz Zentrum Munchen, Res Unit Mol Epidemiol, Munich, Germany.;Helmholtz Zentrum Munchen, Inst Epidemiol 2, Munich, Germany.;German Ctr Diabet Res DZD, Munich, Germany..
    Ripatti, Samuli
    Univ Helsinki, FIMM, Helsinki, Finland.;Univ Helsinki, Fac Med, Publ Hlth, Helsinki, Finland.;Wellcome Trust Sanger Inst, Hinxton, England..
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Pedersen, Nancy L.
    Karolinska Inst, Dept Med Epidemiol & Biostat MEB, Stockholm, Sweden..
    Sundström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Ingelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Stanford Univ, Dept Med, Sch Med, Div Cardiovasc Med, Stanford, CA 94305 USA..
    Fall, Tove
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Effect of Insulin Resistance on Monounsaturated Fatty Acid Levels: A Multi-cohort Non-targeted Metabolomics and Mendelian Randomization Study2016In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 12, no 10, article id e1006379Article in journal (Refereed)
    Abstract [en]

    Insulin resistance (IR) and impaired insulin secretion contribute to type 2 diabetes and cardiovascular disease. Both are associated with changes in the circulating metabolome, but causal directions have been difficult to disentangle. We combined untargeted plasma metabolomics by liquid chromatography/mass spectrometry in three non-diabetic cohorts with Mendelian Randomization (MR) analysis to obtain new insights into early metabolic alterations in IR and impaired insulin secretion. In up to 910 elderly men we found associations of 52 metabolites with hyperinsulinemic-euglycemic clamp-measured IR and/or beta-cell responsiveness (disposition index) during an oral glucose tolerance test. These implicated bile acid, glycerophospholipid and caffeine metabolism for IR and fatty acid biosynthesis for impaired insulin secretion. In MR analysis in two separate cohorts (n = 2,613) followed by replication in three independent studies profiled on different metabolomics platforms (n = 7,824 / 8,961 / 8,330), we discovered and replicated causal effects of IR on lower levels of palmitoleic acid and oleic acid. A trend for a causal effect of IR on higher levels of tyrosine reached significance only in meta-analysis. In one of the largest studies combining "gold standard" measures for insulin responsiveness with non-targeted metabolomics, we found distinct metabolic profiles related to IR or impaired insulin secretion. We speculate that the causal effects on monounsaturated fatty acid levels could explain parts of the raised cardiovascular disease risk in IR that is independent of diabetes development.

  • 211.
    Nowak, Christoph
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Sundstrom, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Ingelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Fall, Tove
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Type 2 diabetes, glycaemic traits and cardiovascular disease: a Mendelian Randomization studyManuscript (preprint) (Other academic)
    Abstract [en]

    Type 2 diabetes (T2D) and its hallmarks insulin resistance, impaired insulin secretion, and hyperglycaemia affect over 400 million persons worldwide and are associated with raised cardiovascular risk, but their causal role has been difficult to dissect due to overlap between risk factors. We used Mendelian randomization analysis, which utilises genetic polymorphisms associated with a risk factor, to assess causal effects of T2D, insulin resistance, insulin secretion, and fasting glucose on mortality, ischaemic stroke, and coronary artery disease (CAD) risk in 120,091 adults in the UK Biobank and in the CARDIoGRAMplusC4D consortium (63,746 cases of CAD and 130,681 controls). We found evidence for a causal effect of T2D on raised CAD risk (odds ratio (OR) per doubling in the odds of T2D, 1.07, 95% confidence interval (CI) 1.05 – 1.09, P = 1.2 x 10-9) and for a causal effect of impaired insulin secretion on the risk of CAD (OR per SD-unit decrease, 1.14, 95% CI 1.06 – 1.22, P = 0.002). The genetic score for insulin resistance was associated with increased coronary artery disease risk; however, sensitivity analysis indicated that the instrument might not be appropriate to use for robust causal inference testing. Our results support previous reports of a causal role of T2D and impaired insulin secretion in coronary artery disease and point to a complex relationship between variants affecting insulin resistance and cardiovascular outcomes.

  • 212.
    Nowak, Christoph
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Sundstrom, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Salihovic, Samira
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Ganna, Andrea
    Massachusetts General Hospital, Harvard Medical School and Broad Institute, Boston, Massachusetts.
    Shen, Xia
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm , Sweden.
    Broeckling, Corey D.
    Proteomics and Metabolomics Facility, Colorado State University, Fort Collins, Colorado, USA.
    Prenni, Jessica
    Proteomics and Metabolomics Facility, Colorado State University, Fort Collins, Colorado, USA.
    Berne, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Giedraitis, Vilmantas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Ärnlöv, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology. School of Health and Social Studies, Dalarna University, Falun, Sweden.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Fall, Tove
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ingelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California, USA.
    Metabolite profiles during an oral glucose tolerance test reveal new associations with clamp-measured insulin sensitivityManuscript (preprint) (Other academic)
    Abstract [en]

    Impaired insulin sensitivity (IS) is a major risk factor for cardiovascular disease and type 2 diabetes. Metabolomic profiling during an oral glucose tolerance test (OGTT) can reveal early pathogenic alterations in healthy individuals. Our aim was to identify IS biomarkers and gain new pathophysiologic insights by applying untargeted metabolomics to repeated OGTT plasma samples in association with a hyperinsulinemic-euglycemic clamp assessment. We studied 192 metabolites identified by non-targeted liquid chromatography/mass spectrometry in plasma samples taken at 0, 30, and 120 min during an OGTT in 470 non-diabetic 71-yr-old men. Insulin sensitivity was associated with 35 metabolites at one or more time points in multivariable-adjusted linear regression. The trajectories of nine metabolites during the OGTT were related to IS, six of which (oleic and palmitoleic acid, decanoyl- and dodecanoylcarnitine, deoxycholate-glycine and hexose) showed no associations with IS in the baseline fasting state. The strongest effects were detected for medium-chain acylcarnitines, which increased between 30-120 min in insulin-resistant individuals compared to those with normal IS. In this large community sample, we identified novel associations between clamp-measured IS and metabolite profiles that became apparent only after an oral glucose challenge. Associations of differential medium-chain acylcarnitine and monounsaturated fatty acid trajectories with IS provide new insights into the pathogenesis of insulin resistance.

  • 213.
    Nowak, Christoph
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Sundström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Gustafsson, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Giedraitis, Vilmantas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Ingelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Fall, Tove
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Protein Biomarkers for Insulin Resistance and Type 2 Diabetes Risk in Two Large Community Cohorts2016In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 65, no 1, p. 276-284Article in journal (Refereed)
    Abstract [en]

    Insulin resistance (IR) is a precursor of type 2 diabetes (T2D), and improved risk prediction and understanding of the pathogenesis are needed. We used a novel high-throughput 92-protein assay to identify circulating biomarkers for HOMA of IR in two cohorts of community residents without diabetes (n = 1,367) (mean age 73 ± 3.6 years). Adjusted linear regression identified cathepsin D and confirmed six proteins (leptin, renin, interleukin-1 receptor antagonist [IL-1ra], hepatocyte growth factor, fatty acid-binding protein 4, and tissue plasminogen activator [t-PA]) as IR biomarkers. Mendelian randomization analysis indicated a positive causal effect of IR on t-PA concentrations. Two biomarkers, IL-1ra (hazard ratio [HR] 1.28, 95% CI 1.03-1.59) and t-PA (HR 1.30, 1.02-1.65) were associated with incident T2D, and t-PA predicted 5-year transition to hyperglycemia (odds ratio 1.30, 95% CI 1.02-1.65). Additional adjustment for fasting glucose rendered both coefficients insignificant and revealed an association between renin and T2D (HR 0.79, 0.62-0.99). LASSO regression suggested a risk model including IL-1ra, t-PA, and the Framingham Offspring Study T2D score, but prediction improvement was nonsignificant (difference in C-index 0.02, 95% CI -0.08 to 0.12) over the T2D score only. In conclusion, proteomic blood profiling indicated cathepsin D as a new IR biomarker and suggested a causal effect of IR on t-PA.

  • 214.
    Nowak, J.
    et al.
    Tech Univ Dresden, Chair Magnetofluiddynam Measuring & Automat Techn, D-01062 Dresden, Germany..
    Nowak, Christoph
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Odenbach, S.
    Tech Univ Dresden, Chair Magnetofluiddynam Measuring & Automat Techn, D-01062 Dresden, Germany..
    Consequences of Sheep Blood Used as Diluting Agent for the Magnetoviscous Effect in Biocompatible Ferrofluids2015In: Applied Rheology, ISSN 1430-6395, E-ISSN 1617-8106, Vol. 25, no 5, p. 20-27, article id 53250Article in journal (Refereed)
    Abstract [en]

    Magnetic nanoparticles suspended in suitable carrier liquids can be adopted for use in biomedicine. For this to be achieved, the biocompatibility of these ferrofluids needs to be ascertained. In cancer treatment, potential applications currently under investigation include, e.g. drug targeting by using magneticfields and the destruction of diseased cells by applying alternating magnetic fields, which cause heating of magnetic nanoparticles. To enable the use of ferrofluids in the actual biomedical context, detailed knowledge of the flow characteristics is essential to ensure safe treatment. From ferrofluids used in the engineering context, a rise of viscosity when a magnetic field is applied the magnetoviscous effect is well known. This effect, which leads to an increased viscosity and profound alteration of a fluid's rheological behavior, has also been demonstrated for biocompatible ferrofluids used in the aforementioned applications. In biomedical applications, ferrofluids will be diluted in the blood stream. Therefore, the interaction between whole blood and the ferrofluid has to be investigated. This is the focus of the current experimental study, which makes use of two different ferrofluids diluted in sheep blood to gain a deeper understanding of the fluid mixtures primarily regarding the relative change in viscosity if an external magnetic field is applied. The results demonstrate a strong interaction between blood cells and structures formed by the magnetic nanoparticles and show a high deviation of results compared to ferrofluids diluted in water. These findings have to be taken into account for future research and applications of similar biocompatible fluids to guarantee safe and effective use in living organisms.

  • 215.
    Nylander, Ruta
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Wikström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Lindahl, Bertil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Arnlöv, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Berglund, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Ahlström, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Johansson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Larsson, Elna-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Relation between Cardiovascular Disease Risk Markers and Brain Infarcts Detected by Magnetic Resonance Imaging in an Elderly Population2015In: Journal of Stroke & Cerebrovascular Diseases, ISSN 1052-3057, E-ISSN 1532-8511, Vol. 24, no 2, p. 312-318Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    Established cardiovascular risk markers, such as hypertension, are associated with increased risk of brain infarcts. The newer markers N-terminal pro-brain natriuretic peptide, troponin I, C-reactive protein, and cystatin C may affect the risk of cardiovascular events and potentially, thereby, also stroke. We investigated the association between established and new risk markers for cardiovascular disease and brain infarcts detected by magnetic resonance imaging (MRI) at age 75.

    METHODS:

    Four hundred six randomly selected subjects from the Prospective Investigation of the Vasculature in Uppsala Seniors study were examined with MRI of the brain at age 75. Blood samples, measurements, and dedicated questionnaires at age 70 were used for analysis of risk markers. A history of diseases had been obtained at age 70 and 75. MRI was evaluated regarding lacunar and cortical infarcts. Univariate associations between outcomes and risk markers were assessed with logistic regression models.

    RESULTS:

    One or more infarcts were seen in 23% of the subjects (20% had only lacunar infarcts, 1% had only cortical infarcts, and 2% had both). Hypertension (odds ratio [OR] 2.6, 95% confidence interval [CI] 1.4, 4.7) and obesity (OR 1.3; CI 1.0, 1.8) were significantly associated with increased risk of brain infarction. The newer risk markers were not significantly associated with the brain infarcts.

    CONCLUSIONS:

    The new markers were not associated with the predominantly lacunar infarcts in our 75-year-old population, why troponin I and NT-proBNP may be associated mainly with cardioembolic infarcts as shown recently.

  • 216. Nystrom, Petter K.
    et al.
    Carlsson, Axel C.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Leander, Karin
    de Faire, Ulf
    Hellenius, Mai-Lis
    Gigante, Bruna
    Obesity, Metabolic Syndrome and Risk of Atrial Fibrillation: A Swedish, Prospective Cohort Study2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 5, article id e0127111Article in journal (Refereed)
    Abstract [en]

    Aim We aimed to investigate whether different measures of obesity could similarly predict atrial fibrillation, and whether the atrial fibrillation risk associated with obesity is dependent on presence of metabolic syndrome. Material and Methods We performed our study in a population-based longitudinal cardiovascular study, comprising 1 924 men and 2 097 women, aged 60 years, from Stockholm. Body mass index, waist circumference, sagittal abdominal diameter and components of metabolic syndrome (systolic- and diastolic blood pressure, fasting glucose, triglycerides, high-density lipoprotein-cholesterol) were recorded at baseline. Participants were classified by their body mass index (normal weight, overweight or obese), waist circumference (normal, semi-elevated or elevated), and according to presence of metabolic syndrome. Atrial fibrillation risk was estimated by Cox proportional hazards regression models, adjusted for common atrial fibrillation risk factors, expressed as HR and 95% CI. Results During a mean follow-up of 13.6 years, 285 incident atrial fibrillation cases were recorded. One standard deviation increment of each obesity measure was associated with increased atrial fibrillation risk as: bodymass index 1.25 (1.12 - 1.40), waist circumference 1.35 (1.19 - 1.54) and sagittal abdominal diameter 1.28 (1.14 - 1.44). Compared to normal weight subjects without metabolic syndrome, increased atrial fibrillation risk was noted for overweight subjects with metabolic syndrome, 1.67 (1.16 - 2.41), obese subjects without metabolic syndrome, 1.75 (1.11 - 2.74) and obese subjects withmetabolic syndrome, 1.92 (1.34 - 2.74). Compared to subjects with normal waist circumference without metabolic syndrome, subjects with elevated waist circumference and metabolic syndrome suffered increased atrial fibrillation risk, 2.03 (1.44 - 2.87). Conclusions Body mass index, waist circumference and sagittal abdominal diameter could similarly predict atrial fibrillation. Obesity was associated with an increased atrial fibrillation risk regardless of metabolic syndrome, whereas overweight and elevated waist circumference was associated with increased atrial fibrillation risk only if metabolic syndrome was present.

  • 217.
    Ohlund, M.
    et al.
    Swedish Univ Agr Sci, Dept Clin Sci, POB 7054, SE-75007 Uppsala, Sweden..
    Egenvall, A.
    Swedish Univ Agr Sci, Dept Clin Sci, POB 7054, SE-75007 Uppsala, Sweden..
    Fall, Tove
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hansson-Hamlin, H.
    Swedish Univ Agr Sci, Dept Clin Sci, POB 7054, SE-75007 Uppsala, Sweden..
    Rocklinsberg, H.
    Swedish Univ Agr Sci, Dept Anim Environm & Hlth, Uppsala, Sweden..
    Holst, B. S.
    Swedish Univ Agr Sci, Dept Clin Sci, POB 7054, SE-75007 Uppsala, Sweden..
    Environmental Risk Factors for Diabetes Mellitus in Cats2017In: Journal of Veterinary Internal Medicine, ISSN 0891-6640, E-ISSN 1939-1676, Vol. 31, no 1, p. 29-35Article in journal (Refereed)
    Abstract [en]

    BackgroundDiabetes in cats resembles type 2 diabetes in people. The etiology is not fully understood, but both genetic and environmental factors are believed to contribute. ObjectivesTo assess the associations of environmental risk factors with diabetes in cats. AnimalsCats with a diagnosis of diabetes (n = 396) insured by a Swedish insurance company during years 2009-2013, and a control group (n = 1,670) matched on birth year. MethodsA web-based questionnaire was used in a case-control study. An invitation to participate was sent to owners of 1,369 diabetic cats and 5,363 control cats. The survey contained questions related to the cat's breed, age, sex, neutering status, body condition, housing, access to the outdoors, activity level, diet, eating behavior, feeding routine, general health, stressful events, other pets in the household, medications, and vaccination status. Data were analyzed by multiple logistic regression. ResultsResponse rate was 35% for the diabetic group and 32% for the control group. Indoor confinement, being a greedy eater, and being overweight were associated with an increased risk of diabetes. In cats assessed by owners as being normal weight, there was an association between eating predominantly dry food and an increased risk of diabetes (Odds ratio 3.8; 95% confidence intervals 1.3-11.2). Conclusions and Clinical ImportanceDry food is commonly fed to cats worldwide. The association found between dry food and an increased risk of diabetes in cats assessed as normal weight by owners warrants further attention.

  • 218.
    Ohlund, M.
    et al.
    Swedish Univ Agr Sci, Dept Clin Sci, SE-75007 Uppsala, Sweden..
    Fall, Tove
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Holst, B. Strom
    Swedish Univ Agr Sci, Dept Clin Sci, SE-75007 Uppsala, Sweden..
    Hansson-Hamlin, H.
    Swedish Univ Agr Sci, Dept Clin Sci, SE-75007 Uppsala, Sweden..
    Bonnett, B.
    Int Partnership Dogs, Georgian Bluffs, ON, Canada..
    Egenvall, A.
    Swedish Univ Agr Sci, Dept Clin Sci, SE-75007 Uppsala, Sweden..
    Incidence of Diabetes Mellitus in Insured Swedish Cats in Relation to Age, Breed and Sex2015In: Journal of Veterinary Internal Medicine, ISSN 0891-6640, E-ISSN 1939-1676, Vol. 29, no 5, p. 1342-1347Article in journal (Refereed)
    Abstract [en]

    Background: Diabetes mellitus ( DM) is a common endocrinopathy in cats. Most affected cats suffer from a type of diabetes similar to type 2 diabetes in humans. An increasing prevalence has been described in cats, as in humans, related to obesity and other lifestyle factors. Objectives: To describe the incidence of DM in insured Swedish cats and the association of DM with demographic risk factors, such as age, breed and sex. Animals: A cohort of 504,688 individual cats accounting for 1,229,699 cat- years at risk ( CYAR) insured by a Swedish insurance company from 2009 to 2013. Methods: We used reimbursed insurance claims for the diagnosis of DM. Overall incidence rates and incidence rates stratified on year, age, breed, and sex were estimated. Results: The overall incidence rate of DM in the cohort was 11.6 cases ( 95% confidence interval [ CI], 11.0- 12.2) per 10,000 CYAR. Male cats had twice as high incidence rate ( 15.4; 95% CI, 14.4- 16.4) as females ( 7.6; 95% CI, 6.9- 8.3). Domestic cats were at higher risk compared to purebred cats. A significant association with breed was seen, with the Burmese, Russian Blue, Norwegian Forest cat, and Abyssinian breeds at a higher risk compared to other cats. No sex predisposition was found among Burmese cats. Several breeds with a lower risk of DM were identified. Conclusions and clinical importance: Our results verify that the Burmese breed is at increased risk of developing DM. We also identified several previously unreported breeds with increased or decreased risk of DM.

  • 219.
    Olsson, Mia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Frankowiack, Marcel
    Tengvall, Katarina
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Roosje, Petra
    Fall, Tove
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ivansson, Emma
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Bergvall, Kerstin
    Hansson-Hamlin, Helene
    Sundberg, Katarina
    Hedhammar, Ake
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hammarstrom, Lennart
    The dog as a genetic model for immunoglobulin A (IgA) deficiency: Identification of several breeds with low serum IgA concentrations2014In: Veterinary Immunology and Immunopathology, ISSN 0165-2427, E-ISSN 1873-2534, Vol. 60, no 3-4, p. 255-259Article in journal (Refereed)
    Abstract [en]

    Immunoglobulin A (IgA) serves as the basis of the secretory immune system by protecting the lining of mucosal sites from pathogens. In both humans and dogs, IgA deficiency (IgAD) is associated with recurrent infections of mucosal sites and immune-mediated diseases. Low concentrations of serum IgA have previously been reported to occur in a number of dog breeds but no generally accepted cut-off value has been established for canine IgAD. The current study represents the largest screening to date of IgA in dogs in terms of both number of dogs (n = 1267) and number of breeds studied (n = 22). Serum IgA concentrations were quantified by using capture ELISA and were found to vary widely between breeds. We also found IgA to be positively correlated with age (p < 0.0001). Apart from the two breeds previously reported as predisposed to low IgA (Shar-Pei and German shepherd), we identified six additional breeds in which > 10% of all tested dogs had very low (<0.07 g/l) IgA concentrations (Hovawart, Norwegian elkhound, Nova Scotia duck tolling retriever, Bullterrier, Golden retriever and Labrador retriever). In addition, we discovered low IgA concentrations to be significantly associated with canine atopic dermatitis (CAD, p < 0.0001) and pancreatic acinar atrophy (PAA, p = 0.04) in German shepherds.

  • 220. Ortqvist, Anne K.
    et al.
    Lundholm, Cecilia
    Kieler, Helle
    Ludvigsson, Jonas F.
    Fall, Tove
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ye, Weimin
    Almqvist, Catarina
    Antibiotics in fetal and early life and subsequent childhood asthma: nationwide population based study with sibling analysis2014In: BMJ-BRITISH MEDICAL JOURNAL, ISSN 1756-1833, Vol. 349, p. g6979-Article in journal (Refereed)
    Abstract [en]

    Objective To investigate the association between exposure to antibiotics in fetal and early life and asthma in childhood, with adjustment for confounding factors. Design Nationwide prospective population based cohort study, including sibling control design. Setting Swedish population identified from national demographic and health registers. Participants 493 785 children born 2006-10; 180 894 of these were eligible for sibling analyses. Main outcome measure Asthma defined as having both an asthma diagnosis and dispensed asthma drugs. The association between antibiotic exposure and asthma was investigated in the whole cohort with Cox proportional hazard regression. A stratified proportional hazards model conditional on sibling group was used to adjust for shared factors within families. Confounding by respiratory infections was assessed by investigating whether specific groups of antibiotics were associated with asthma. Results Antibiotic exposure in fetal life was associated with an increased risk of asthma in cohort analyses (hazard ratio 1.28, 95% confidence interval 1.25 to 1.32), but not in sibling analyses (0.99, 0.92 to 1.07). In cohort analyses, antibiotics used to treat respiratory infections in childhood were associated with a more pronounced increased risk of asthma (4.12, 3.78 to 4.50) than antibiotics used for urinary tract and skin infections (1.54, 1.24 to 1.92). In sibling analyses, the excess risks after exposure to antibiotics for respiratory infections decreased (2.36, 1.78 to 3.13) and disappeared for antibiotics for urinary tract and skin (0.85, 0.47 to 1.55). Conclusions Previous positive associations between exposure to antibiotics in fetal and early life and subsequent childhood asthma could have been caused by confounding by shared familial factors, in addition to confounding by respiratory infections.

  • 221.
    Parikh, Nisha I.
    et al.
    Univ Calif San Francisco, Dept Med, Div Cardiol, San Francisco, CA 94143 USA..
    Norberg, Margareta
    Umea Univ, Dept Publ Hlth & Clin Med, Epidemiol & Global Hlth, S-90187 Umea, Sweden..
    Ingelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Stanford Univ, Dept Med, Div Cardiovasc Med, Sch Med, Stanford, CA 94305 USA..
    Cnattingius, Sven
    Karolinska Inst, Dept Med Solna, Clin Epidemiol Unit, Stockholm, Sweden..
    Vasan, Ramachandran S.
    Boston Univ, Sch Med, Prevent Med Sect, Boston, MA 02215 USA.;Boston Univ, Sch Med, Cardiol Sect, Boston, MA 02215 USA.;Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02215 USA..
    Domellof, Magnus
    Umea Univ, Pediat Unit, Dept Clin Sci, S-90187 Umea, Sweden..
    Jansson, Jan Hakan
    Umea Univ, Dept Publ Hlth & Clin Med, Res Unit Skelleftea, S-90187 Umea, Sweden..
    Bonamy, Anna-Karin Edstedt
    Karolinska Inst, Dept Med Solna, Clin Epidemiol Unit, Stockholm, Sweden.;Karolinska Inst, Dept Womens Childrens Hlth, Stockholm, Sweden..
    Association of Pregnancy Complications and Characteristics With Future Risk of Elevated Blood Pressure The Västerbotten Intervention Program2017In: Hypertension, ISSN 0194-911X, E-ISSN 1524-4563, Vol. 69, no 3, p. 475-483Article in journal (Refereed)
    Abstract [en]

    Pregnancy characteristics are associated with risk of cardiovascular diseases, but their independent associations with hypertension or blood pressure (BP) levels remain uncertain. We linked the Swedish Medical Birth Register with Vesterbotten Intervention Program data (Northern Sweden). Using linear and logistic regression, we related pregnancy factors in any prior pregnancy with BP and hypertension at 40 years of age in 15 896 parous women free of prepregnancy hypertension. Pregnancy factors included parity, age at first delivery, preeclampsia, gestational diabetes mellitus, placental abruption, shortest gestational age small for gestational age baby (<third percentile for birth weight) or stillbirth. We defined hypertension as systolic BP >= 140 mm Hg and diastolic BP >= 90 mm Hg or antihypertensive use. Multivariable models were adjusted for all pregnancy factors and potential lifestyle and sociodemographic confounders. At 40 years of age, 1535 women (9.6%) had hypertension. In multivariable models, lower parity, younger age at first birth, preeclampsia, small for gestational age, and placental abruption were independently associated with higher systolic and diastolic BP levels at 40 years of age. Younger age at first birth, preeclampsia, gestational age <32 versus >= 37 weeks, and small for gestational age were independently associated with hypertension. Our findings raise the possibility that earlier and more frequent BP screening may be desirable in women with these pregnancy characteristics.

  • 222.
    Penell, Johanna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Fall, Tove
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Axelsson, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lundmark, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Morris, Andrew P
    Lindgren, Cecilia
    Mahajan, Anubha
    Salihovic, Samira
    van Bavel, Bert
    Ingelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lind, P Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Genetic variation in the CYP2B6 Gene is related to circulating 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) concentrations: an observational population-based study2014In: Environmental health, ISSN 1476-069X, E-ISSN 1476-069X, Vol. 13, p. 34-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    Since human CYP2B6 has been identified as the major CYP enzyme involved in the metabolism of 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) and that human 2B6 is a highly polymorphic CYP, with known functional variants, we evaluated if circulating concentrations of a major brominated flame retardant, BDE-47, were related to genetic variation in the CYP2B6 gene in a population sample.

    METHODS:

    In the population-based Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study (men and women all aged 70), 25 single nucleotide polymorphisms (SNPs) in the CYP2B6 gene were genotyped. Circulating concentrations of BDE-47 were analyzed by high-resolution gas chromatography coupled to high-resolution mass spectrometry (HRGC/ HRMS).

    RESULTS:

    Several SNPs in the CYP2B6 gene were associated with circulating concentrations of BDE-47 (P = 10-4 to 10-9). The investigated SNPs came primarily from two haplotypes, although the correlation between the haplotypes was rather high. Conditional analyses adjusting for the SNP with the strongest association with the exposure (rs2014141) did not provide evidence for independent signals.

    CONCLUSION:

    Circulating concentrations of BDE-47 were related to genetic variation in the CYP2B6 gene in an elderly population.

  • 223.
    Pereira, Maria J
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Palming, Jenny
    Svensson, Maria K
    Rizell, Magnus
    Dalenbäck, Jan
    Hammar, Mårten
    Fall, Tove
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Sidibeh, Cherno O
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Svensson, Per-Arne
    Eriksson, Jan W
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    FKBP5 expression in human adipose tissue increases following dexamethasone exposure and is associated with insulin resistance2014In: Metabolism: Clinical and Experimental, ISSN 0026-0495, E-ISSN 1532-8600, Vol. 63, no 9, p. 1198-1208Article in journal (Refereed)
    Abstract [en]

    Objective

    To study effects of dexamethasone on gene expression in human adipose tissue aiming to identify potential novel mechanisms for glucocorticoid-induced insulin resistance.

    Materials/methods

    Subcutaneous and omental adipose tissue, obtained from non-diabetic donors (10 M/15 F; age: 28–60 years; BMI: 20.7–30.6 kg/m2), was incubated with or without dexamethasone (0.003–3 μmol/L) for 24 h. Gene expression was assessed by microarray and real time-PCR and protein expression by immunoblotting.

    Results

    FKBP5 (FK506-binding protein 5) and CNR1 (cannabinoid receptor 1) were the most responsive genes to dexamethasone in both subcutaneous and omental adipose tissue (~ 7-fold). Dexamethasone increased FKBP5 gene and protein expression in a dose-dependent manner in both depots. The gene product, FKBP51 protein, was 10-fold higher in the omental than in the subcutaneous depot, whereas the mRNA levels were similar. Higher FKBP5 gene expression in omental adipose tissue was associated with reduced insulin effects on glucose uptake in both depots. Furthermore, FKBP5 gene expression in subcutaneous adipose tissue was positively correlated with serum insulin, HOMA-IR and subcutaneous adipocyte diameter and negatively with plasma HDL-cholesterol. FKBP5 SNPs were found to be associated with type 2 diabetes and diabetes-related phenotypes in large population-based samples.

    Conclusions

    Dexamethasone exposure promotes expression of FKBP5 in adipose tissue, a gene that may be implicated in glucocorticoid-induced insulin resistance.

  • 224.
    Pereira, Maria J
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Skrtic, S.
    AstraZeneca R&D, Molndal, Sweden..
    Katsogiannos, Petros
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Abrahamsson, Niclas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Kullberg, Joel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Nowak, Christoph
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Eriksson, Jan W
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    CDKN2C expression is low in type 2 diabetes and associated with reduced lipid storage capacity in subcutaneous adipose tissue and elevated free fatty acid levels2017In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 60, no S1, p. S272-S272, article id 598Article in journal (Other academic)
  • 225.
    Pereira, Maria João
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Palming, J.
    Svensson, M. K.
    Rizell, M.
    Dalenback, J.
    Hammar, M.
    Fall, Tove
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Sidibeh, Cherno O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Svensson, P. -A
    Eriksson, Jan W.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    FKBP5 gene polymorphisms and expression in human adipose tissue are associated with insulin resistance and type 2 diabetes2014In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 57, no S1, p. S239-S239Article in journal (Other academic)
  • 226. Perry, John R. B.
    et al.
    Day, Felix
    Elks, Cathy E.
    Sulem, Patrick
    Thompson, Deborah J.
    Ferreira, Teresa
    He, Chunyan
    Chasman, Daniel I.
    Esko, Toenu
    Thorleifsson, Gudmar
    Albrecht, Eva
    Ang, Wei Q.
    Corre, Tanguy
    Cousminer, Diana L.
    Feenstra, Bjarke
    Franceschini, Nora
    Ganna, Andrea
    Johnson, Andrew D.
    Kjellqvist, Sanela
    Lunetta, Kathryn L.
    McMahon, George
    Nolte, Ilja M.
    Paternoster, Lavinia
    Porcu, Eleonora
    Smith, Albert V.
    Stolk, Lisette
    Teumer, Alexander
    Tsernikova, Natalia
    Tikkanen, Emmi
    Ulivi, Sheila
    Wagner, Erin K.
    Amin, Najaf
    Bierut, Laura J.
    Byrne, Enda M.
    Hottenga, Jouke-Jan
    Koller, Daniel L.
    Mangino, Massimo
    Pers, Tune H.
    Yerges-Armstrong, Laura M.
    Zhao, Jing Hua
    Andrulis, Irene L.
    Anton-Culver, Hoda
    Atsma, Femke
    Bandinelli, Stefania
    Beckmann, Matthias W.
    Benitez, Javier
    Blomqvist, Carl
    Bojesen, Stig E.
    Bolla, Manjeet K.
    Bonanni, Bernardo
    Brauch, Hiltrud
    Brenner, Hermann
    Buring, Julie E.
    Chang-Claude, Jenny
    Chanock, Stephen
    Chen, Jinhui
    Chenevix-Trench, Georgia
    Collee, J. Margriet
    Couch, Fergus J.
    Couper, David
    Coviello, Andrea D.
    Cox, Angela
    Czene, Kamila
    D'adamo, Adamo Pio
    Smith, George Davey
    De Vivo, Immaculata
    Demerath, Ellen W.
    Dennis, Joe
    Devilee, Peter
    Dieffenbach, Aida K.
    Dunning, Alison M.
    Eiriksdottir, Gudny
    Eriksson, Johan G.
    Fasching, Peter A.
    Ferrucci, Luigi
    Flesch-Janys, Dieter
    Flyger, Henrik
    Foroud, Tatiana
    Franke, Lude
    Garcia, Melissa E.
    Garcia-Closas, Montserrat
    Geller, Frank
    de Geus, Eco E. J.
    Giles, Graham G.
    Gudbjartsson, Daniel F.
    Gudnason, Vilmundur
    Guenel, Pascal
    Guo, Suiqun
    Hall, Per
    Hamann, Ute
    Haring, Robin
    Hartman, Catharina A.
    Heath, AndrewC.
    Hofman, Albert
    Hooning, Maartje J.
    Hopper, John L.
    Hu, Frank B.
    Hunter, David J.
    Karasik, David
    Kiel, Douglas P.
    Knight, Julia A.
    Kosma, Veli-Matti
    Kutalik, Zoltan
    Lai, Sandra
    Lambrechts, Diether
    Lindblom, Annika
    Maegi, Reedik
    Magnusson, Patrik K.
    Mannermaa, Arto
    Martin, Nicholas G.
    Masson, Gisli
    McArdle, Patrick F.
    McArdle, Wendy L.
    Melbye, Mads
    Michailidou, Kyriaki
    Mihailov, Evelin
    Milani, Lili
    Milne, Roger L.
    Nevanlinna, Heli
    Neven, Patrick
    Nohr, Ellen A.
    Oldehinkel, Albertine J.
    Oostra, Ben A.
    Palotie, Aarno
    Peacock, Munro
    Pedersen, Nancy L.
    Peterlongo, Paolo
    Peto, Julian
    Pharoah, Paul D. P.
    Postma, Dirkje S.
    Pouta, Anneli
    Pylkaes, Katri
    Radice, Paolo
    Ring, Susan
    Rivadeneira, Fernando
    Robino, Antonietta
    Rose, Lynda M.
    Rudolph, Anja
    Salomaa, Veikko
    Sanna, Serena
    Schlessinger, David
    Schmidt, Marjanka K.
    Southey, Mellissa C.
    Sovio, Ulla
    Stampfer, Meir J.
    Stoeckl, Doris
    Storniolo, Anna M.
    Timpson, Nicholas J.
    Tyrer, Jonathan
    Visser, Jenny A.
    Vollenweider, Peter
    Voelzke, Henry
    Waeber, Gerard
    Waldenberger, Melanie
    Wallaschofski, Henri
    Wang, Qin
    Willemsen, Gonneke
    Winqvist, Robert
    Wolffenbuttel, Bruce H. R.
    Wright, Margaret J.
    Boomsma, Dorret I.
    Econs, Michael J.
    Khaw, Kay-Tee
    Loos, Ruth J. F.
    McCarthy, Mark I.
    Montgomery, Grant W.
    Rice, John P.
    Streeten, Elizabeth A.
    Thorsteinsdottir, Unnur
    van Duijn, Cornelia M.
    Alizadeh, Behrooz Z.
    Bergmann, Sven
    Boerwinkle, Eric
    Boyd, Heather A.
    Crisponi, Laura
    Gasparini, Paolo
    Gieger, Christian
    Harris, Tamara B.
    Ingelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Jaervelin, Marjo-Riitta
    Kraft, Peter
    Lawlor, Debbie
    Metspalu, Andres
    Pennell, Craig E.
    Ridker, Paul M.
    Snieder, Harold
    Sorensen, Thorkild I. A.
    Spector, Tim D.
    Strachan, David P.
    Uitterlinden, Andre G.
    Wareham, Nicholas J.
    Widen, Elisabeth
    Zygmunt, Marek
    Murray, Anna
    Easton, Douglas F.
    Stefansson, Kari
    Murabito, Joanne M.
    Ong, Ken K.
    Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche2014In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 514, no 7520, p. 92-+Article in journal (Refereed)
    Abstract [en]

    Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-causemortality(1). Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation(2,3), but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P < 5 x 10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and gamma-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition.

  • 227. Perry, John R. B.
    et al.
    Hsu, Yi-Hsiang
    Chasman, Daniel I.
    Johnson, Andrew D.
    Elks, Cathy
    Albrecht, Eva
    Andrulis, Irene L.
    Beesley, Jonathan
    Berenson, Gerald S.
    Bergmann, Sven
    Bojesen, Stig E.
    Bolla, Manjeet K.
    Brown, Judith
    Buring, Julie E.
    Campbell, Harry
    Chang-Claude, Jenny
    Chenevix-Trench, Georgia
    Corre, Tanguy
    Couch, Fergus J.
    Cox, Angela
    Czene, Kamila
    D'adamo, Adamo Pio
    Davies, Gail
    Deary, Ian J.
    Dennis, Joe
    Easton, Douglas F.
    Engelhardt, Ellen G.
    Eriksson, Johan G.
    Esko, Tonu
    Fasching, Peter A.
    Figueroa, Jonine D.
    Flyger, Henrik
    Fraser, Abigail
    Garcia-Closas, Montse
    Gasparini, Paolo
    Gieger, Christian
    Giles, Graham
    Guenel, Pascal
    Hägg, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hall, Per
    Hayward, Caroline
    Hopper, John
    Ingelsson, Erik
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Kardia, L. R.
    Kasiman, Katherine
    Knight, Julia A.
    Lahti, Jari
    Lawlor, Debbie A.
    Magnusson, Patrik K. E.
    Margolin, Sara
    Marsh, Julie A.
    Metspalu, Andres
    Olson, Janet E.
    Pennell, Craig E.
    Polasek, Ozren
    Rahman, Iffat
    Ridker, Paul M.
    Robino, Antonietta
    Rudan, Igor
    Rudolph, Anja
    Salumets, Andres
    Schmidt, Marjanka K.
    Schoemaker, Minouk J.
    Smith, Erin N.
    Smith, Jennifer A.
    Southey, Melissa
    Stoeckl, Doris
    Swerdlow, Anthony J.
    Thompson, Deborah J.
    Truong, Therese
    Ulivi, Sheila
    Waldenberger, Melanie
    Wang, Qin
    Wild, Sarah
    Wilson, James F.
    Wright, Alan F.
    Zgaga, Lina
    Ong, Ken K.
    Murabito, Joanne M.
    Karasik, David
    Murray, Anna
    DNA mismatch repair gene MSH6 implicated in determining age at natural menopause2014In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 23, no 9, p. 2490-2497Article in journal (Refereed)
    Abstract [en]

    The length of female reproductive lifespan is associated with multiple adverse outcomes, including breast cancer, cardiovascular disease and infertility. The biological processes that govern the timing of the beginning and end of reproductive life are not well understood. Genetic variants are known to contribute to 50 of the variation in both age at menarche and menopause, but to date the known genes explain 15 of the genetic component. We have used genome-wide association in a bivariate meta-analysis of both traits to identify genes involved in determining reproductive lifespan. We observed significant genetic correlation between the two traits using genome-wide complex trait analysis. However, we found no robust statistical evidence for individual variants with an effect on both traits. A novel association with age at menopause was detected for a variant rs1800932 in the mismatch repair gene MSH6 (P 1.9 10(9)), which was also associated with altered expression levels of MSH6 mRNA in multiple tissues. This study contributes to the growing evidence that DNA repair processes play a key role in ovarian ageing and could be an important therapeutic target for infertility.

  • 228. Pers, Tune H.
    et al.
    Karjalainen, Juha M.
    Chan, Yingleong
    Westra, Harm-Jan
    Wood, Andrew R.
    Yang, Jian
    Lui, Julian C.
    Vedantam, Sailaja
    Gustafsson, Stefan
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Esko, Tonu
    Frayling, Tim
    Speliotes, Elizabeth K.
    Boehnke, Michael
    Raychaudhuri, Soumya
    Fehrmann, Rudolf S. N.
    Hirschhorn, Joel N.
    Franke, Lude
    Biological interpretation of genome-wide association studies using predicted gene functions2015In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 6, article id 5890Article in journal (Refereed)
    Abstract [en]

    The main challenge for gaining biological insights from genetic associations is identifying which genes and pathways explain the associations. Here we present DEPICT, an integrative tool that employs predicted gene functions to systematically prioritize the most likely causal genes at associated loci, highlight enriched pathways and identify tissues/cell types where genes from associated loci are highly expressed. DEPICT is not limited to genes with established functions and prioritizes relevant gene sets for many phenotypes.

  • 229.
    Persson, Jonas
    et al.
    Danderyd Hosp, Dept Clin Sci, Div Cardiovasc Med, Karolinska Inst, S-18288 Danderyd, Sweden..
    Strawbridge, Rona J.
    Karolinska Inst, Dept Med Solna, Atherosclerosis Res Unit, Stockholm, Sweden..
    McLeod, Olga
    Karolinska Inst, Dept Med Solna, Atherosclerosis Res Unit, Stockholm, Sweden..
    Gertow, Karl
    Karolinska Inst, Dept Med Solna, Atherosclerosis Res Unit, Stockholm, Sweden.;Karolinska Inst, Div Cardiovasc Epidemiol, Inst Environm Med, Stockholm, Sweden..
    Silveira, Angela
    Karolinska Inst, Dept Med Solna, Atherosclerosis Res Unit, Stockholm, Sweden..
    Baldassarre, Damiano
    Univ Milan, Dipartimento Sci Farmacol & Biomol, Milan, Italy..
    Van Zuydam, Natalie
    Univ Dundee, Ninewells Hosp & Med Sch, Med Res Inst, Dundee DD1 4HN, Scotland..
    Shah, Sonia
    UCL, Genet Inst, London, England.;Univ Queensland, Diamantina Inst, Brisbane, Qld 4072, Australia.;Univ Queensland, Queensland Brain Inst, Brisbane, Qld 4072, Australia..
    Fava, Cristiano
    Lund Univ, Skane Univ Hosp, Dept Clin Sci, Clin Res Ctr, Malmo, Sweden.;Univ Verona, Hosp Policlin GB Rossi, Dept Med, Div Internal Med C, I-37100 Verona, Italy..
    Gustafsson, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Veglia, Fabrizio
    Univ Milan, Dipartimento Sci Farmacol & Biomol, Milan, Italy..
    Sennblad, Bengt
    Karolinska Inst, Dept Med Solna, Atherosclerosis Res Unit, Stockholm, Sweden.;Karolinska Inst, Sci Life Lab, Stockholm, Sweden..
    Larsson, Malin
    Linkoping Univ, IFM Bioinformat, Linkoping, Sweden..
    Sabater-Lleal, Maria
    Karolinska Inst, Dept Med Solna, Atherosclerosis Res Unit, Stockholm, Sweden..
    Leander, Karin
    Gigante, Bruna
    Danderyd Hosp, Dept Clin Sci, Div Cardiovasc Med, Karolinska Inst, S-18288 Danderyd, Sweden.;Karolinska Inst, Div Cardiovasc Epidemiol, Inst Environm Med, Stockholm, Sweden..
    Tabak, Adam
    Semmelweis Univ, Fac Med, Dept Med 1, H-1085 Budapest, Hungary..
    Kivimaki, Mika
    UCL, Dept Epidemiol & Publ Hlth, London, England..
    Kauhanen, Jussi
    Univ Eastern Finland, Inst Publ Hlth & Clin Nutr, Kuopio, Finland..
    Rauramaa, Rainer
    Kuopio Res Inst Exercise Med, Kuopio, Finland.;Kuopio Univ Hosp, Dept Clin Physiol & Nucl Med, SF-70210 Kuopio, Finland..
    Smit, Andries J.
    Univ Groningen, Univ Med Ctr Groningen, Dept Med, NL-9700 AB Groningen, Netherlands..
    Mannarino, Elmo
    Univ Perugia, Dept Clin & Expt Med, Internal Med Angiol & Arteriosclerosis Dis, I-06100 Perugia, Italy..
    Giral, Philippe
    Grp Hosp Pitie Salpetriere, AP HP, Serv Endocrinol Metab, Unites Prevent Cardiovasc, F-75634 Paris, France..
    Humphries, Steve E.
    UCL, Ctr Cardiovasc Genet, London, England..
    Tremoli, Elena
    Univ Milan, Dipartimento Sci Farmacol & Biomol, Milan, Italy..
    de Faire, Ulf
    Karolinska Inst, Div Cardiovasc Epidemiol, Inst Environm Med, Stockholm, Sweden..
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Ingelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Hedblad, Bo
    Lund Univ, Skane Univ Hosp, Dept Clin Sci, Clin Res Ctr, Malmo, Sweden..
    Melander, Olle
    Lund Univ, Skane Univ Hosp, Dept Clin Sci, Clin Res Ctr, Malmo, Sweden..
    Kumari, Meena
    UCL, Genet Epidemiol Grp, Dept Epidemiol & Publ Hlth, London, England..
    Hingorani, Aroon
    Karolinska Inst, Dept Med Solna, Atherosclerosis Res Unit, Stockholm, Sweden.;UCL, Genet Epidemiol Grp, Dept Epidemiol & Publ Hlth, London, England..
    Morris, Andrew D.
    Univ Dundee, Ninewells Hosp & Med Sch, Med Res Inst, Dundee DD1 4HN, Scotland..
    Palmer, Colin N. A.
    Univ Dundee, Ninewells Hosp & Med Sch, Med Res Inst, Dundee DD1 4HN, Scotland..
    Lundman, Pia
    Danderyd Hosp, Dept Clin Sci, Div Cardiovasc Med, Karolinska Inst, S-18288 Danderyd, Sweden..
    Ohrvik, John
    Karolinska Inst, Dept Med Solna, Atherosclerosis Res Unit, Stockholm, Sweden..
    Soderberg, Stefan
    Umea Univ, Dept Publ Hlth & Clin Med, Div Med, S-90187 Umea, Sweden..
    Sex-Specific Effects of Adiponectin on Carotid Intima-Media Thickness and Incident Cardiovascular Disease2015In: Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease, ISSN 2047-9980, E-ISSN 2047-9980, Vol. 4, no 8, article id e001853Article in journal (Refereed)
    Abstract [en]

    Background-Plasma adiponectin levels have previously been inversely associated with carotid intima-media thickness (IMT), a marker of subclinical atherosclerosis. In this study, we used a sex-stratified Mendelian randomization approach to investigate whether adiponectin has a causal protective influence on IMT. Methods and Results-Baseline plasma adiponectin concentrationwas tested for association with baseline IMT, IMT progression over 30 months, and occurrence of cardiovascular events within 3 years in 3430 participants (women, n=1777; men, n=1653) with high cardiovascular risk but no prevalent disease. Plasma adiponectin levels were inversely associated with baseline mean bifurcation IMT after adjustment for established risk factors (beta=-0.018, P<0.001) in men but not in women (beta=-0.006, P=0.185; P for interaction=0.061). Adiponectin levels were inversely associated with progression of mean common carotid IMT in men (beta=-0.0022, P=0.047), whereas no association was seen in women (0.0007, P=0.475; P for interaction=0.018). Moreover, we observed that adiponectin levels were inversely associated with coronary events in women (hazard ratio 0.57, 95% CI 0.37 to 0.87) but not in men (hazard ratio 0.82,95% CI0.54 to 1.25). Agenescore of adiponectin-raisingalleles in6loci, reported recently inalarge multi-ethnic metaanalysis, was inversely associated with baseline mean bifurcation IMT in men (beta=-0.0008, P=0.004) but not in women (beta=-0.0003, P=0.522; P for interaction=0.007). Conclusions-This report provides some evidence for adiponectin protecting against atherosclerosis, with effects being confined to men; however, compared with established cardiovascular risk factors, the effect of plasma adiponectin was modest. Further investigation involving mechanistic studies is warranted.

  • 230.
    Peura, Sari
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Swedish Univ Agr Sci, Dept Forest Mycol & Plant Pathol, Sci Life Labs, Almas Alle 5, S-75007 Uppsala, Sweden.
    Fall, Tove
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Almqvist, Catarina
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden; Karolinska Univ Hosp, Astrid Lindgren Childrens Hosp, Unit Paediat Allergy & Pulmonol, Stockholm, Sweden.
    Andolf, Ellika
    Karolinska Inst, Danderyd Hosp, Div Obstet & Gynaecol, Dept Clin Sci, Stockholm, Sweden.
    Hedman, Anna
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden.
    Pershagen, Göran
    Karolinska Inst, Inst Environm Med, Stockholm, Sweden.
    Helmersson-Karlqvist, Johanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Normal values for calprotectin in stool samples of infants from the population-based longitudinal born into life study2018In: Scandinavian Journal of Clinical and Laboratory Investigation, ISSN 0036-5513, E-ISSN 1502-7686, Vol. 78, no 1-2, p. 120-124Article in journal (Refereed)
    Abstract [en]

    Faecal calprotectin is a protein used as a diagnostic marker for inflammatory bowel diseases. We determined upper limits for normal calprotectin values for neonatal, 6, 12 and 24 months old children using a turbidimetric immunoassay in a cohort of Swedish children. The advantage of the method is that opposite to previously used enzyme-linked immunosorbent assay (ELISA) method, it enables measuring single samples, and thus, shortens the analysis time significantly. There were 72 samples (41.7% female) collected neonatally, 63 samples (34.9% female) at 6 months, 60 samples (40.0% female) at 12 months and 51 samples (43.1% female) at 24 months. The upper limits for normal values were 233, 615, 136 and 57 µg mg-1 for infants aged 0, 6, 12 and 24 months, respectively.

  • 231. Prokopenko, Inga
    et al.
    Poon, Wenny
    Mägi, Reedik
    Prasad B, Rashmi
    Salehi, S Albert
    Almgren, Peter
    Osmark, Peter
    Bouatia-Naji, Nabila
    Wierup, Nils
    Fall, Tove
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Stančáková, Alena
    Barker, Adam
    Lagou, Vasiliki
    Osmond, Clive
    Xie, Weijia
    Lahti, Jari
    Jackson, Anne U
    Cheng, Yu-Ching
    Liu, Jie
    O'Connell, Jeffrey R
    Blomstedt, Paul A
    Fadista, Joao
    Alkayyali, Sami
    Dayeh, Tasnim
    Ahlqvist, Emma
    Taneera, Jalal
    Lecoeur, Cecile
    Kumar, Ashish
    Hansson, Ola
    Hansson, Karin
    Voight, Benjamin F
    Kang, Hyun Min
    Levy-Marchal, Claire
    Vatin, Vincent
    Palotie, Aarno
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Mari, Andrea
    Weedon, Michael N
    Loos, Ruth J F
    Ong, Ken K
    Nilsson, Peter
    Isomaa, Bo
    Tuomi, Tiinamaija
    Wareham, Nicholas J
    Stumvoll, Michael
    Widen, Elisabeth
    Lakka, Timo A
    Langenberg, Claudia
    Tönjes, Anke
    Rauramaa, Rainer
    Kuusisto, Johanna
    Frayling, Timothy M
    Froguel, Philippe
    Walker, Mark
    Eriksson, Johan G
    Ling, Charlotte
    Kovacs, Peter
    Ingelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.
    McCarthy, Mark I
    Shuldiner, Alan R
    Silver, Kristi D
    Laakso, Markku
    Groop, Leif
    Lyssenko, Valeriya
    A Central Role for GRB10 in Regulation of Islet Function in Man2014In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 10, no 4, article id e1004235Article in journal (Refereed)
    Abstract [en]

    Variants in the growth factor receptor-bound protein 10 (GRB10) gene were in a GWAS meta-analysis associated with reduced glucose-stimulated insulin secretion and increased risk of type 2 diabetes (T2D) if inherited from the father, but inexplicably reduced fasting glucose when inherited from the mother. GRB10 is a negative regulator of insulin signaling and imprinted in a parent-of-origin fashion in different tissues. GRB10 knock-down in human pancreatic islets showed reduced insulin and glucagon secretion, which together with changes in insulin sensitivity may explain the paradoxical reduction of glucose despite a decrease in insulin secretion. Together, these findings suggest that tissue-specific methylation and possibly imprinting of GRB10 can influence glucose metabolism and contribute to T2D pathogenesis. The data also emphasize the need in genetic studies to consider whether risk alleles are inherited from the mother or the father.

  • 232. Pulit, Sara L.
    et al.
    Gustafsson, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lannfelt, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Ingelsson, Erik
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Sheth, Kevin
    Atrial fibrillation genetic risk differentiates cardioembolic stroke from other stroke subtypes2018In: NEUROLOGY-GENETICS, ISSN 2376-7839, Vol. 4, no 6, article id e293Article in journal (Refereed)
    Abstract [en]

    Objective We sought to assess whether genetic risk factors for atrial fibrillation (AF) can explain cardioembolic stroke risk. Methods We evaluated genetic correlations between a previous genetic study of AF and AF in the presence of cardioembolic stroke using genome-wide genotypes from the Stroke Genetics Network (N = 3,190 AF cases, 3,000 cardioembolic stroke cases, and 28,026 referents). We tested whether a previously validated AF polygenic risk score (PRS) associated with cardioembolic and other stroke subtypes after accounting for AF clinical risk factors. Results We observed a strong correlation between previously reported genetic risk for AF, AF in the presence of stroke, and cardioembolic stroke (Pearson r = 0.77 and 0.76, respectively, across SNPs with p < 4.4 x 10(-4) in the previous AF meta-analysis). An AF PRS, adjusted for clinical AF risk factors, was associated with cardioembolic stroke (odds ratio [OR] per SD = 1.40, p = 1.45 x 10(-48)), explaining similar to 20% of the heritable component of cardioembolic stroke risk. The AF PRS was also associated with stroke of undetermined cause (OR per SD = 1.07,p = 0.004), but no other primary stroke subtypes (all p > 0.1). Conclusions Genetic risk of AF is associated with cardioembolic stroke, independent of clinical risk factors. Studies are warranted to determine whether AF genetic risk can serve as a biomarker for strokes caused by AF.

  • 233.
    Quertermous, Thomas
    et al.
    Stanford Univ, Dept Med, Div Cardiovasc Med, Stanford, CA 94305 USA.;Stanford Univ, Cardiovasc Inst, Sch Med, Stanford, CA 94305 USA..
    Ingelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Stanford Univ, Dept Med, Div Cardiovasc Med, Stanford, CA 94305 USA.;Stanford Univ, Cardiovasc Inst, Sch Med, Stanford, CA 94305 USA..
    Coronary Artery Disease and Its Risk Factors Leveraging Shared Genetics to Discover Novel Biology2016In: Circulation Research, ISSN 0009-7330, E-ISSN 1524-4571, Vol. 118, no 1, p. 14-16Article in journal (Other academic)
  • 234. Rahmioglu, Nilufer
    et al.
    Macgregor, Stuart
    Drong, Alexander W.
    Hedman, Åsa K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Harris, Holly R.
    Randall, Joshua C.
    Prokopenko, Inga
    Nyholt, Dale R.
    Morris, Andrew P.
    Montgomery, Grant W.
    Missmer, Stacey A.
    Lindgren, Cecilia M.
    Zondervan, Krina T.
    Genome-wide enrichment analysis between endometriosis and obesity-related traits reveals novel susceptibility loci2015In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 24, no 4, p. 1185-1199Article in journal (Refereed)
    Abstract [en]

    Endometriosis is a chronic inflammatory condition in women that results in pelvic pain and subfertility, and has been associated with decreased body mass index (BMI). Genetic variants contributing to the heritable component have started to emerge from genome-wide association studies (GWAS), although the majority remain unknown. Unexpectedly, we observed an intergenic locus on 7p15.2 that was genome-wide significantly associated with both endometriosis and fat distribution (waist-to-hip ratio adjusted for BMI; WHRadjBMI) in an independent meta-GWAS of European ancestry individuals. This led us to investigate the potential overlap in genetic variants underlying the aetiology of endometriosis, WHRadjBMI and BMI using GWAS data. Our analyses demonstrated significant enrichment of common variants between fat distribution and endometriosis (P = 3.7 x 10(-3)), which was stronger when we restricted the investigation to more severe (Stage B) cases (P = 4.5 x 10(-4)). However, no genetic enrichment was observed between endometriosis and BMI (P = 0.79). In addition to 7p15.2, we identify four more variants with statistically significant evidence of involvement in both endometriosis and WHRadjBMI (in/near KIFAP3, CAB39L, WNT4, GRB14); two of these, KIFAP3 and CAB39L, are novel associations for both traits. KIFAP3, WNT4 and 7p15.2 are associated with the WNT signalling pathway; formal pathway analysis confirmed a statistically significant (P = 6.41 x 10(-4)) overrepresentation of shared associations in developmental processes/WNT signalling between the two traits. Our results demonstrate an example of potential biological pleiotropy that was hitherto unknown, and represent an opportunity for functional follow-up of loci and further cross-phenotype comparisons to assess how fat distribution and endometriosis pathogenesis research fields can inform each other.

  • 235. Richmond, Rebecca C.
    et al.
    Smith, George Davey
    Ness, Andy R.
    den Hoed, Marcel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    McMahon, George
    Timpson, Nicholas J.
    Assessing Causality in the Association between Child Adiposity and Physical Activity Levels: A Mendelian Randomization Analysis2014In: PLoS Medicine, ISSN 1549-1277, E-ISSN 1549-1676, Vol. 11, no 3Article in journal (Refereed)
    Abstract [en]

    Background Cross-sectional studies have shown that objectively measured physical activity is associated with childhood adiposity, and a strong inverse dose-response association with body mass index (BMI) has been found. However, few studies have explored the extent to which this association reflects reverse causation. We aimed to determine whether childhood adiposity causally influences levels of physical activity using genetic variants reliably associated with adiposity to estimate causal effects. Methods and Findings The Avon Longitudinal Study of Parents and Children collected data on objectively assessed activity levels of 4,296 children at age 11 y with recorded BMI and genotypic data. We used 32 established genetic correlates of BMI combined in a weighted allelic score as an instrumental variable for adiposity to estimate the causal effect of adiposity on activity. In observational analysis, a 3.3 kg/m(2) (one standard deviation) higher BMI was associated with 22.3 (95% CI, 17.0, 27.6) movement counts/min less total physical activity (p = 1.6x10(-16)), 2.6 (2.1, 3.1) min/d less moderate-to-vigorous-intensity activity (p = 3.7x10(-29)), and 3.5 (1.5, 5.5) min/d more sedentary time (p = 5.0x10(-4)). In Mendelian randomization analyses, the same difference in BMI was associated with 32.4 (0.9, 63.9) movement counts/min less total physical activity (p = 0.04) (similar to 5.3% of the mean counts/minute), 2.8 (0.1, 5.5) min/d less moderate-to-vigorous-intensity activity (p = 0.04), and 13.2 (1.3, 25.2) min/d more sedentary time (p = 0.03). There was no strong evidence for a difference between variable estimates from observational estimates. Similar results were obtained using fat mass index. Low power and poor instrumentation of activity limited causal analysis of the influence of physical activity on BMI. Conclusions Our results suggest that increased adiposity causes a reduction in physical activity in children and support research into the targeting of BMI in efforts to increase childhood activity levels. Importantly, this does not exclude lower physical activity also leading to increased adiposity, i.e., bidirectional causation. Please see later in the article for the Editors' Summary Editors' Summary Background The World Health Organization estimates that globally at least 42 million children under the age of five are obese. The World Health Organization recommends that all children undertake at least one hour of physical activity daily, on the basis that increased physical activity will reduce or prevent excessive weight gain in children and adolescents. In practice, while numerous studies have shown that body mass index (BMI) shows a strong inverse correlation with physical activity (i.e., active children are thinner than sedentary ones), exercise programs specifically targeted at obese children have had only very limited success in reducing weight. The reasons for this are not clear, although environmental factors such as watching television and lack of exercise facilities are traditionally blamed. Why Was This Study Done? ? One of the reasons why obese children do not lose weight through exercise might be that being fat in itself leads to a decrease in physical activity. This is termed reverse causation, i.e. , obesity causes sedentary behavior, rather than the other way around. The potential influence of environmental factors (e.g., lack of opportunity to exercise) makes it difficult to prove this argument. Recent research has demonstrated that specific genotypes are related to obesity in children. Specific variations within the DNA of individual genes (single nucleotide polymorphisms, or SNPs) are more common in obese individuals and predispose to greater adiposity across the weight distribution. While adiposity itself can be influenced by many environmental factors that complicate the interpretation of observed associations, at the population level, genetic variation is not related to the same factors, and over the life course cannot be changed. Investigations that exploit these properties of genetic associations to inform the interpretation of observed associations are termed Mendelian randomization studies. This research technique is used to reduce the influence of confounding environmental factors on an observed clinical condition. The authors of this study use Mendelian randomization to determine whether a genetic tendency towards high BMI and fat mass is correlated with reduced levels of physical activity in a large cohort of children. What Did the Researchers Do and Find? ? The researchers looked at a cohort of children from a large long-term health research project (the Avon Longitudinal Study of Parents and Children). BMI and total body fat were recorded. Total daily activity was measured via a small movement-counting device. In addition, the participants underwent genotyping to detect the presence of several SNPs known to be linked to obesity. For each child a total BMI allelic score was determined based on the number of obesity-related genetic variants carried by that individual. The association between obesity and reduced physical activity was then studied in two ways. Direct correlation between actual BMI and physical activity was measured (observational data). Separately, the link between BMI allelic score and physical activity was also determined (Mendelian randomization or instrumental variable analysis). The observational data showed that boys were more active than girls and had lower BMI. Across both sexes, a higher-than-average BMI was associated with lower daily activity. In genetic analyses, allelic score had a positive correlation with BMI, with one particular SNP being most strongly linked to high BMI and total fat mass. A high allelic score for BMI was also correlated with lower levels of daily physical activity. The authors conclude that children who are obese and have an inherent predisposition to high BMI also have a propensity to reduced levels of physical activity, which may compound their weight gain. What Do These Findings Mean? ? This study provides evidence that being fat is in itself a risk factor for low activity levels, separately from external environmental influences. This may be an example of "reverse causation," i.e., high BMI causes a reduction in physical activity. Alternatively, there may be a bidirectional causality, so that those with a genetic predisposition to high fat mass exercise less, leading to higher BMI, and so on, in a vicious circle. A significant limitation of the study is that validated allelic scores for physical activity are not available. Thus, it is not possible to determine whether individuals with a high allelic score for BMI also have a propensity to exercise less, or whether it is simply the circumstance of being overweight that discourages activity. This study does suggest that trying to persuade obese children to lose weight by exercising more is likely to be ineffective unless additional strategies to reduce BMI, such as strict diet control, are also implemented. Additional Information Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001618. The US Centers for Disease Control and Prevention provides obesity-related statistics, details of prevention programs, and an overview on public health strategy in the United States A more worldwide view is given by the World Health Organization The UK National Health Service website gives information on physical activity guidelines for different age groups The International Obesity Task Force is a network of organizations that seeks to alert the world to the growing health crisis threatened by soaring levels of obesity MedlinePlus-which brings together authoritative information from the US National Library of Medicine, National Institutes of Health, and other government agencies and health-related organizations-has a page on obesity Additional information on the Avon Longitudinal Study of Parents and Children is available The British Medical Journal has an article that describes <ext-link ext-link-type="uri" xlink:href="http://www.bmj.com/content/345/bmj. e7325" xlink:type="simple">Mendelian randomization

  • 236.
    Robinson, Matthew R.
    et al.
    Univ Queensland, Inst Mol Biosci, Brisbane, Qld, Australia.;Univ Lausanne, Dept Computat Biol, Lausanne, Switzerland..
    English, Geoffrey
    Univ Queensland, Inst Mol Biosci, Brisbane, Qld, Australia..
    Moser, Gerhard
    Univ Queensland, Inst Mol Biosci, Brisbane, Qld, Australia..
    Lloyd-Jones, Luke R.
    Univ Queensland, Inst Mol Biosci, Brisbane, Qld, Australia..
    Triplett, Marcus A.
    Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia..
    Zhu, Zhihong
    Univ Queensland, Inst Mol Biosci, Brisbane, Qld, Australia..
    Nolte, Ilja M.
    Univ Groningen, Dept Epidemiol, Univ Med Ctr Groningen, Groningen, Netherlands..
    van Vliet-Ostaptchouk, Jana V.
    Univ Groningen, Dept Epidemiol, Univ Med Ctr Groningen, Groningen, Netherlands.;Univ Groningen, Dept Endocrinol, Univ Med Ctr Groningen, Groningen, Netherlands..
    Snieder, Harold
    Univ Groningen, Dept Epidemiol, Univ Med Ctr Groningen, Groningen, Netherlands..
    Esko, Tonu
    Univ Tartu, Estonia Genome Ctr, Tartu, Estonia.;Boston Childrens Hosp, Div Endocrinol, Cambridge, MA USA.;Broad Inst, Program Med & Populat Genet, Cambridge, MA USA.;Harvard Med Sch, Dept Genet, Boston, MA USA..
    Milani, Lili
    Univ Tartu, Estonia Genome Ctr, Tartu, Estonia..
    Magi, Reedik
    Univ Tartu, Estonia Genome Ctr, Tartu, Estonia..
    Metspalu, Andres
    Univ Tartu, Estonia Genome Ctr, Tartu, Estonia.;Univ Tartu, Inst Mol & Cell Biol, Tartu, Estonia..
    Magnusson, Patrik K. E.
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Pedersen, Nancy L.
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Ingelsson, Erik
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Stanford Univ, Sch Med, Dept Med, Div Cardiovasc Med, Stanford, CA 94305 USA..
    Johannesson, Magnus
    Stockholm Sch Econ, Stockholm, Sweden..
    Yang, Jian
    Univ Queensland, Inst Mol Biosci, Brisbane, Qld, Australia..
    Cesarini, David
    NYU, Dept Econ, Ctr Expt Social Sci, 550 1St Ave, New York, NY 10003 USA..
    Visscher, Peter M.
    Univ Queensland, Inst Mol Biosci, Brisbane, Qld, Australia..
    Genotype-covariate interaction effects and the heritability of adult body mass index2017In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 49, no 8, p. 1174-1181Article in journal (Refereed)
    Abstract [en]

    Obesity is a worldwide epidemic, with major health and economic costs. Here we estimate heritability for body mass index (BMI) in 172,000 sibling pairs and 150,832 unrelated individuals and explore the contribution of genotype-covariate interaction effects at common SNP loci. We find evidence for genotype-age interaction (likelihood ratio test (LRT) = 73.58, degrees of freedom (df) = 1, P = 4.83 x 10(-18)), which contributed 8.1% (1.4% s.e.) to BMI variation. Across eight self-reported lifestyle factors, including diet and exercise, we find genotype-environment interaction only for smoking behavior (LRT = 19.70, P = 5.03 x 10(-5) and LRT = 30.80, P = 1.42 x 10(-8)), which contributed 4.0% (0.8% s.e.) to BMI variation. Bayesian association analysis suggests that BMI is highly polygenic, with 75% of the SNP heritability attributable to loci that each explain <0.01% of the phenotypic variance. Our findings imply that substantially larger sample sizes across ages and lifestyles are required to understand the full genetic architecture of BMI.

  • 237.
    Robinson, Matthew R.
    et al.
    Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia..
    Hemani, Gibran
    Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia..
    Medina-Gomez, Carolina
    Erasmus Univ, Dept Internal Med, Med Ctr, Rotterdam, Netherlands..
    Mezzavilla, Massimo
    Ist Ricovero & Cura Carattere Sci IRCCS, Inst Maternal & Child Hlth, Trieste, Italy.;Wellcome Trust Sanger Inst, Hinxton, Cambs, England..
    Esko-, Tonu
    Univ Tartu, Estonian Genome Ctr, EE-50090 Tartu, Estonia.;Boston Childrens Hosp, Ctr Basic & Translat Obes Res, Boston, MA USA.;Broad Inst MIT & Harvard, Cambridge, MA USA.;Harvard Univ, Sch Med, Dept Genet, Boston, MA USA..
    Shakhbazov, Konstantin
    Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia..
    Powell, Joseph E.
    Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia.;Univ Queensland, Translat Res Inst, Diamantina Inst, Brisbane, Qld, Australia..
    Vinkhuyzen, Anna
    Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia..
    Berndt, Sonja I.
    NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA..
    Gustafsson, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Justice, Anne E.
    Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA..
    Kahali, Bratati
    Univ Michigan, Dept Internal Med, Div Gastroenterol, Ann Arbor, MI 48109 USA.;Univ Michigan, Dept Computat Med & Bioinformat, Ann Arbor, MI 48109 USA..
    Locke, Adam E.
    Univ Michigan, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 USA..
    Pers, Tune H.
    Boston Childrens Hosp, Ctr Basic & Translat Obes Res, Boston, MA USA.;Broad Inst MIT & Harvard, Cambridge, MA USA.;Harvard Univ, Sch Med, Dept Genet, Boston, MA USA.;Tech Univ Denmark, Dept Syst Biol, Ctr Biol Sequence Anal, DK-2800 Lyngby, Denmark..
    Vedantam, Sailaja
    Boston Childrens Hosp, Ctr Basic & Translat Obes Res, Boston, MA USA.;Broad Inst MIT & Harvard, Cambridge, MA USA..
    Wood, Andrew R.
    van Rheenen, Wouter
    Univ Med Ctr Utrecht, Brain Ctr Rudolf Magnus, Dept Neurol & Neurosurg, Utrecht, Netherlands..
    Andreassen, Ole A.
    Univ Oslo, Oslo Univ Hosp, Norwegian Ctr Mental Disorders Res NORMENT, KG Jebsen Ctr Psychosis Res,Div Mental Hlth & Add, Oslo, Norway.;Univ Oslo, Inst Clin Med, Oslo, Norway..
    Gasparini, Paolo
    Ist Ricovero & Cura Carattere Sci IRCCS, Inst Maternal & Child Hlth, Trieste, Italy..
    Metspalu, Andres
    Univ Tartu, Estonian Genome Ctr, EE-50090 Tartu, Estonia..
    van den Berg, Leonard H.
    Univ Med Ctr Utrecht, Brain Ctr Rudolf Magnus, Dept Neurol & Neurosurg, Utrecht, Netherlands..
    Veldink, Jan H.
    Univ Med Ctr Utrecht, Brain Ctr Rudolf Magnus, Dept Neurol & Neurosurg, Utrecht, Netherlands..
    Rivadeneira, Fernando
    Erasmus Univ, Dept Internal Med, Med Ctr, Rotterdam, Netherlands..
    Werge, Thomas M.
    Mental Hlth Devices Copenhagen, MHC Sct Hans, Inst Biol Psychiat, Roskilde, Denmark.;Univ Copenhagen, Dept Clin Med, Fac Hlth & Med Sci, Copenhagen, Denmark.;Lundbeck Fdn Initiat Integrat Psychiat Res iPSYCH, Aarhus, Denmark..
    Abecasis, Goncalo R.
    Univ Michigan, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 USA..
    Boomsma, Dorret I.
    Vrije Univ Amsterdam Med Ctr, Amsterdam, Netherlands.;Vrije Univ Amsterdam Med Ctr, EMGO Inst Hlth & Care Res, Amsterdam, Netherlands.;Vrije Univ Amsterdam, Dept Biol Psychol, Amsterdam, Netherlands..
    Chasman, Daniel I.
    Harvard Univ, Sch Med, Dept Genet, Boston, MA USA.;Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02115 USA..
    de Geus, Eco J. C.
    Vrije Univ Amsterdam Med Ctr, Amsterdam, Netherlands.;Vrije Univ Amsterdam Med Ctr, EMGO Inst Hlth & Care Res, Amsterdam, Netherlands.;Vrije Univ Amsterdam, Dept Biol Psychol, Amsterdam, Netherlands..
    Frayling, Timothy M.
    Univ Exeter, Sch Med, Genet Complex Traits, Exeter, Devon, England..
    Hirschhorn, Joel N.
    Univ Tartu, Estonian Genome Ctr, EE-50090 Tartu, Estonia.;Boston Childrens Hosp, Ctr Basic & Translat Obes Res, Boston, MA USA.;Broad Inst MIT & Harvard, Cambridge, MA USA.;Harvard Univ, Sch Med, Dept Genet, Boston, MA USA..
    Hottenga, Jouke Jan
    Vrije Univ Amsterdam Med Ctr, Amsterdam, Netherlands.;Vrije Univ Amsterdam Med Ctr, EMGO Inst Hlth & Care Res, Amsterdam, Netherlands.;Vrije Univ Amsterdam, Dept Biol Psychol, Amsterdam, Netherlands..
    Ingelsson, Erik
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England..
    Loos, Ruth J. F.
    Univ Cambridge, Addenbrookes Hosp, Inst Metab Sci, MRC,Epidemiol Unit, Cambridge CB2 2QQ, England.;Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA.;Icahn Sch Med Mt Sinai, Genet Obes & Related Metab Traits Program, New York, NY 10029 USA.;Icahn Sch Med Mt Sinai, Mindich Child Hlth & Dev Inst, New York, NY 10029 USA..
    Magnusson, Patrik K. E.
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Martin, Nicholas G.
    QIMR Berghofer Med Res Inst, Brisbane, Qld, Australia..
    Montgomery, Grant W.
    QIMR Berghofer Med Res Inst, Brisbane, Qld, Australia..
    North, Kari E.
    Univ Michigan, Dept Internal Med, Div Gastroenterol, Ann Arbor, MI 48109 USA.;Univ Michigan, Dept Computat Med & Bioinformat, Ann Arbor, MI 48109 USA.;Univ N Carolina, Carolina Ctr Genome Sci, Chapel Hill, NC USA..
    Pedersen, Nancy L.
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Spector, Timothy D.
    Kings Coll London, St Thomas Hosp, Dept Twin Res & Genet Epidemiol, London WC2R 2LS, England..
    Speliotes, Elizabeth K.
    Univ Michigan, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 USA..
    Goddard, Michael E.
    Dept Primary Ind, Biosci Res Div, Melbourne, Vic, Australia.;Univ Melbourne, Dept Food & Agr Syst, Melbourne, Vic, Australia..
    Yang, Jian
    Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia.;Univ Queensland, Translat Res Inst, Diamantina Inst, Brisbane, Qld, Australia..
    Visscher, Peter M.
    Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia.;Univ Queensland, Translat Res Inst, Diamantina Inst, Brisbane, Qld, Australia..
    Population genetic differentiation of height and body mass index across Europe2015In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 47, no 11, p. 1357-1362Article in journal (Refereed)
    Abstract [en]

    Across-nation differences in the mean values for complex traits are common(1-8), but the reasons for these differences are unknown. Here we find that many independent loci contribute to population genetic differences in height and body mass index (BMI) in 9,416 individuals across 14 European countries. Using discovery data on over 250,000 individuals and unbiased effect size estimates from 17,500 sibling pairs, we estimate that 24% (95% credible interval (CI) = 9%, 41%) and 8% (95% CI = 4%, 16%) of the captured additive genetic variance for height and BMI, respectively, reflect population genetic differences. Population genetic divergence differed significantly from that in a null model (height, P < 3.94 x 10(-8); BMI, P < 5.95 x 10(-4)), and we find an among-population genetic correlation for tall and slender individuals (r = -0.80, 95% CI = -0.95, -0.60), consistent with correlated selection for both phenotypes. Observed differences in height among populations reflected the predicted genetic means (r = 0.51; P < 0.001), but environmental differences across Europe masked genetic differentiation for BMI (P < 0.58).

  • 238.
    Roos, Vendela
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Elmstahl, Solve
    Lund Univ, Malmo Univ Hosp, Dept Hlth Sci, Div Geriatr Med, Malmo, Sweden..
    Ingelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Stanford Univ, Sch Med, Dept Med, Div Cardiovasc Med, Stanford, CA 94305 USA.;.
    Sundström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Ärnlöv, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Dalarna Univ, Sch Hlth & Social Studies, Falun, Sweden..
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Alterations in Multiple Lifestyle Factors in Subjects with the Metabolic Syndrome Independently of Obesity2017In: Metabolic Syndrome and Related Disorders, ISSN 1540-4196, E-ISSN 1557-8518, Vol. 15, no 3, p. 118-123Article in journal (Refereed)
    Abstract [en]

    Background: Many lifestyle factors have been associated with the metabolic syndrome (MetS). However, most of these studies have not considered the potential impact of obesity and have often only investigated one lifestyle factor at the time. We aimed to investigate the interplay between body mass index (BMI) and MetS with respect to multiple lifestyle factors. Methods: BMI and MetS [National Cholesterol Education Program (NCEP)/Adult Treatment Panel III criteria] were assessed in a sample of 18,880 subjects aged 45-75 years from the population-based EpiHealth study. Participants were categorized into six groups according to BMI category (normal weight/BMI <25 kg/m(2), overweight/BMI 25-30 kg/m(2), and obesity/BMI > 30 kg/m(2)) and MetS status (+/-, NCEP criteria). A wide range of lifestyle factors related to physical activity, smoking, alcohol, sleep quality, working conditions, quality of life and stress, and eating patterns were assessed using a questionnaire. Results: Prevalent MetS (23% in the sample) was associated with less physical activity (P < 0.0001), more TV watching (P < 0.0001), more years of smoking (P < 0.0001), lower education level (P = 0.007), and experiencing a poor general quality of life (P < 0.0001). These lifestyle factors were all associated with MetS, independently of each other and independently of BMI. Similar results were generated when number of MetS components and presence/absence of individual MetS components were used as outcomes. Conclusions: This cross-sectional study identified alterations in a number of lifestyle factors associated with MetS independently of each other and independently of BMI. Future longitudinal studies are needed to assess causal and temporal relationships between lifestyle factors and MetS development.

  • 239.
    Roos, Vendela
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Elmstahl, Solve
    Lund Univ, Malmo Univ Hosp, Div Geriatr Med, Dept Hlth Sci, Malmo, Sweden..
    Ingelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Stanford Univ, Sch Med, Dept Med, Div Cardiovasc Med, Stanford, CA 94305 USA..
    Sundström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Ärnlöv, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Dalarna Univ, Sch Hlth & Social Studies, Falun, Sweden..
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Metabolic Syndrome Development During Aging with Special Reference to Obesity Without the Metabolic Syndrome2017In: Metabolic Syndrome and Related Disorders, ISSN 1540-4196, E-ISSN 1557-8518, Vol. 15, no 1, p. 36-43Article in journal (Refereed)
    Abstract [en]

    Background: Obesity and its associated metabolic complications continue to increase worldwide. We investigated the development of metabolic syndrome (MetS) during aging in relation to body mass index (BMI) and exercise habits. We assigned special emphasis to the metabolic stability in individuals with obesity, but without MetS, a condition often referred to as metabolically healthy obesity. Materials and Methods: Cross-sectional analysis was carried out in a sample of 19,129 men and women aged 45-75 years from the EpiHealth study. In addition, longitudinal analyses were carried out in the ULSAM study (2322 men at baseline followed from age 50 to age 77) and in the PIVUS study (1016 men and women at baseline followed from age 70 to age 80). Participants were categorized into six groups according to BMI category (normal weight/BMI <25 kg/m(2), overweight/BMI 25-30 kg/m(2), and obesity/BMI >30 kg/m(2)) and MetS status (+/-, National Cholesterol Education Program criteria). Results: MetS prevalence and number of MetS components increased with age in all three samples. The PIVUS study showed that high baseline BMI, low baseline physical activity, and increasing BMI during follow-up were related to increasing MetS prevalence and increasing numbers of MetS components during follow-up. One-third to half of individuals initially belonging to the obesity without MetS category acquired MetS during aging. Conclusions: MetS prevalence increased during aging, especially in individuals with high BMI, low level of physical activity, and weight gain. Obesity without MetS was not a stable condition over time as many of those individuals gained metabolic disturbances during aging.

  • 240.
    Roselli, Carolina
    et al.
    Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA USA.
    Chaffin, Mark D.
    Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA USA.
    Weng, Lu-Chen
    Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA USA;Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA.
    Aeschbacher, Stefanie
    Univ Hosp Basel, Basel, Switzerland;Cardiovasc Res Inst Basel, Basel, Switzerland.
    Ahlberg, Gustav
    Copenhagen Univ Hosp, Dept Cardiol, Heart Ctr, Lab Mol Cardiol,Rigshosp, Copenhagen, Denmark;Univ Copenhagen, Dept Biomed Sci, Danish Natl Res Fdn Ctr Cardiac Arrhythmia, Copenhagen, Denmark;Univ Copenhagen, Fac Hlth & Med Sci, Dept Clin Med, Copenhagen, Denmark.
    Albert, Christine M.
    Brigham & Womens Hosp, Div Prevent & Cardiovasc Med, 75 Francis St, Boston, MA 02115 USA;Harvard Med Sch, Boston, MA USA.
    Almgren, Peter
    Lund Univ, Dept Clin Sci, Malmo, Sweden.
    Alonso, Alvaro
    Emory Univ, Rollins Sch Publ Hlth, Dept Epidemiol, Atlanta, GA 30322 USA.
    Anderson, Christopher D.
    Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA USA;Massachusetts Gen Hosp, Ctr Genom Med, Boston, MA 02114 USA.
    Aragam, Krishna G.
    Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA USA;Massachusetts Gen Hosp, Ctr Genom Med, Boston, MA 02114 USA.
    Arking, Dan E.
    Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD USA.
    Barnard, John
    Cleveland Clin, Dept Cardiovasc Med, Cleveland, OH USA;Cleveland Clin, Dept Cellular & Mol Med, Cleveland, OH USA;Cleveland Clin, Dept Mol Cardiol, Cleveland, OH USA;Cleveland Clin, Dept Quantitat Hlth Sci, Cleveland, OH USA.
    Bartz, Traci M.
    Univ Washington, Dept Med, Cardiovasc Hlth Res Unit Dept, Seattle, WA 98195 USA;Univ Washington, Dept Biostat, Seattle, WA 98195 USA.
    Benjamin, Emelia J.
    NHLBI, Framingham, MA USA;Boston Univ, Framingham Heart Study, Framingham, MA USA;Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA;Boston Univ, Dept Epidemiol, Sch Publ Hlth, Boston, MA USA.
    Bihlmeyer, Nathan A.
    Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Predoctoral Training Program Human Genet, Baltimore, MD USA.
    Bis, Joshua C.
    Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA.
    Bloom, Heather L.
    Emory Univ, Div Cardiol, Atlanta, GA 30322 USA;Atlanta VA Med Ctr, Atlanta, GA USA.
    Boerwinkle, Eric
    Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA.
    Bottinger, Erwin B.
    Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA;Icahn Sch Med Mt Sinai, Dept Pharmacol & Syst Therapeut, New York, NY 10029 USA.
    Brody, Jennifer A.
    Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA.
    Calkins, Hugh
    Johns Hopkins Univ, Baltimore, MD USA.
    Campbell, Archie
    Univ Edinburgh, Inst Genet & Mol Med, Ctr Genom & Expt Med, Generat Scotland, Edinburgh, Midlothian, Scotland.
    Cappola, Thomas P.
    Univ Penn, Penn Cardiovasc Inst, Philadelphia, PA 19104 USA;Univ Penn, Dept Med, Perelman Sch Med, Philadelphia, PA 19104 USA.
    Carlquist, John
    Intermt Med Ctr, Intermt Heart Inst, Murray, UT USA;Univ Utah, Div Cardiovasc Med, Salt Lake City, UT USA.
    Chasman, Daniel I.
    Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA USA;Harvard Med Sch, Boston, MA USA;Harvard Med Sch, Boston, MA USA;Brigham & Womens Hosp, Div Prevent Med, 75 Francis St, Boston, MA 02115 USA;Brigham & Womens Hosp, Div Genet, 75 Francis St, Boston, MA 02115 USA.
    Chen, Lin Y.
    Univ Minnesota, Sch Med, Dept Med, Div Cardiovasc, Minneapolis, MN 55455 USA.
    Chen, Yii-Der Ida
    Harbor UCLA Med Ctr, Dept Pediat, LABioMed, Inst Translat Genom & Populat Sci, Torrance, CA 90509 USA.
    Choi, Eue-Keun
    Seoul Natl Univ Hosp, Seoul, South Korea.
    Choi, Seung Hoan
    Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA USA.
    Christophersen, Ingrid E.
    Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA USA;Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA;Vestre Viken Hosp Trust, Baerum Hosp, Dept Med Res, Drammen, Norway.
    Chung, Mina K.
    Cleveland Clin, Dept Cardiovasc Med, Cleveland, OH USA;Cleveland Clin, Dept Cellular & Mol Med, Cleveland, OH USA;Cleveland Clin, Dept Mol Cardiol, Cleveland, OH USA;Cleveland Clin, Dept Quantitat Hlth Sci, Cleveland, OH USA.
    Cole, John W.
    Baltimore Vet Affairs Med Ctr, Dept Neurol, Baltimore, MD USA;Univ Maryland, Sch Med, Dept Neurol, Baltimore, MD 21201 USA.
    Conen, David
    Univ Hosp Basel, Basel, Switzerland;Cardiovasc Res Inst Basel, Basel, Switzerland;McMaster Univ, Populat Hlth Res Inst, Hamilton, ON, Canada.
    Cook, James
    Univ Liverpool, Dept Biostat, Liverpool, Merseyside, England.
    Crijns, Harry J.
    Maastricht Univ, Med Ctr, Maastricht, Netherlands;Maastricht Univ, Cardiovasc Res Inst Maastricht, Dept Cardiol, Maastricht, Netherlands.
    Cutler, Michael J.
    Intermt Med Ctr, Intermt Heart Inst, Murray, UT USA.
    Damrauer, Scott M.
    Univ Penn, Dept Surg, Perelman Sch Med, Philadelphia, PA 19104 USA;Corporal Michael Crescenz VA Med Ctr, Dept Surg, Philadelphia, PA USA.
    Daniels, Brian R.
    Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA USA.
    Darbar, Dawood
    Univ Illinois, Chicago, IL USA.
    Delgado, Graciela
    Heidelberg Univ, Med Fac Mannheim, Dept Med 5, Heidelberg, Germany.
    Denny, Joshua C.
    Vanderbilt Univ, Med Ctr, Dept Med, Nashville, TN USA.
    Dichgans, Martin
    Univ Hosp, LMU Munich, Inst Stroke & Dementia Res ISD, Munich, Germany;Munich Cluster Syst Neurol SyNergy, Munich, Germany;German Ctr Neurodegenerat Dis DZNE, Munich, Germany.
    Doerr, Marcus
    Univ Med Greifswald, Dept Internal Med B, Greifswald, Germany;Partner Site Greifswald, DZHK German Ctr Cardiovasc Res, Greifswald, Germany.
    Dudink, Elton A.
    Maastricht Univ, Med Ctr, Maastricht, Netherlands;Maastricht Univ, Cardiovasc Res Inst Maastricht, Dept Cardiol, Maastricht, Netherlands.
    Dudley, Samuel C.
    Univ Minnesota, Div Cardiovasc, Minneapolis, MN 55455 USA;Univ Minnesota, Lillehei Heart Inst, Minneapolis, MN USA.
    Esa, Nada
    Univ Massachusetts, Med Sch Worcester, Worcester, MA 01605 USA.
    Esko, Tonu
    Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA USA;Univ Tartu, Estonian Genome Ctr, Tartu, Estonia.
    Eskola, Markku
    Tampere Univ Hosp, Dept Cardiol, Heart Ctr, Tampere, Finland;Univ Tampere, Fac Med & Life Sci, Tampere, Finland.
    Fatkin, Diane
    Victor Chang Cardiac Res Inst, Darlinghurst, NSW, Australia;St Vincent Hosp, Darlinghurst, NSW, Australia;Univ New South Wales, Fac Med, Kensington, NSW, Australia.
    Felix, Stephan B.
    Univ Med Greifswald, Dept Internal Med B, Greifswald, Germany;Partner Site Greifswald, DZHK German Ctr Cardiovasc Res, Greifswald, Germany.
    Ford, Ian
    Univ Glasgow, Robertson Ctr Biostat, Glasgow, Lanark, Scotland.
    Franco, Oscar H.
    Erasmus Univ, Med Ctr Rotterdam, Dept Epidemiol, Rotterdam, Netherlands.
    Geelhoed, Bastiaan
    Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, Groningen, Netherlands.
    Grewal, Raji P.
    St Francis Med Ctr, Dept Neurosci, Trenton, NJ USA;Seton Hall Univ, Sch Hlth & Med Sci, S Orange, NJ USA.
    Gudnason, Vilmundur
    Icelandic Heart Assoc, Kopavogur, Iceland;Univ Iceland, Fac Med, Reykavik, Iceland.
    Guo, Xiuqing
    Harbor UCLA Med Ctr, Dept Pediat, LABioMed, Inst Translat Genom & Populat Sci, Torrance, CA 90509 USA.
    Gupta, Namrata
    Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA USA.
    Gustafsson, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Gutmann, Rebecca
    Univ Iowa, Div Cardiovasc Med, Abboud Cardiovasc Res Ctr, Iowa City, IA USA.
    Hamsten, Anders
    Karolinska Inst, Dept Med Solna, Atherosclerosis Res Unit, Cardiovasc Genet & Genom Grp, Stockholm, Sweden.
    Harris, Tamara B.
    NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA.
    Hayward, Caroline
    Univ Edinburgh, Inst Genet & Mol Med, MRC Human Genet Unit, Edinburgh, Midlothian, Scotland.
    Heckbert, Susan R.
    Univ Washington, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA;Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA;Kaiser Permanente, Washington Hlth Res Inst, Seattle, WA USA.
    Hernesniemi, Jussi
    Tampere Univ Hosp, Dept Cardiol, Heart Ctr, Tampere, Finland;Univ Tampere, Fac Med & Life Sci, Tampere, Finland;Univ Tampere, Fac Med & Life Sci, Dept Clin Chem, Fimlab Labs, Tampere, Finland;Univ Tampere, Fac Med & Life Sci, Finnish Cardiovasc Res Ctr Tampere, Tampere, Finland.
    Hocking, Lynne J.
    Univ Aberdeen, Inst Med Sci, Aberdeen, Scotland.
    Hofman, Albert
    Erasmus Univ, Med Ctr Rotterdam, Dept Epidemiol, Rotterdam, Netherlands.
    Horimoto, Andrea R. V. R.
    Univ Sao Paulo, Heart Inst, Lab Genet & Mol Cardiol, Sao Paulo, Brazil.
    Huang, Jie
    Boston VA Res Inst Inc, Boston, MA USA.
    Huang, Paul L.
    Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA.
    Huffman, Jennifer
    Univ Edinburgh, Inst Genet & Mol Med, MRC Human Genet Unit, Edinburgh, Midlothian, Scotland.
    Ingelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab. UStanford Univ, Dept Med, Sch Med, Div Cardiovasc Med, Stanford, CA 94305 USA.
    Ipek, Esra Gucuk
    Johns Hopkins Univ, Baltimore, MD USA.
    Ito, Kaoru
    RIKEN, Ctr Integrat Med Sci, Lab Cardiovasc Dis, Yokohama, Kanagawa, Japan.
    Jimenez-Conde, Jordi
    Inst Hosp Mar Invest Med, Hosp Mar, Dept Neurol, Neurovasc Res Grp IMIM, Barcelona, Spain;Univ Autonoma Barcelona, Med Dept, Barcelona, Spain.
    Johnson, Renee
    Victor Chang Cardiac Res Inst, Darlinghurst, NSW, Australia.
    Jukema, J. Wouter
    Leiden Univ, Med Ctr, Dept Cardiol, Leiden, Netherlands;Durrer Ctr Cardiogenet Res, Amsterdam, Netherlands;Interuniv Cardiol Inst Netherlands, Utrecht, Netherlands.
    Kaeaeb, Stefan
    Ludwig Maximilians Univ Munchen, Univ Hosp Munich, Dept Med 1, Munich, Germany;DZHK German Ctr Cardiovasc Res, Partner Site Munich Heart Alliance, Munich, Germany.
    Kahonen, Mika
    Univ Tampere, Fac Med & Life Sci, Tampere Univ Hosp, Dept Clin Physiol, Tampere, Finland;Univ Tampere, Fac Med & Life Sci, Finnish Cardiovasc Res Center Tampere, Tampere, Finland.
    Kamatani, Yoichiro
    RIKEN, Ctr Integrat Med Sci, Lab Stat Anal, Yokohama, Kanagawa, Japan.
    Kane, John P.
    Univ Calif San Francisco, Cardiovasc Res Inst, San Francisco, CA 94143 USA.
    Kastrati, Adnan
    DZHK German Ctr Cardiovasc Res, Partner Site Munich Heart Alliance, Munich, Germany;Tech Univ Munich, Klin Herz & Kreislauferkrankungen, Deutsch Herzzentrum Munchen, Munich, Germany.
    Kathiresan, Sekar
    Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA USA;Massachusetts Gen Hosp, Ctr Genom Med, Boston, MA 02114 USA.
    Katschnig-Winter, Petra
    Med Univ Graz, Dept Neurol, Graz, Austria.
    Kavousi, Maryam
    Erasmus Univ, Med Ctr Rotterdam, Dept Epidemiol, Rotterdam, Netherlands.
    Kessler, Thorsten
    Tech Univ Munich, Klin Herz & Kreislauferkrankungen, Deutsch Herzzentrum Munchen, Munich, Germany.
    Kietselaer, Bas L.
    Maastricht Univ, Med Ctr, Maastricht, Netherlands;Maastricht Univ, Cardiovasc Res Inst Maastricht, Dept Cardiol, Maastricht, Netherlands.
    Kirchhof, Paulus
    Univ Birmingham, Inst Cardiovasc Sci, Birmingham, W Midlands, England;Sandwell & West Birmingham Hosp NHS Trust, Birmingham, W Midlands, England;Univ Hosp Birmingham NHS Fdn Trust, Birmingham, W Midlands, England;AFNET, Munster, Germany.
    Kleber, Marcus E.
    Heidelberg Univ, Med Fac Mannheim, Dept Med 5, Heidelberg, Germany.
    Knight, Stacey
    Intermt Med Ctr, Intermt Heart Inst, Murray, UT USA;Univ Utah, Dept Med, Salt Lake City, UT 84112 USA.
    Krieger, Jose E.
    Univ Sao Paulo, Heart Inst, Lab Genet & Mol Cardiol, Sao Paulo, Brazil.
    Kubo, Michiaki
    RIKEN, Ctr Integrat Med Sci, Yokohama, Kanagawa, Japan.
    Launer, Lenore J.
    NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA.
    Laurikka, Jari
    Univ Tampere, Fac Med & Life Sci, Finnish Cardiovasc Res Center Tampere, Tampere, Finland;Univ Tampere, Fac Med & Life Sci, Tampere Univ Hosp, Heart Ctr,Dept Cardiothoracic Surg, Tampere, Finland.
    Lehtimaki, Terho
    Univ Tampere, Fac Med & Life Sci, Dept Clin Chem, Fimlab Labs, Tampere, Finland;Univ Tampere, Fac Med & Life Sci, Finnish Cardiovasc Res Ctr Tampere, Tampere, Finland.
    Leineweber, Kirsten
    Bayer, Dept Dis Genom, Wuppertal, Germany.
    Lemaitre, Rozenn N.
    Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA.
    Li, Man
    Johns Hopkins Univ, Dept Epidemiol, Baltimore, MD USA;Univ Utah, Sch Med, Div Nephrol & Hypertens Internal Med, Salt Lake City, UT USA.
    Lim, Hong Euy
    Korea Univ, Guro Hosp, Seoul, South Korea.
    Lin, Henry J.
    Harbor UCLA Med Ctr, Dept Pediat, LABioMed, Inst Translat Genom & Populat Sci, Torrance, CA 90509 USA.
    Lin, Honghuang
    NHLBI, Framingham, MA USA;Boston Univ, Framingham Heart Study, Framingham, MA USA;Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Lindgren, Cecilia M.
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.
    Lokki, Marja-Liisa
    Univ Helsinki, Medicum, Transplantat Lab, Helsinki, Finland.
    London, Barry
    Univ Iowa, Div Cardiovasc Med, Abboud Cardiovasc Res Ctr, Iowa City, IA USA.
    Loos, Ruth J. F.
    Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA;Icahn Sch Med Mt Sinai, Genet Obes & Related Metab Traits Program, New York, NY 10029 USA;Icahn Sch Med Mt Sinai, Mindich Child Hlth & Dev Inst, New York, NY USA.
    Low, Siew-Kee
    RIKEN, Ctr Integrat Med Sci, Lab Stat Anal, Yokohama, Kanagawa, Japan.
    Lu, Yingchang
    Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA;Icahn Sch Med Mt Sinai, Genet Obes & Related Metab Traits Program, New York, NY 10029 USA.
    Lyytikainen, Leo-Pekka
    Univ Tampere, Fac Med & Life Sci, Dept Clin Chem, Fimlab Labs, Tampere, Finland;Univ Tampere, Fac Med & Life Sci, Finnish Cardiovasc Res Ctr Tampere, Tampere, Finland.
    Macfarlane, Peter W.
    Univ Glasgow, Coll Med Vet & Life Sci, Inst Hlth & Wellbeing, Glasgow, Lanark, Scotland.
    Magnusson, Patrik K.
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden.
    Mahajan, Anubha
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.
    Malik, Rainer
    Univ Hosp, LMU Munich, Inst Stroke & Dementia Res ISD, Munich, Germany.
    Mansur, Alfredo J.
    Univ Sao Paulo, Heart Inst, Sao Paulo, Brazil.
    Marcus, Gregory M.
    Univ Calif San Francisco, Div Cardiol, San Francisco, CA 94143 USA.
    Margolin, Lauren
    Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA USA.
    Margulies, Kenneth B.
    Univ Penn, Penn Cardiovasc Inst, Philadelphia, PA 19104 USA;Univ Penn, Dept Med, Perelman Sch Med, Philadelphia, PA 19104 USA.
    Maerz, Winfried
    Med Univ Graz, Clin Inst Med & Chem Lab Diagnost, Graz, Austria;Synlab Serv GmbH, Synlab Acad, Mannheim, Germany.
    McManus, David D.
    Univ Massachusetts, Med Sch Worcester, Worcester, MA 01605 USA.
    Melander, Olle
    Lund Univ, Dept Internal Med Clin Sci, Malmo, Sweden.
    Mohanty, Sanghamitra
    St Davids Med Ctr, Texas Cardiac Arrhythmia Inst, Austin, TX USA;Dell Med Sch, Austin, TX USA.
    Montgomery, Jay A.
    Vanderbilt Univ, Med Ctr, Dept Med, Nashville, TN USA.
    Morley, Michael P.
    Univ Penn, Penn Cardiovasc Inst, Philadelphia, PA 19104 USA;Univ Penn, Dept Med, Perelman Sch Med, Philadelphia, PA 19104 USA.
    Morris, Andrew P.
    Univ Liverpool, Dept Biostat, Liverpool, Merseyside, England.
    Mueller-Nurasyid, Martina
    Ludwig Maximilians Univ Munchen, Univ Hosp Munich, Dept Med 1, Munich, Germany;DZHK German Ctr Cardiovasc Res, Partner Site Munich Heart Alliance, Munich, Germany;Helmholtz Zentrum Munchen German Res Ctr Environm, Inst Genet Epidemiol, Neuherberg, Germany.
    Natale, Andrea
    St Davids Med Ctr, Texas Cardiac Arrhythmia Inst, Austin, TX USA;Dell Med Sch, Austin, TX USA.
    Nazarian, Saman
    Univ Penn, Philadelphia, PA USA.
    Neumann, Benjamin
    Ludwig Maximilians Univ Munchen, Univ Hosp Munich, Dept Med 1, Munich, Germany.
    Newton-Cheh, Christopher
    Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA USA;Massachusetts Gen Hosp, Ctr Genom Med, Boston, MA 02114 USA.
    Niemeijer, Maartje N.
    Erasmus Univ, Med Ctr Rotterdam, Dept Epidemiol, Rotterdam, Netherlands.
    Nikus, Kjell
    Tampere Univ Hosp, Dept Cardiol, Heart Ctr, Tampere, Finland;Univ Tampere, Fac Med & Life Sci, Tampere, Finland.
    Nilsson, Peter
    Lund Univ, Dept Clin Sci, Malmo, Sweden;Skane Univ Hosp, Malmo, Sweden.
    Noordam, Raymond
    Leiden Univ, Med Ctr, Dept Internal Med, Sect Gerontol & Geriatr, Leiden, Netherlands.
    Oellers, Heidi
    Atrial Fibrillat NETwork, Munster, Germany.
    Olesen, Morten S.
    Copenhagen Univ Hosp, Dept Cardiol, Heart Ctr, Lab Mol Cardiol,Rigshosp, Copenhagen, Denmark;Univ Copenhagen, Dept Biomed Sci, Danish Natl Res Fdn Ctr Cardiac Arrhythmia, Copenhagen, Denmark;Univ Copenhagen, Fac Hlth & Med Sci, Dept Clin Med, Copenhagen, Denmark.
    Orho-Melander, Marju
    Lund Univ, Dept Clin Sci, Malmo, Sweden.
    Padmanabhan, Sandosh
    Univ Glasgow, BHF Glasgow Cardiovasc Res Ctr, Inst Cardiovasc & Med Sci, Glasgow, Lanark, Scotland.
    Pak, Hui-Nam
    Yonsei Univ Hlth Syst, Seoul, South Korea.
    Pare, Guillaume
    McMaster Univ, Populat Hlth Res Inst, Hamilton, ON, Canada;McMaster Univ, Dept Pathol & Mol Med, Hamilton, ON, Canada.
    Pedersen, Nancy L.
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden.
    Pera, Joanna
    Jagiellonian Univ, Med Coll, Fac Med, Dept Neurol, Krakow, Poland.
    Pereira, Alexandre
    Univ Sao Paulo, Heart Inst, Lab Genet & Mol Biol, Sao Paulo, Brazil;Harvard Med Sch, Dept Genet, Boston, MA USA.
    Porteous, David
    Univ Edinburgh, Inst Genet & Mol Med, Ctr Genom & Expt Med, Generat Scotland, Edinburgh, Midlothian, Scotland.
    Psaty, Bruce M.
    Kaiser Permanente, Washington Hlth Res Inst, Seattle, WA USA;Univ Washington, Cardiovasc Hlth Res Unit, Dept Med, Seattle, WA 98195 USA;Univ Washington, Dept Epidemiol & Hlth Serv, Seattle, WA 98195 USA.
    Pulit, Sara L.
    Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA USA;Univ Utrecht, Univ Med Ctr Utrecht, Ctr Mol Med, Dept Genet, Utrecht, Netherlands;Univ Oxford, Big Data Inst, Li Ka Shing Ctr Hlth Informat & Discovery, Oxford, England.
    Pullinger, Clive R.
    Univ Calif San Francisco, Cardiovasc Res Inst, San Francisco, CA 94143 USA.
    Rader, Daniel J.
    Univ Penn, Perelman Sch Med, Dept Med, Div Cardiovasc Med, Philadelphia, PA USA.
    Refsgaard, Lena
    Copenhagen Univ Hosp, Dept Cardiol, Heart Ctr, Lab Mol Cardiol,Rigshosp, Copenhagen, Denmark;Univ Copenhagen, Dept Biomed Sci, Danish Natl Res Fdn Ctr Cardiac Arrhythmia, Copenhagen, Denmark;Univ Copenhagen, Fac Hlth & Med Sci, Dept Clin Med, Copenhagen, Denmark.
    Ribases, Marta
    Univ Autonoma Barcelona, Vall dHebron Res Inst VHIR, Grp Psychiat Mental Hlth & Addict, Psychiatr Genet Unit, Barcelona, Spain;Hosp Univ Vall dHebron, Dept Psychiat, Barcelona, Spain;Inst Salud Carlos III, Biomed Network Res Ctr Mental Hlth CIBERSAM, Madrid, Spain.
    Ridker, Paul M.
    Brigham & Womens Hosp, Div Prevent & Cardiovasc Med, 75 Francis St, Boston, MA 02115 USA;Harvard Med Sch, Boston, MA USA.
    Rienstra, Michiel
    Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, Groningen, Netherlands.
    Risch, Lorenz
    Univ Bern, Univ Inst Clin Chem, Bern, Switzerland;Lab Med Zentrum Dr Risch, Schaan, Liechtenstein.
    Roden, Dan M.
    Vanderbilt Univ, Med Ctr, Dept Med, Nashville, TN USA.
    Rosand, Jonathan
    Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA USA;Massachusetts Gen Hosp, Ctr Genom Med, Boston, MA 02114 USA.
    Rosenberg, Michael A.
    Massachusetts Gen Hosp, Ctr Genom Med, Boston, MA 02114 USA;Univ Colorado, Sch Med, Aurora, CO USA.
    Rost, Natalia
    Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA USA;Massachusetts Gen Hosp, J Philip Kistler Stroke Res Ctr, Boston, MA 02114 USA.
    Rotter, Jerome I.
    Harbor UCLA Med Ctr, LABioMed, Inst Translat Genom & Populat Sci, Dept Pediat, Torrance, CA 90509 USA;Harbor UCLA Med Ctr, LABioMed, Dept Med, Torrance, CA 90509 USA.
    Saba, Samir
    Univ Pittsburgh, Div Cardiol, Pittsburgh, PA USA.
    Sandhu, Roopinder K.
    Univ Alberta, Div Cardiol, Edmonton, AB, Canada.
    Schnabel, Renate B.
    Univ Heart Ctr Hamburg, Dept Gen & Intervent Cardiol, Hamburg, Germany;DZHK German Ctr Cardiovasc Res, Partner Site Hamburg Kiel Lubeck, Hamburg, Germany.
    Schramm, Katharina
    Ludwig Maximilians Univ Munchen, Univ Hosp Munich, Dept Med 1, Munich, Germany;Helmholtz Zentrum Munchen German Res Ctr Environm, Inst Genet Epidemiol, Neuherberg, Germany.
    Schunkert, Heribert
    DZHK German Ctr Cardiovasc Res, Partner Site Munich Heart Alliance, Munich, Germany;Tech Univ Munich, Klin Herz & Kreislauferkrankungen, Deutsch Herzzentrum Munchen, Munich, Germany.
    Schurman, Claudia
    Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA;Icahn Sch Med Mt Sinai, Genet Obes & Related Metab Traits Program, New York, NY 10029 USA.
    Scott, Stuart A.
    Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA.
    Seppala, Ilkka
    Univ Tampere, Fac Med & Life Sci, Dept Clin Chem, Fimlab Labs, Tampere, Finland;Univ Tampere, Fac Med & Life Sci, Finnish Cardiovasc Res Ctr Tampere, Tampere, Finland.
    Shaffer, Christian
    Vanderbilt Univ, Med Ctr, Dept Med, Nashville, TN USA.
    Shah, Svati
    Duke Univ, Sch Med, Dept Med, Div Cardiol, Durham, NC 27706 USA.
    Shalaby, Alaa A.
    Univ Pittsburgh, Div Cardiol, Pittsburgh, PA USA;Pittsburgh VA Healthcare Syst, Cardiol Div, Pittsburgh, PA USA.
    Shim, Jaemin
    Korea Univ, Anam Hosp, Seoul, South Korea.
    Shoemaker, M. Benjamin
    Vanderbilt Univ, Med Ctr, Dept Med, Nashville, TN USA.
    Siland, Joylene E.
    Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, Groningen, Netherlands.
    Sinisalo, Juha
    Univ Helsinki, Cent Hosp, Heart & Lung Ctr HUS, Helsinki, Finland.
    Sinner, Moritz F.
    Ludwig Maximilians Univ Munchen, Univ Hosp Munich, Dept Med 1, Munich, Germany;DZHK German Ctr Cardiovasc Res, Partner Site Munich Heart Alliance, Munich, Germany.
    Slowik, Agnieszka
    Jagiellonian Univ, Med Coll, Fac Med, Dept Neurol, Krakow, Poland.
    Smith, Albert V.
    Icelandic Heart Assoc, Kopavogur, Iceland;Univ Iceland, Fac Med, Reykavik, Iceland.
    Smith, Blair H.
    Univ Dundee, Div Populat Hlth Sci, Dundee, Scotland.
    Smith, J. Gustav
    Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA USA;Lund Univ, Dept Cardiol Clin Sci, Lund, Sweden;Skane Univ Hosp, Lund, Sweden.
    Smith, Jonathan D.
    Cleveland Clin, Dept Cardiovasc Med, Cleveland, OH USA;Cleveland Clin, Dept Cellular & Mol Med, Cleveland, OH USA;Cleveland Clin, Dept Mol Cardiol, Cleveland, OH USA;Cleveland Clin, Dept Quantitat Hlth Sci, Cleveland, OH USA.
    Smith, Nicholas L.
    Univ Washington, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA;Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA;Kaiser Permanente, Washington Hlth Res Inst, Seattle, WA USA.
    Soliman, Elsayed Z.
    Wake Forest Sch Med, Epidemiol Cardiol Res Ctr EPICARE, Winston Salem, NC USA.
    Sotoodehnia, Nona
    Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA;Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA.
    Stricker, Bruno H.
    Erasmus Univ, Med Ctr Rotterdam, Dept Epidemiol & Internal Med, Rotterdam, Netherlands;Inspectorate Hlth Care, Utrecht, Netherlands.
    Sun, Albert
    Duke Univ, Sch Med, Dept Med, Div Cardiol, Durham, NC 27706 USA.
    Sun, Han
    Cleveland Clin, Dept Cardiovasc Med, Cleveland, OH USA;Cleveland Clin, Dept Cellular & Mol Med, Cleveland, OH USA;Cleveland Clin, Dept Mol Cardiol, Cleveland, OH USA;Cleveland Clin, Dept Quantitat Hlth Sci, Cleveland, OH USA.
    Svendsen, Jesper H.
    Copenhagen Univ Hosp, Dept Cardiol, Heart Ctr, Lab Mol Cardiol,Rigshosp, Copenhagen, Denmark;Univ Copenhagen, Fac Hlth & Med Sci, Dept Clin Med, Copenhagen, Denmark.
    Tanaka, Toshihiro
    Tokyo Med & Dent Univ, Grad Sch Med & Dent Sci, Dept Human Genet & Dis Div, Tokyo, Japan.
    Tanriverdi, Kahraman
    Univ Massachusetts, Med Sch Worcester, Worcester, MA 01605 USA.
    Taylor, Kent D.
    Harbor UCLA Med Ctr, Dept Pediat, LABioMed, Inst Translat Genom & Populat Sci, Torrance, CA 90509 USA.
    Teder-Laving, Maris
    Univ Tartu, Estonian Genome Ctr, Tartu, Estonia.
    Teumer, Alexander
    Partner Site Greifswald, DZHK German Ctr Cardiovasc Res, Greifswald, Germany;Univ Med Greifswald, Inst Community Med, Greifswald, Germany.
    Theriault, Sebastien
    McMaster Univ, Populat Hlth Res Inst, Hamilton, ON, Canada;McMaster Univ, Dept Pathol & Mol Med, Hamilton, ON, Canada.
    Trompet, Stella
    Leiden Univ, Med Ctr, Dept Cardiol, Leiden, Netherlands;Leiden Univ, Med Ctr, Dept Internal Med, Sect Gerontol & Geriatr, Leiden, Netherlands.
    Tucker, Nathan R.
    Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA USA;Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA.
    Tveit, Arnljot
    Vestre Viken Hosp Trust, Baerum Hosp, Dept Med Res, Drammen, Norway;Univ Oslo, Inst Clin Med, Oslo, Norway.
    Uitterlinden, Andre G.
    Erasmus Univ, Med Ctr Rotterdam, Dept Epidemiol & Internal Med, Rotterdam, Netherlands.
    Van Der Harst, Pim
    Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, Groningen, Netherlands.
    Van Gelder, Isabelle C.
    Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, Groningen, Netherlands.
    Van Wagoner, David R.
    Cleveland Clin, Dept Cardiovasc Med, Cleveland, OH USA;Cleveland Clin, Dept Cellular & Mol Med, Cleveland, OH USA;Cleveland Clin, Dept Mol Cardiol, Cleveland, OH USA;Cleveland Clin, Dept Quantitat Hlth Sci, Cleveland, OH USA.
    Verweij, Niek
    Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, Groningen, Netherlands.
    Vlachopoulou, Efthymia
    Univ Helsinki, Medicum, Transplantat Lab, Helsinki, Finland.
    Voelker, Uwe
    Partner Site Greifswald, DZHK German Ctr Cardiovasc Res, Greifswald, Germany;Univ Med Ernst Moritz Arndt Univ Greifswald, Interfac Inst Genet & Funct Gen, Greifswald, Germany.
    Wang, Biqi
    Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA.
    Weeke, Peter E.
    Copenhagen Univ Hosp, Dept Cardiol, Heart Ctr, Lab Mol Cardiol,Rigshosp, Copenhagen, Denmark;Vanderbilt Univ, Med Ctr, Dept Med, Nashville, TN USA.
    Weijs, Bob
    Maastricht Univ, Med Ctr, Maastricht, Netherlands;Maastricht Univ, Cardiovasc Res Inst Maastricht, Dept Cardiol, Maastricht, Netherlands.
    Weiss, Raul
    Ohio State Univ, Div Cardiovasc Med, Columbus, OH 43210 USA.
    Weiss, Stefan
    Partner Site Greifswald, DZHK German Ctr Cardiovasc Res, Greifswald, Germany;Univ Med Ernst Moritz Arndt Univ Greifswald, Interfac Inst Genet & Funct Gen, Greifswald, Germany.
    Wells, Quinn S.
    Vanderbilt Univ, Med Ctr, Dept Med, Nashville, TN USA.
    Wiggins, Kerri L.
    Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA.
    Wong, Jorge A.
    McMaster Univ, Div Cardiol Hamilton Hlth Sci, Hamilton, ON, Canada.
    Woo, Daniel
    Univ Cincinnati, Coll Med, Cincinnati, OH USA.
    Worrall, Bradford B.
    Univ Virginia Hlth Syst, Dept Neurol, Charlottesville, VA USA;Univ Virginia Hlth Syst, Dept Publ Hlth Sci, Charlottesville, VA USA.
    Yang, Pil-Sung
    Yonsei Univ Hlth Syst, Seoul, South Korea.
    Yao, Jie
    Harbor UCLA Med Ctr, Dept Pediat, LABioMed, Inst Translat Genom & Populat Sci, Torrance, CA 90509 USA.
    Yoneda, Zachary T.
    Vanderbilt Univ, Med Ctr, Dept Med, Nashville, TN USA.
    Zeller, Tanja
    Univ Heart Ctr Hamburg, Dept Gen & Intervent Cardiol, Hamburg, Germany;DZHK German Ctr Cardiovasc Res, Partner Site Hamburg Kiel Lubeck, Hamburg, Germany.
    Zeng, Lingyao
    Tech Univ Munich, Klin Herz & Kreislauferkrankungen, Deutsch Herzzentrum Munchen, Munich, Germany.
    Lubitz, Steven A.
    Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA USA;Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA;Massachusetts Gen Hosp, Cardiac Arrhythmia Serv, Boston, MA 02114 USA.
    Lunetta, Kathryn L.
    NHLBI, Framingham, MA USA;Boston Univ, Framingham Heart Study, Framingham, MA USA;Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA.
    Ellinor, Patrick T.
    Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA USA;Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA;Massachusetts Gen Hosp, Cardiac Arrhythmia Serv, Boston, MA 02114 USA.
    Multi-ethnic genome-wide association study for atrial fibrillation2018In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 50, no 9, p. 1225-1233Article in journal (Refereed)
    Abstract [en]

    Atrial fibrillation (AF) affects more than 33 million individuals worldwide(1) and has a complex heritability(2). We conducted the largest meta-analysis of genome-wide association studies (GWAS) for AF to date, consisting of more than half a million individuals, including 65,446 with AF. In total, we identified 97 loci significantly associated with AF, including 67 that were novel in a combined-ancestry analysis, and 3 that were novel in a European-specific analysis. We sought to identify AF-associated genes at the GWAS loci by performing RNA-sequencing and expression quantitative trait locus analyses in 101 left atrial samples, the most relevant tissue for AF. We also performed transcriptome-wide analyses that identified 57 AF-associated genes, 42 of which overlap with GWAS loci. The identified loci implicate genes enriched within cardiac developmental, electrophysiological, contractile and structural pathways. These results extend our understanding of the biological pathways underlying AF and may facilitate the development of therapeutics for AF.

  • 241.
    Ruge, Toralph
    et al.
    Karolinska Inst, Dept Med, Stockholm, Sweden; Karolinska Inst, Dept Med, Stockholm, Sweden.
    Carlsson, Axel C
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Karolinska Inst, Dept Neurobiol Care Sci & Soc, Div Family Med & Primary Care, Huddinge, Sweden.
    Ingelsson, Erik
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Stanford Univ, Sch Med, Div Cardiovasc Med, Stanford, CA USA.
    Risérus, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Sundström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Ärnlöv, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Center for Clinical Research Dalarna. Karolinska Inst, Dept Neurobiol Care Sci & Soc, Div Family Med & Primary Care, Huddinge, Sweden.
    Circulating endostatin and the incidence of heart failure.2018In: Scandinavian Cardiovascular Journal, ISSN 1401-7431, E-ISSN 1651-2006, Vol. 52, no 5, p. 244-249Article in journal (Refereed)
    Abstract [en]

    Objective: Circulating levels of endostatin are elevated in many underlying conditions leading to heart failure such as hypertension, diabetes, chronic kidney disease and ischemic heart disease. Yet, the association between endostatin and the incidence of heart failure has not been reported previously in the community.

    Design: We investigated the longitudinal association between serum endostatin levels and incident heart failure in two community-based cohorts of elderly: Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS, n = 966; mean age 70 years, 51% women, 81 events, mean follow-up 10 years) and Uppsala Longitudinal Study of Adult Men (ULSAM, n = 747 men; mean age 78 years, 98 heart failure events, mean follow-up 8 years). We also investigated the cross-sectional association between endostatin and echocardiographic left ventricular systolic function and diastolic function (ejection fraction and E/A-ratio, respectively).

    Results: Higher serum endostatin was associated with an increased risk for heart failure in both cohorts after adjustment for established heart failure risk factors, glomerular filtration rate and N-terminal pro-brain natriuretic peptide (NT-proBNP) (PIVUS: multivariable hazard ratio (HR) per 1-standard deviation (SD) increase, HR 1.46 (95%CI, 1.17-1.82, p < .001); ULSAM: HR 1.29 (95%CI, 1.00-1.68, p < .05). In cross-sectional analyses at baseline, higher endostatin was significantly associated with both worsened left ventricular systolic and diastolic function in both cohorts.

    Conclusion: Higher serum endostatin was associated with left ventricular dysfunction and an increased heart failure risk in two community-based cohorts of elderly. Our findings encourage further experimental studies that investigate the role of endostatin in the development of heart failure.

  • 242. Ruge, Toralph
    et al.
    Carlsson, Axel C
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Larsson, Tobias E
    Carrero, Juan-Jesús
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Ärnlöv, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Endostatin Level is Associated with Kidney Injury in the Elderly: Findings from Two Community-Based Cohorts2014In: American Journal of Nephrology, ISSN 0250-8095, E-ISSN 1421-9670, Vol. 40, no 5, p. 417-424Article in journal (Refereed)
    Abstract [en]

    Background: We aimed to investigate the associations between circulating endostatin and the different aspects of renal dysfunction, namely, estimated (cystatin C) glomerular filtration rate (GFR) and urine albumin-creatinine ratio (ACR).

    Methods: Two independent longitudinal community-based cohorts of elderly. ULSAM, n = 786 men; age 78 years; median GFR 74 ml/min/1.73 m(2); median ACR 0.80 mg/mmol); and PIVUS, n = 815; age 75 years; 51% women; median GFR; 67 ml/min/1.73 m(2); median ACR 1.39 mg/mmol. Cross-sectional associations between the endostatin levels and GFR as well as ACR, and longitudinal association between endostatin at baseline and incident CKD (defined as GFR <60 ml/min/1.73 m(2)) were assessed.

    Results: In cross-sectional regression analyses adjusting for age, gender, inflammation, and cardiovascular risk factors, serum endostatin was negatively associated with GFR (ULSAM: B-coefficient per SD increase -0.51, 95% CI (-0.57, -0.45), p < 0.001; PIVUS -0.47, 95% CI (-0.54, -0.41), p < 0.001) and positively associated with ACR (ULSAM: B-coefficient per SD increase 0.24, 95% CI (0.15, 0.32), p < 0.001; PIVUS 0.13, 95% CI (0.06-0.20), p < 0.001) in both cohorts. Moreover, in longitudinal multivariable analyses, higher endostatin levels were associated with increased risk for incident CKD defined as GFR <60 ml/min/1.73 m(2) at re-investigations in both ULSAM (odds ratio per SD increase of endostatin 1.39 (95% CI 1.01-1.90) and PIVUS 1.68 (95% CI 1.36-2.07)).

    Conclusions: Higher circulating endostatin is associated with lower GFR and higher albuminuria and independently predicts incident CKD in elderly subjects. Further studies are warranted to investigate the underlying mechanisms linking endostatin to kidney pathology, and to evaluate the clinical relevance of our findings.

  • 243.
    Saleheen, Danish
    et al.
    Univ Penn, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA.;Ctr Noncommunicable Dis, Karachi, Pakistan..
    Zhao, Wei
    Univ Penn, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA..
    Young, Robin
    Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England..
    Nelson, Christopher P.
    Univ Leicester, Dept Cardiovascular Sci, Leicester, Leics, England..
    Ho, WeangKee
    Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England..
    Ferguson, Jane F.
    Vanderbilt Univ, Dept Med, Cardiol Div, Nashville, TN USA..
    Rasheed, Asif
    Ctr Noncommunicable Dis, Karachi, Pakistan..
    Ou, Kristy
    Vanderbilt Univ, Dept Med, Cardiol Div, Nashville, TN USA..
    Nurnberg, Sylvia T.
    Univ Penn, Perelman Sch Med, Dept Med, Div Translat Med & Human Genet, Philadelphia, PA 19104 USA..
    Bauer, Robert C.
    Columbia Univ, Med Ctr, Dept Med, Cardiol Div, New York, NY USA.;Columbia Univ, Med Ctr, Irving Inst Clin & Translat Res, New York, NY USA..
    Goel, Anuj
    Univ Oxford, Radcliffe Dept Med, Div Cardiovasc Med, Oxford, England.;Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England..
    Do, Ron
    Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA.;Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA..
    Stewart, Alexandre F. R.
    Univ Ottawa, Heart Inst, Ruddy Canadian Cardiovasc Genet Ctr, Ottawa, ON, Canada..
    Hartiala, Jaana
    Univ Southern Calif, Keck Sch Med, Inst Med Genet, Los Angeles, CA USA.;Univ Southern Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA USA..
    Zhang, Weihua
    Imperial Coll London, Dept Epidemiol & Biostat, London, England.;Ealing Hosp NHS Trust, Dept Cardiol, Southall, Middx, England..
    Thorleifsson, Gudmar
    deCODE Genet, Sturlugata 8, IS-101 Reykjavik, Iceland.;Univ Iceland, Sch Med, Reykjavik, Iceland..
    Strawbridge, Rona J.
    Karolinska Inst, Cardiovasc Med Unit, Dept Med Solna, Stockholm, Sweden..
    Sinisalo, Juha
    Helsinki Univ Cent Hosp HUCH Heart & Lung Ctr, Helsinki, Uusimaa, Finland..
    Kanoni, Stavroula
    William Harvey Res Inst, Barts, England.;Queen Mary Univ London, London Sch Med & Dent, London, England..
    Sedaghat, Sanaz
    Erasmus Univ, Med Ctr, Dept Epidemiol, Rotterdam, Netherlands..
    Marouli, Eirini
    William Harvey Res Inst, Barts, England.;Queen Mary Univ London, London Sch Med & Dent, London, England.;Harokopio Univ, Dept Dietet Nutr, Athens, Greece..
    Kristiansson, Kati
    Natl Inst Hlth & Welf, Helsinki, Finland..
    Zhao, Jing Hua
    Univ Cambridge, Sch Clin Med, Inst Metab Sci, MRC Epidemiol Unit, Cambridge Biomed Campus, Cambridge, England..
    Scott, Robert
    Univ Cambridge, Sch Clin Med, Inst Metab Sci, MRC Epidemiol Unit, Cambridge Biomed Campus, Cambridge, England..
    Gauguier, Dominique
    INSERM, UMRS1138, Ctr Rech Cordeliers, Paris, France..
    Shah, Svati H.
    Duke Univ, Med Ctr, Dept Med, Div Cardiol, Durham, NC 27710 USA..
    Smith, Albert Vernon
    Iceland Heart Assoc, Kopavogur, Iceland.;Univ Iceland, Fac Med, Reykjavik, Iceland..
    van Zuydam, Natalie
    Univ Dundee, Med Res Inst, Ninewells Hosp & Med Sch, Dundee, Scotland..
    Cox, Amanda J.
    Wake Forest Sch Med, Ctr Genom & Personalized Med Res, Winston Salem, NC USA..
    Willenborg, Christina
    Univ Lubeck, Inst Integrat & Experimentelle Genom, Lubeck, Germany.;DZHK German Res Ctr Cardiovasc Res, Hamburg, Germany..
    Kessler, Thorsten
    Tech Univ Munich, Deutsch Herzzentrum Munchen, Munich, Germany.;Klinikum Rechts Der Isar, Munich, Germany..
    Zeng, Lingyao
    Tech Univ Munich, Deutsch Herzzentrum Munchen, Munich, Germany.;DZHK German Res Ctr Cardiovasc Res, Partner Site Munich Heart Alliance, Munich, Germany..
    Province, Michael A.
    Washington Univ, Sch Med, Dept Genet, St Louis, MO USA..
    Ganna, Andrea
    Massachusetts Gen Hosp, Dept Med, Analyt & Translat Genet Unit, Boston, MA 02114 USA.;Harvard Med Sch, Boston, MA 02114 USA.;Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA USA..
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Pedersen, Nancy L.
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    White, Charles C.
    Boston Univ, Sch Publ Hlth Framingham Heart Study, Dept Biostat, Boston, MA 02215 USA..
    Joensuu, Anni
    Natl Inst Hlth & Welf, Helsinki, Finland.;Univ Helsinki, Inst Mol Med, Helsinki, Finland..
    Kleber, Marcus Edi
    Heidelberg Univ, Mannheim Med Fac, Dept Med, Heidelberg, Germany..
    Hall, Alistair S.
    Univ Leeds, Leeds Inst Genet Hlth & Therapeut, Leeds, W Yorkshire, England..
    Maerz, Winfried
    Synlab Serv GmbH, Synlab Acad, Mannheim, Germany.;Med Univ Graz, Clin Inst Med & Chem Lab Diagnost, Graz, Austria..
    Salomaa, Veikko
    Natl Inst Hlth & Welf, Helsinki, Finland..
    O'Donnell, Christopher
    NHLBI, Bldg 10, Bethesda, MD 20892 USA.;NIH, Framingham Heart Study, Bethesda, MD USA..
    Ingelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Feitosa, Mary F.
    Washington Univ, Sch Med, Dept Genet, St Louis, MO USA..
    Erdmann, Jeanette
    Univ Lubeck, Inst Integrat & Experimentelle Genom, Lubeck, Germany.;DZHK German Res Ctr Cardiovasc Res, Hamburg, Germany..
    Bowden, Donald W.
    Wake Forest Sch Med, Ctr Genom & Personalized Med Res, Winston Salem, NC USA..
    Palmer, Colin N. A.
    Univ Dundee, Med Res Inst, Ninewells Hosp & Med Sch, Dundee, Scotland..
    Gudnason, Vilmundur
    Iceland Heart Assoc, Kopavogur, Iceland.;Univ Iceland, Fac Med, Reykjavik, Iceland..
    De Faire, Ulf
    Karolinska Inst, Inst Environm Med, Div Cardiovasc Epidemiol, Stockholm, Sweden..
    Zalloua, Pierre
    Lebanese Amer Univ, Sch Med, Beirut, Lebanon..
    Wareham, Nicholas
    INSERM, UMRS1138, Ctr Rech Cordeliers, Paris, France..
    Thompson, John R.
    Univ Leicester, Dept Hlth Sci, Leicester, Leics, England..
    Kuulasmaa, Kari
    Natl Inst Hlth & Welf, Helsinki, Finland..
    Dedoussis, George
    Harokopio Univ, Dept Dietet Nutr, Athens, Greece..
    Perola, Markus
    Natl Inst Hlth & Welf, Helsinki, Finland.;Univ Helsinki, Inst Mol Med, Helsinki, Finland..
    Dehghan, Abbas
    Erasmus Univ, Med Ctr, Dept Epidemiol, Rotterdam, Netherlands..
    Chambers, John C.
    Imperial Coll London, Dept Epidemiol & Biostat, London, England.;Ealing Hosp NHS Trust, Dept Cardiol, Southall, Middx, England.;Imperial Coll Healthcare NHS Trust, London, England..
    Kooner, Jaspal
    Imperial Coll London, Dept Epidemiol & Biostat, London, England.;Imperial Coll Healthcare NHS Trust, London, England.;Imperial Coll London, Natl Heart & Lung Inst, Cardiovasc Sci, London, England..
    Allayee, Hooman
    Univ Southern Calif, Keck Sch Med, Inst Med Genet, Los Angeles, CA USA.;Univ Southern Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA USA..
    Deloukas, Panos
    William Harvey Res Inst, Barts, England.;Queen Mary Univ London, London Sch Med & Dent, London, England.;King Abdulaziz Univ, Princess Al Jawhara Al Brahim Ctr Excellence Res, Jeddah, Saudi Arabia..
    McPherson, Ruth
    Univ Ottawa, Heart Inst, Ruddy Canadian Cardiovasc Genet Ctr, Ottawa, ON, Canada..
    Stefansson, Kari
    deCODE Genet, Sturlugata 8, IS-101 Reykjavik, Iceland.;Univ Iceland, Sch Med, Reykjavik, Iceland..
    Schunkert, Heribert
    Tech Univ Munich, Deutsch Herzzentrum Munchen, Munich, Germany.;DZHK German Res Ctr Cardiovasc Res, Partner Site Munich Heart Alliance, Munich, Germany..
    Kathiresan, Sekar
    MIT, Broad Inst, Cambridge, MA 02139 USA.;Harvard Univ, Cambridge, MA 02138 USA.;Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA USA.;Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA.;Harvard Med Sch, Dept Med, Boston, MA USA..
    Farrall, Martin
    Univ Oxford, Radcliffe Dept Med, Div Cardiovasc Med, Oxford, England.;Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England..
    Frossard, Philippe Marcel
    Ctr Noncommunicable Dis, Karachi, Pakistan..
    Rader, Daniel J.
    Univ Penn, Dept Genet, Philadelphia, PA 19104 USA.;Univ Penn, Perelman Sch Med, Dept Med, Div Translat Med & Human Genet, Philadelphia, PA 19104 USA..
    Samani, Nilesh J.
    Univ Leicester, Dept Cardiovascular Sci, Leicester, Leics, England..
    Reilly, Muredach P.
    Columbia Univ, Med Ctr, Dept Med, Cardiol Div, New York, NY USA.;Columbia Univ, Med Ctr, Irving Inst Clin & Translat Res, New York, NY USA..
    Loss of Cardioprotective Effects at the ADAMTS7 Locus as a Result of Gene-Smoking Interactions2017In: Circulation, ISSN 0009-7322, E-ISSN 1524-4539, Vol. 135, no 24, p. 2336-2353Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Common diseases such as coronary heart disease (CHD) are complex in etiology. The interaction of genetic susceptibility with lifestyle factors may play a prominent role. However, gene-lifestyle interactions for CHD have been difficult to identify. Here, we investigate interaction of smoking behavior, a potent lifestyle factor, with genotypes that have been shown to associate with CHD risk.

    METHODS: We analyzed data on 60 919 CHD cases and 80 243 controls from 29 studies for gene-smoking interactions for genetic variants at 45 loci previously reported to be associated with CHD risk. We also studied 5 loci associated with smoking behavior. Study-specific gene-smoking interaction effects were calculated and pooled using fixed-effects meta-analyses. Interaction analyses were declared to be significant at a P value of < 1.0x10-3 (Bonferroni correction for 50 tests).

    RESULTS: We identified novel gene-smoking interaction for a variant upstream of the ADAMTS7 gene. Every T allele of rs7178051 was associated with lower CHD risk by 12% in never-smokers (P= 1.3x10(-16)) in comparison with 5% in ever-smokers (P= 2.5x10-4), translating to a 60% loss of CHD protection conferred by this allelic variation in people who smoked tobacco (interaction P value= 8.7x10-5). The protective T allele at rs7178051 was also associated with reduced ADAMTS7 expression in human aortic endothelial cells and lymphoblastoid cell lines. Exposure of human coronary artery smooth muscle cells to cigarette smoke extract led to induction of ADAMTS7.

    CONCLUSIONS: Allelic variation at rs7178051 that associates with reduced ADAMTS7 expression confers stronger CHD protection in never-smokers than in ever-smokers. Increased vascular ADAMTS7 expression may contribute to the loss of CHD protection in smokers.

  • 244.
    Salihovic, Samira
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab. MTM Research Centre, School of Science and Technology, Örebro University.
    Fall, Tove
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Ganna, Andrea
    Broeckling, Corey D
    Prenni, Jessica E
    Hyötyläinen, Tuulia
    Kärrman, Anna
    Lind, P. Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Ingelsson, Erik
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Identification of metabolic profiles associated with human exposure to perfluoroalkyl substances.2019In: Journal of Exposure Science and Environmental Epidemiology, ISSN 1559-0631, E-ISSN 1559-064X, Vol. 29, no 2, p. 196-205Article in journal (Refereed)
    Abstract [en]

    Recent epidemiological studies suggest that human exposure to perfluoroalkyl substances (PFASs) may be associated with type 2 diabetes and other metabolic phenotypes. To gain further insights regarding PFASs exposure in humans, we here aimed to characterize the associations between different PFASs and the metabolome. In this cross-sectional study, we investigated 965 individuals from Sweden (all aged 70 years, 50% women) sampled in 2001-2004. PFASs were analyzed in plasma using isotope-dilution ultra-pressure liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS). Non-target metabolomics profiling was performed in plasma using UPLC coupled to time-of-flight mass spectrometry (UPLC-QTOFMS) operated in positive electrospray mode. Multivariate linear regression analysis was used to investigate associations between circulating levels of PFASs and metabolites. In total, 15 metabolites, predominantly from lipid pathways, were associated with levels of PFASs following adjustment for sex, smoking, exercise habits, education, energy, and alcohol intake, after correction for multiple testing. Perfluorononanoic acid (PFNA) and perfluoroundecanoic acid (PFUnDA) were strongly associated with multiple glycerophosphocholines and fatty acids including docosapentaenoic acid (DPA) and docosahexaenoic acid (DHA). We also found that the different PFASs evaluated were associated with distinctive metabolic profiles, suggesting potentially different biochemical pathways in humans.

  • 245.
    Salihovic, Samira
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. MTM Research Centre, School of Science and Technology, Örebro University, SE-701 82 Örebro, Sweden.
    Kärrman, Anna
    MTM Research Centre, School of Science and Technology, Örebro University, SE-701 82 Örebro, Sweden.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Lind, P. Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Lindström, Gunilla
    MTM Research Centre, School of Science and Technology, Örebro University, SE-701 82 Örebro, Sweden.
    van Bavel, Bert
    MTM Research Centre, School of Science and Technology, Örebro University, SE-701 82 Örebro, Sweden.
    Perfluoroalkyl substances (PFAS) including structural PFOS isomers in plasma from elderly men and women from Sweden: Results from the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS)2015In: Environment International, ISSN 0160-4120, E-ISSN 1873-6750, Vol. 82, p. 21-27Article in journal (Refereed)
    Abstract [en]

    Per- and polyfluoroalkyl substances (PFASs) are a class of compounds with unique chemical properties that have been shown useful in a wide variety of applications because they provide materials with reduced surface tension and exceptional non-stick properties. PFASs are commonly found in impregnation materials, coatings of papers and textiles, fire-fighting foams, pesticides, and cleaning agents. The potential for human exposure to PFASs is high because of their widespread distribution. The aim of this study was to investigate levels of PFASs in men and women from Sweden and to assess the influence of gender and parity among women. Levels of 13 PFASs were determined in plasma samples collected during 2001-2004 from 1016 (507 women) 70 year-old participants from the population-based Prospective Study of the Vasculature in Uppsala Seniors (PIVUS). The PFASs studied were nine perfluorinated carboxylic acids (PFCAs), four perfluorinated sulfonic acids (PFSAs) and perfluorooctane sulfonamide (PFOSA). In addition, structural isomers of perfluorooctane sulfonic acid (PFOS) were determined in a subset of 398 individuals. The detection rates were high and the majority of the studied compounds were detected in more than 75% of the participants. Levels of the selected analytes were found to be similar to other studies of non-occupationally exposed populations. Gender differences were observed in levels of PFHpA which was higher in men, while PFHxS was higher in women. Parity among women was shown to have a minor effect on PFAS concentrations and we found primi- and multiparous women to have slightly lower levels of PFUnDA when compared to nulliparous women.

  • 246.
    Salihovic, Samira
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Orebro Univ, Sch Sci & Technol, MTM Res Ctr, Orebro, Sweden.
    Stubleski, Jordan
    Orebro Univ, Sch Sci & Technol, MTM Res Ctr, Orebro, Sweden.
    Kärrman, Anna
    Orebro Univ, Sch Sci & Technol, MTM Res Ctr, Orebro, Sweden.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Fall, Tove
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Lind, P. Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Changes in markers of liver function in relation to changes in perfluoroalkyl substances - A longitudinal study2018In: Environment International, ISSN 0160-4120, E-ISSN 1873-6750, Vol. 117, p. 196-203Article in journal (Refereed)
    Abstract [en]

    Background: While it is known that perfluoroalkyl substances (PFASs) induce liver toxicity in experimental studies, the evidence of an association in humans is inconsistent.

    Objective: The main aim of the present study was to examine the association of PFAS concentrations and markers of liver function using panel data.

    Methods: We investigated 1002 individuals from Sweden (50% women) at ages 70, 75 and 80 in 2001-2014. Eight PFASs were measured in plasma using isotope dilution ultra-performance liquid chromatography/tandem mass spectrometry (UPLC-MS/MS). Bilirubin and hepatic enzymes alanine aminotransferase (ALT), alkaline phosphatase (ALP), and gamma-glutamyltransferase (GGT) were determined in serum using an immunoassay methodology. Mixed-effects linear regression models were used to examine the relationship between the changes in markers of liver function and changes in PFAS levels.

    Results: The changes in majority of PFAS concentrations were positively associated with the changes in activity of ALT, ALP, and GGT and inversely associated with the changes in circulating bilirubin after adjustment for gender and the time-updated covariates LDL- and HDL-cholesterol, serum triglycerides, BMI, statin use, smoking, fasting glucose levels and correction for multiple testing. For example, changes in perfluorononanoic acid (PFNA) were associated with the changes liver function markers beta(BILIRUBIN) = -1.56, 95% confidence interval (CI) -1.93 to -1.19, beta(ALT)= 0.04, 95% CI 0.03-0.06, and beta(ALP)= 0.11, 95% CI 0.06-0.15.

    Conclusion: Our longitudinal assessment established associations between changes in markers of liver function and changes in plasma PFAS concentrations. These findings suggest a relationship between low-dose background PFAS exposure and altered liver function in the general population.

  • 247.
    Schmidt, Amand F.
    et al.
    UCL, Inst Cardiovasc Sci, London NW1 2DA, England.;UCL, UCL Inst Hlth Informat, Farr Inst Hlth Informat Res, London, England..
    Swerdlow, Daniel I.
    UCL, Inst Cardiovasc Sci, London NW1 2DA, England.;Imperial Coll London, Dept Med, Fac Med, London, England..
    Holmes, Michael V.
    Univ Oxford, Clin Trial Serv Unit, Nuffield Dept Populat Hlth, Oxford, England.;Univ Oxford, Epidemiol Studies Unit CTSU, Nuffield Dept Populat Hlth, Oxford, England.;Univ Oxford, Med Res Council, Populat Hlth Res Unit, Oxford, England..
    Patel, Riyaz S.
    UCL, Inst Cardiovasc Sci, London NW1 2DA, England.;UCL, UCL Inst Hlth Informat, Farr Inst Hlth Informat Res, London, England.;St Bartholomews Hosp, Barts Heart Ctr, London, England..
    Fairhurst-Hunter, Zammy
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England..
    Lyall, Donald M.
    Univ Glasgow, Inst Hlth & Wellbeing, Glasgow, Lanark, Scotland..
    Hartwig, Fernando Pires
    Univ Fed Pelotas, Postgrad Program Epidemiol, Pelotas, Brazil..
    Horta, Bernardo Lessa
    Univ Fed Pelotas, Postgrad Program Epidemiol, Pelotas, Brazil..
    Hypponen, Elina
    Univ South Australia, Ctr Populat Hlth Res, Sansom Inst Hlth Res, Adelaide, SA, Australia.;UCL Great Ormond St Inst Child Hlth, Populat Policy & Practice, London, England.;South Australian Hlth & Med Res Inst, Adelaide, SA, Australia..
    Power, Christine
    UCL Great Ormond St Inst Child Hlth, Populat Policy & Practice, London, England..
    Moldovan, Max
    Univ South Australia, Sch Hlth Sci, Adelaide, SA, Australia.;EMBL Australia, South Australian Hlth & Med Res Inst, Adelaide, SA, Australia..
    van Iperen, Erik
    Netherlands Heart Inst, Durrer Ctr Cardiovasc Res, Utrecht, Netherlands.;Acad Med Ctr, Dept Clin Epidemiol Biostat & Bioinformat, Amsterdam, Netherlands..
    Hovingh, G. Kees
    Acad Med Ctr, Dept Vasc Med, Amsterdam, Netherlands..
    Demuth, Ilja
    Charite Univ Med Berlin, Charite Res Grp Geriatr, Berlin, Germany.;Charite Univ Med Berlin, Inst Med & Human Genet, Berlin, Germany..
    Norman, Kristina
    Charite Univ Med Berlin, Charite Res Grp Geriatr, Berlin, Germany..
    Steinhagen-Thiessen, Elisabeth
    Charite Univ Med Berlin, Charite Res Grp Geriatr, Berlin, Germany..
    Demuth, Juri
    E CA Econ GmbH, Berlin, Germany..
    Bertram, Lars
    Imperial Coll London, Neuroepidemiol & Ageing Res Unit, Fac Med, London, England.;Univ Lubeck, Lubeck Interdisciplinary Platform Genome Analyt L, Inst Neurogenet, Lubeck, Germany.;Univ Lubeck, Lubeck Interdisciplinary Platform Genome Analyt L, Inst Integrat & Expt Genom, Lubeck, Germany..
    Liu, Tian
    Max Planck Inst Human Dev, Berlin, Germany.;Max Planck Inst Mol Genet, Berlin, Germany..
    Coassin, Stefan
    Med Univ Innsbruck, Dept Med Genet Mol & Clin Pharmacol, Div Genet Epidemiol Innsbruck, Innsbruck, Austria..
    Willeit, Johann
    Med Univ Innsbruck, Dept Neurol, Innsbruck, Austria..
    Kiechl, Stefan
    Med Univ Innsbruck, Dept Neurol, Innsbruck, Austria..
    Willeit, Karin
    Med Univ Innsbruck, Dept Neurol, Innsbruck, Austria..
    Mason, Dan
    Bradford Royal Infirm, Bradford Inst Hlth Res, Bradford, W Yorkshire, England..
    Wright, John
    Bradford Royal Infirm, Bradford Inst Hlth Res, Bradford, W Yorkshire, England..
    Morris, Richard
    Univ Bristol, Sch Social & Community Med, Bristol, Avon, England..
    Wanamethee, Goya
    UCL, Dept Primary Care & Populat Hlth, London, England..
    Whincup, Peter
    St Georges Univ London, Populat Hlth Res Inst, London, England..
    Ben-Shlomo, Yoav
    Univ Bristol, Sch Social & Community Med, Bristol, Avon, England..
    McLachlan, Stela
    Univ Edinburgh, Ctr Populat Hlth Sci, Usher Inst Populat Hlth Sci & Informat, Edinburgh, Midlothian, Scotland..
    Price, Jackie F.
    Univ Edinburgh, Ctr Populat Hlth Sci, Usher Inst Populat Hlth Sci & Informat, Edinburgh, Midlothian, Scotland..
    Kivimaki, Mika
    UCL, UCL Inst Epidemiol & Hlth Care, Dept Epidemiol & Publ Hlth, London, England..
    Welch, Catherine
    UCL, UCL Inst Epidemiol & Hlth Care, Dept Epidemiol & Publ Hlth, London, England..
    Sanchez-Galvez, Adelaida
    UCL, UCL Inst Epidemiol & Hlth Care, Dept Epidemiol & Publ Hlth, London, England..
    Marques-Vidal, Pedro
    Univ Lausanne Hosp, Dept Med, Internal Med Unit, Lausanne, Switzerland..
    Nicolaides, Andrew
    Imperial Coll London, Dept Vasc Surg, Fac Med, London, England.;Univ Nicosia, Nicosia Med Sch, Dept Surg, Nicosia, Cyprus..
    Panayiotou, Andrie G.
    Cyprus Univ Technol, Cyprus Int Inst Environm & Publ Hlth, Limassol, Cyprus..
    Onland-Moret, N. Charlotte
    Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, Utrecht, Netherlands..
    van der Schouw, Yvonne T.
    Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, Utrecht, Netherlands..
    Matullo, Giuseppe
    Human Genet Fdn, Turin, Italy.;Univ Turin, Dept Med Sci, Turin, Italy..
    Fiorito, Giovanni
    Human Genet Fdn, Turin, Italy.;Univ Turin, Dept Med Sci, Turin, Italy..
    Guarrera, Simonetta
    Human Genet Fdn, Turin, Italy.;Univ Turin, Dept Med Sci, Turin, Italy..
    Sacerdote, Carlotta
    San Giovanni Battista Hosp, Canc Epidemiol Unit, Turin, Italy.;CPO Piemonte, Ctr Oncol Prevent, Turin, Italy..
    Wareham, Nicholas J.
    Univ Cambridge, Sch Clin Med, MRC Epidemiol Unit, Inst Metab Sci, Cambridge, England..
    Langenberg, Claudia
    Univ Cambridge, Sch Clin Med, MRC Epidemiol Unit, Inst Metab Sci, Cambridge, England..
    Scott, Robert
    Univ Cambridge, Sch Clin Med, MRC Epidemiol Unit, Inst Metab Sci, Cambridge, England..
    Luan, Jian'an
    Univ Cambridge, Sch Clin Med, MRC Epidemiol Unit, Inst Metab Sci, Cambridge, England..
    Bobak, Martin
    UCL, UCL Inst Epidemiol & Hlth Care, Dept Epidemiol & Publ Hlth, London, England..
    Malyutina, Sofi A.
    Novosibirsk State Med Univ, Novosibirsk, Russia.;Russian Acad Med Sci, Inst Internal & Prevent Med, Siberian Branch, Novosibirsk, Russia..
    Pajak, Andrzej
    Jagiellonian Univ, Coll Med, Krakow, Poland..
    Kubinova, Ruzena
    Natl Inst Publ Hlth, Prague, Czech Republic..
    Tamosiunas, Abdonas
    Lithuanian Univ Hlth Sci, Kaunas, Lithuania..
    Pikhart, Hynek
    UCL, UCL Inst Epidemiol & Hlth Care, Dept Epidemiol & Publ Hlth, London, England..
    Husemoen, Lise Lotte Nystrup
    Capital Reg Denmark, Res Ctr Prevent & Hlth, Copenhagen, Denmark..
    Grarup, Niels
    Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn, Ctr Basic Metab Res, Copenhagen, Denmark..
    Pedersen, Oluf
    Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn, Ctr Basic Metab Res, Copenhagen, Denmark..
    Hansen, Torben
    Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn, Ctr Basic Metab Res, Copenhagen, Denmark..
    Linneberg, Allan
    Capital Reg Denmark, Res Ctr Prevent & Hlth, Copenhagen, Denmark.;Rigshosp, Dept Clin Expt Res, Copenhagen, Denmark.;Univ Copenhagen, Fac Hlth & Med Sci, Dept Clin Med, Copenhagen, Denmark..
    Simonsen, Kenneth Starup
    Capital Reg Denmark, Res Ctr Prevent & Hlth, Copenhagen, Denmark..
    Cooper, Jackie
    UCL, Ctr Cardiovasc Genet, London, England..
    Humphries, Steve E.
    UCL, Ctr Cardiovasc Genet, London, England..
    Brilliant, Murray
    Marshfield Clin Res Fdn, Ctr Human Genet, Marshfield, WI USA..
    Kitchner, Terrie
    Marshfield Clin Res Fdn, Ctr Human Genet, Marshfield, WI USA..
    Hakonarson, Hakon
    Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA..
    Carrell, David S.
    Grp Hlth Res Inst, Seattle, WA USA..
    McCarty, Catherine A.
    Essentia Inst Rural Hlth, Duluth, MN USA..
    Kirchner, H. Lester
    Geisinger Med Clin, Ctr Hlth Res, Danville, PA USA..
    Larson, Eric B.
    Grp Hlth Res Inst, Seattle, WA USA..
    Crosslin, David R.
    Grp Hlth Res Inst, Seattle, WA USA..
    de Andrade, Mariza
    Mayo Clin, Div Biomed Stat & Informat, Rochester, MN USA..
    Roden, Dan M.
    Vanderbilt Univ, Sch Med, Dept Med, Nashville, TN 37212 USA.;Vanderbilt Univ, Sch Med, Dept Pharmacol, Nashville, TN 37212 USA..
    Denny, Joshua C.
    Vanderbilt Univ, Sch Med, Dept Biomed Informat, Nashville, TN 37212 USA..
    Carty, Cara
    George Washington Univ, Washington, DC USA..
    Hancock, Stephen
    Univ Newcastle, Newcastle, NSW, Australia..
    Attia, John
    Univ Newcastle, Newcastle, NSW, Australia..
    Holliday, Elizabeth
    Univ Newcastle, Newcastle, NSW, Australia..
    Donnell, Martin O'
    Populat Hlth Res Inst, Hamilton, ON, Canada..
    Yusuf, Salim
    Populat Hlth Res Inst, Hamilton, ON, Canada..
    Chong, Michael
    Populat Hlth Res Inst, Hamilton, ON, Canada..
    Pare, Guillaume
    Populat Hlth Res Inst, Hamilton, ON, Canada..
    van der Harst, Pim
    Netherlands Heart Inst, Durrer Ctr Cardiovasc Res, Utrecht, Netherlands.;Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, Groningen, Netherlands.;Univ Groningen, Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands..
    Said, M. Abdullah
    Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, Groningen, Netherlands..
    Eppinga, Ruben N.
    Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, Groningen, Netherlands..
    Verweij, Niek
    Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, Groningen, Netherlands..
    Snieder, Harold
    Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, Groningen, Netherlands..
    Christen, Tim
    Leiden Univ, Med Ctr, Dept Clin Epidemiol, Leiden, Netherlands..
    Mook-Kanamori, Dennis O.
    Leiden Univ, Med Ctr, Dept Clin Epidemiol, Leiden, Netherlands..
    Gustafsson, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Ingelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Stanford Univ, Dept Med, Sch Med, Div Cardiovasc Med, Stanford, CA 94305 USA..
    Pazoki, Raha
    Erasmus Univ, Med Ctr, Dept Epidemiol, Rotterdam, Netherlands..
    Franco, Oscar
    Erasmus Univ, Med Ctr, Dept Epidemiol, Rotterdam, Netherlands..
    Hofman, Albert
    Erasmus Univ, Med Ctr, Dept Epidemiol, Rotterdam, Netherlands..
    Uitterlinden, Andre
    Erasmus Univ, Med Ctr, Dept Internal Med, Rotterdam, Netherlands..
    Dehghan, Abbas
    Imperial Coll London, Sch Publ Hlth, MRC PHE Ctr Environm & Hlth, Dept Biostat & Epidemiol, London, England.;Erasmus Univ, Med Ctr, Dept Epidemiol, Rotterdam, Netherlands..
    Teumer, Alexander
    Univ Med Greifswald, Inst Community Med, Greifswald, Germany.;German Ctr Cardiovasc Res DZHK, Greifswald, Germany..
    Baumeister, Sebastian
    Univ Med Greifswald, Inst Community Med, Greifswald, Germany.;Univ Regensburg, Dept Epidemiol & Prevent Med, Regensburg, Germany..
    Doerr, Marcus
    Univ Med Greifswald, Dept Internal Med B, Greifswald, Germany.;German Ctr Cardiovasc Res DZHK, Greifswald, Germany..
    Lerch, Markus M.
    Univ Med Greifswald, Dept Med A, Greifswald, Germany..
    Voelker, Uwe
    Univ Med Greifswald, Interfac Inst Genet & Funct Genom, Greifswald, Germany.;German Ctr Cardiovasc Res DZHK, Greifswald, Germany..
    Voelzke, Henry
    Univ Med Greifswald, Inst Community Med, Greifswald, Germany.;German Ctr Cardiovasc Res DZHK, Greifswald, Germany..
    Ward, Joey
    Univ Glasgow, Inst Hlth & Wellbeing, Glasgow, Lanark, Scotland..
    Pell, Jill P.
    Univ Glasgow, Inst Hlth & Wellbeing, Glasgow, Lanark, Scotland..
    Smith, Daniel J.
    Univ Glasgow, Inst Hlth & Wellbeing, Glasgow, Lanark, Scotland..
    Meade, Tom
    London Sch Hyg & Trop Med, Dept Noncommunicable Dis Epidemiol, London, England..
    Maitland-van der Zee, Anke H.
    Acad Med Ctr, Dept Resp Med, Amsterdam, Netherlands.;Univ Utrecht, Fac Sci, Utrecht Inst Pharmaceut Sci, Div Pharmacoepidemiol & Clin Pharmacol, Utrecht, Netherlands..
    Baranova, Ekaterina V.
    Univ Utrecht, Fac Sci, Utrecht Inst Pharmaceut Sci, Div Pharmacoepidemiol & Clin Pharmacol, Utrecht, Netherlands..
    Young, Robin
    Univ Glasgow, Robertson Ctr Biostat, Glasgow, Lanark, Scotland..
    Ford, Ian
    Univ Glasgow, Robertson Ctr Biostat, Glasgow, Lanark, Scotland..
    Campbell, Archie
    Univ Edinburgh, Inst Genet & Mol Med, Edinburgh, Midlothian, Scotland..
    Padmanabhan, Sandosh
    Univ Glasgow, Cardiovasc & Med Sci, Glasgow, Lanark, Scotland..
    Bots, Michiel L.
    Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, Utrecht, Netherlands..
    Grobbee, Diederick E.
    Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, Utrecht, Netherlands..
    Froguel, Philippe
    Imperial Coll London, Fac Med, Dept Genom Common Dis, London, England.;Univ Lille, Inst Pasteur Lille, EGID, CNRS,UMR 8199, Lille, France..
    Thuillier, Dorothee
    Univ Lille, Inst Pasteur Lille, EGID, CNRS,UMR 8199, Lille, France..
    Balkau, Beverley
    INSERM, U1018, Ctr Rech Epidemiol & Sante Populat CESP, Renal & Cardiovasc Epidemiol, Villejuif, France..
    Bonnefond, Amelie
    Imperial Coll London, Fac Med, Dept Genom Common Dis, London, England.;Univ Lille, Inst Pasteur Lille, EGID, CNRS,UMR 8199, Lille, France..
    Cariou, Bertrand
    Univ Nantes, CHU Nantes, Inst Thorax, INSERM,CNRS, Nantes, France..
    Smart, Melissa
    Univ Essex, Inst Social & Econ Res, Colchester, Essex, England..
    Bao, Yanchun
    Univ Essex, Inst Social & Econ Res, Colchester, Essex, England..
    Kumari, Meena
    Univ Essex, Inst Social & Econ Res, Colchester, Essex, England..
    Mahajan, Anubha
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England..
    Ridker, Paul M.
    Harvard Med Sch, Brigham & Womens Hosp, Ctr Cardiovasc Dis Prevent, Boston, MA USA..
    Chasman, Daniel I.
    Harvard Med Sch, Brigham & Womens Hosp, Ctr Cardiovasc Dis Prevent, Boston, MA USA..
    Reiner, Alex P.
    Univ Washington, Fred Hutchinson Canc Res Ctr, Dept Epidemiol, Seattle, WA 98195 USA..
    Lange, Leslie A.
    Univ Colorado, Anschutz Med Campus, Denver, CO 80202 USA..
    Ritchie, Marylyn D.
    Geisinger Hlth Syst, Biomed & Translat Informat, Danville, PA USA.;Penn State Univ, Huck Inst Life Sci, Dept Biochem & Mol Biol, University Pk, PA 16802 USA..
    Asselbergs, Folkert W.
    UCL, Inst Cardiovasc Sci, London NW1 2DA, England.;UCL, UCL Inst Hlth Informat, Farr Inst Hlth Informat Res, London, England.;Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, Utrecht, Netherlands.;Univ Med Ctr Utrecht, Dept Cardiol, Div Heart & Lungs, Utrecht, Netherlands..
    Casas, Juan-Pablo
    UCL, UCL Inst Hlth Informat, Farr Inst Hlth Informat Res, London, England..
    Keating, Brendan J.
    Univ Penn, Dept Surg, Philadelphia, PA 19104 USA..
    Preiss, David
    Univ Oxford, Clin Trial Serv Unit, Nuffield Dept Populat Hlth, Oxford, England.;Univ Oxford, Epidemiol Studies Unit CTSU, Nuffield Dept Populat Hlth, Oxford, England.;Univ Oxford, Med Res Council, Populat Hlth Res Unit, Oxford, England..
    Hingorani, Aroon D.
    UCL, Inst Cardiovasc Sci, London NW1 2DA, England.;UCL, UCL Inst Hlth Informat, Farr Inst Hlth Informat Res, London, England..
    Sattar, Naveed
    Univ Glasgow, Cardiovasc & Med Sci, Glasgow, Lanark, Scotland..
    PCSK9 genetic variants and risk of type 2 diabetes: a mendelian randomisation study2017In: The Lancet Diabetes and Endocrinology, ISSN 2213-8587, E-ISSN 2213-8595, Vol. 5, no 2, p. 97-105Article in journal (Refereed)
    Abstract [en]

    Background Statin treatment and variants in the gene encoding HMG-CoA reductase are associated with reductions in both the concentration of LDL cholesterol and the risk of coronary heart disease, but also with modest hyperglycaemia, increased bodyweight, and modestly increased risk of type 2 diabetes, which in no way off sets their substantial benefi ts. We sought to investigate the associations of LDL cholesterol-lowering PCSK9 variants with type 2 diabetes and related biomarkers to gauge the likely eff ects of PCSK9 inhibitors on diabetes risk. Methods In this mendelian randomisation study, we used data from cohort studies, randomised controlled trials, case control studies, and genetic consortia to estimate associations of PCSK9 genetic variants with LDL cholesterol, fasting blood glucose, HbA 1c, fasting insulin, bodyweight, waist-to-hip ratio, BMI, and risk of type 2 diabetes, using a standardised analysis plan, meta-analyses, and weighted gene-centric scores. Findings Data were available for more than 550 000 individuals and 51 623 cases of type 2 diabetes. Combined analyses of four independent PCSK9 variants (rs11583680, rs11591147, rs2479409, and rs11206510) scaled to 1 mmol/L lower LDL cholesterol showed associations with increased fasting glucose (0.09 mmol/L, 95% CI 0.02 to 0.15), bodyweight (1.03 kg, 0.24 to 1.82), waist-to-hip ratio (0.006, 0.003 to 0.010), and an odds ratio for type diabetes of 1.29 (1.11 to 1.50). Based on the collected data, we did not identify associations with HbA 1c (0.03%, -0.01 to 0.08), fasting insulin (0.00%, -0.06 to 0.07), and BMI (0.11 kg/m(2), -0.09 to 0.30). Interpretation PCSK9 variants associated with lower LDL cholesterol were also associated with circulating higher fasting glucose concentration, bodyweight, and waist-to-hip ratio, and an increased risk of type 2 diabetes. In trials of PCSK9 inhibitor drugs, investigators should carefully assess these safety outcomes and quantify the risks and benefi ts of PCSK9 inhibitor treatment, as was previously done for statins.

  • 248. Scott, R. A.
    et al.
    Pasko, D.
    Fall, Tove
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Yaghootkar, H.
    Barker, A.
    Sharp, S. J.
    Walker, M.
    Wareham, N. J.
    Ingelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Frayling, T.
    Langenberg, C.
    A genetic risk score comprising common variants associated with fasting insulin is associated with OGTT- and clamp-based indices of whole body insulin sensitivity2013In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 56, p. S144-S145Article in journal (Other academic)
  • 249. Scott, Robert A
    et al.
    Fall, Tove
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Pasko, Dorota
    Barker, Adam
    Sharp, Stephen J
    Arriola, Larraitz
    Balkau, Beverley
    Barricarte, Aurelio
    Barroso, Inês
    Boeing, Heiner
    Clavel-Chapelon, Françoise
    Crowe, Francesca L
    Dekker, Jacqueline M
    Fagherazzi, Guy
    Ferrannini, Ele
    Forouhi, Nita G
    Franks, Paul W
    Gavrila, Diana
    Giedraitis, Vilmantas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Grioni, Sara
    Groop, Leif C
    Kaaks, Rudolf
    Key, Timothy J
    Kühn, Tilman
    Lotta, Luca A
    Nilsson, Peter M
    Overvad, Kim
    Palli, Domenico
    Panico, Salvatore
    Quirós, J Ramón
    Rolandsson, Olov
    Roswall, Nina
    Sacerdote, Carlotta
    Sala, Núria
    Sánchez, María-José
    Schulze, Matthias B
    Siddiq, Afshan
    Slimani, Nadia
    Sluijs, Ivonne
    Spijkerman, Annemieke Mw
    Tjonneland, Anne
    Tumino, Rosario
    van der A, Daphne L
    Yaghootkar, Hanieh
    McCarthy, Mark I
    Semple, Robert K
    Riboli, Elio
    Walker, Mark
    Ingelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Frayling, Tim M
    Savage, David B
    Langenberg, Claudia
    Wareham, Nicholas J
    Common genetic variants highlight the role of insulin resistance and body fat distribution in type 2 diabetes, independently of obesity2014In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 63, no 12, p. 4378-4387Article in journal (Refereed)
    Abstract [en]

    We aimed to validate genetic variants as instruments for insulin resistance and secretion, to characterise their association with intermediate phenotypes, and to investigate their role in T2D risk among normal-weight, overweight and obese individuals.We investigated the association of genetic scores with euglycaemic-hyperinsulinaemic clamp- and OGTT-based measures of insulin resistance and secretion, and a range of metabolic measures in up to 18,565 individuals. We also studied their association with T2D risk among normal-weight, overweight and obese individuals in up to 8,124 incident T2D cases. The insulin resistance score was associated with lower insulin sensitivity measured by M/I value (β in SDs-per-allele [95%CI]:-0.03[-0.04,-0.01];p=0.004). This score was associated with lower BMI (-0.01[-0.01,-0.0;p=0.02) and gluteofemoral fat-mass (-0.03[-0.05,-0.02;p=1.4x10-6), and with higher ALT (0.02[0.01,0.03];p=0.002) and gamma-GT (0.02[0.01,0.03];p=0.001). While the secretion score had a stronger association with T2D in leaner individuals (pinteraction=0.001), we saw no difference in the association of the insulin resistance score with T2D among BMI- or waist-strata(pinteraction>0.31). While insulin resistance is often considered secondary to obesity, the association of the insulin resistance score with lower BMI and adiposity and with incident T2D even among individuals of normal weight highlights the role of insulin resistance and ectopic fat distribution in T2D, independently of body size.

  • 250.
    Scott, Robert A.
    et al.
    Univ Cambridge, Sch Clin Med, MRC, Epidemiol Unit,Inst Metab Sci, Cambridge Biomedical Campus, Cambridge CB2 0QQ, England..
    Freitag, Daniel F.
    Univ Cambridge, Strangeways Res Lab, Dept Publ Hlth & Primary Care, Cambridge CB1 8RN, England.;Wellcome Trust Sanger Inst, Cambridge CB10 1SA, England..
    Li, Li
    GlaxoSmithKline, Stat Genet Projects Clin Platforms & Sci PCPS, Res Triangle Pk, NC 27709 USA..
    Chu, Audrey Y.
    Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02115 USA..
    Surendran, Praveen
    Univ Cambridge, Strangeways Res Lab, Dept Publ Hlth & Primary Care, Cambridge CB1 8RN, England..
    Young, Robin
    Univ Cambridge, Strangeways Res Lab, Dept Publ Hlth & Primary Care, Cambridge CB1 8RN, England..
    Grarup, Niels
    Univ Copenhagen, NovoNordisk Fdn, Fac Hlth & Med Sci, Ctr Basic Metab Res, DK-2200 Copenhagen, Denmark..
    Stancakova, Alena
    Univ Eastern Finland, Inst Clin Med, Internal Med, FI-70211 Kuopio, Finland..
    Chen, Yuning
    Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA..
    Varga, Tibor V.
    Lund Univ, Genet & Mol Epidemiol Unit, Dept Clin Sci, SE-205 Malmo, Sweden..
    Yaghootkar, Hanieh
    Univ Exeter, Sch Med, Genet Complex Traits, Exeter EX1 2LU, Devon, England..
    Luan, Jian'an
    Univ Cambridge, Sch Clin Med, MRC, Epidemiol Unit,Inst Metab Sci, Cambridge Biomedical Campus, Cambridge CB2 0QQ, England..
    Zhao, Jing Hua
    Univ Cambridge, Sch Clin Med, MRC, Epidemiol Unit,Inst Metab Sci, Cambridge Biomedical Campus, Cambridge CB2 0QQ, England..
    Willems, Sara M.
    Univ Cambridge, Sch Clin Med, MRC, Epidemiol Unit,Inst Metab Sci, Cambridge Biomedical Campus, Cambridge CB2 0QQ, England.;Erasmus Univ, Med Ctr, Dept Epidemiol, Genet Epidemiol Unit, NL-3000 CE Rotterdam, Netherlands..
    Wessel, Jennifer
    Fairbanks Sch Publ Hlth, Dept Epidemiol, Indianapolis, IN 46202 USA.;Indiana Univ Sch Med, Dept Med, Indianapolis, IN 46202 USA..
    Wang, Shuai
    Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA..
    Maruthur, Nisa
    Johns Hopkins Univ, Sch Med, Div Gen Internal Med, Baltimore, MD 21205 USA.;Johns Hopkins Univ, Welch Ctr Prevent Epidemol & Clin Res, Baltimore, MD 21205 USA.;Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA..
    Michailidou, Kyriaki
    Univ Cambridge, Ctr Canc Genet Epidemiol, Dept Publ Hlth & Primary Care, Strangeways Lab, Cambridge CB1 8RN, England..
    Pirie, Ailith
    Univ Cambridge, Ctr Canc Genet Epidemiol, Dept Publ Hlth & Primary Care, Strangeways Lab, Cambridge CB1 8RN, England..
    van der Lee, Sven J.
    Erasmus Univ, Dept Epidemiol, Med Ctr, NL-3000 CA Rotterdam, Netherlands..
    Gillson, Christopher
    Univ Cambridge, Sch Clin Med, MRC, Epidemiol Unit,Inst Metab Sci, Cambridge Biomedical Campus, Cambridge CB2 0QQ, England..
    Al Olama, Ali Amin
    Univ Cambridge, Ctr Canc Genet Epidemiol, Dept Publ Hlth & Primary Care, Strangeways Lab, Cambridge CB1 8RN, England..
    Amouyel, Philippe
    Univ Lille, Ctr Hosp Reg Univ Lille, INSERM, Inst Pasteur Lille,UMR 1167,RID AGE, F-59000 Lille, France..
    Arriola, Larraitz
    Publ Hlth Div Gipuzkoa, San Sebastian 20013, Spain.;Basque Govt, Inst BIOdonostia, San Sebastian 20014, Spain.;CIBER Epidemiol & Salud Publ CIBERESP, Madrid 28029, Spain..
    Arveiler, Dominique
    Univ Strasbourg, Dept Epidemiol & Publ Hlth EA3430, F-67085 Strasbourg, France..
    Aviles-Olmos, Iciar
    UCL Inst Neurol, Sobell Partment Motor Neurosci, London WC1N 3BG, England..
    Balkau, Beverley
    INSERM, Ctr Rech Epidemiol & Sante Populat CESP, F-94807 Villejuif, France.;Univ Paris 11, F-94805 Villejuif, France..
    Barricarte, Aurelio
    CIBER Epidemiol & Salud Publ CIBERESP, Madrid 28029, Spain.;Navarre Publ Hlth Inst ISPN, Pamplona 31003, Spain..
    Barroso, Ines
    Wellcome Trust Sanger Inst, Cambridge CB10 1SA, England.;Univ Paris 11, F-94805 Villejuif, France..
    Garcia, Sara Benlloch
    Univ Cambridge, Ctr Canc Genet Epidemiol, Dept Publ Hlth & Primary Care, Strangeways Lab, Cambridge CB1 8RN, England..
    Bis, Joshua C.
    Univ Washington, Cardiovasc Hlth Res Unit, Dept Med, Seattle, WA 98101 USA..
    Blankenberg, Stefan
    Univ Heart Ctr Hamburg, Dept Gen & Intervent Cardiol, D-20246 Hamburg, Germany..
    Boehnke, Michael
    Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA.;Univ Michigan, Ctr Stat Genet, Ann Arbor, MI 48109 USA..
    Boeing, Heiner
    German Inst Human Nutr, Potsdam Rehbruecke, D-14558 Nuthetal, Germany..
    Boerwinkle, Eric
    Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Human Genet Ctr, Houston, TX 77025 USA.;Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA..
    Borecki, Ingrid B.
    Washington Univ, Sch Med, Div Stat Genom, Dept Genet, St Louis, MO 63108 USA..
    Bork-Jensen, Jette
    Univ Copenhagen, NovoNordisk Fdn, Fac Hlth & Med Sci, Ctr Basic Metab Res, DK-2200 Copenhagen, Denmark..
    Bowden, Sarah
    Univ Birmingham, Inst Canc Studies, Canc Res UK Clin Trials Unit, Birmingham B15 2TT, W Midlands, England..
    Caldas, Carlos
    Univ Cambridge, Canc Res UK Cambridge Inst, Cambridge CB2 0RE, England.;Univ Cambridge, Li Ka Shing Ctr, Dept Oncol, Cambridge CB2 0RE, England..
    Caslake, Muriel
    Univ Glasgow, Glasgow G12 8QQ, Lanark, Scotland..
    Cupples, L. Adrienne
    Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA.;NHLBI, Framingham Heart Study, Framingham, MA 01702 USA..
    Cruchaga, Carlos
    Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA..
    Czajkowski, Jacek
    Washington Univ, Sch Med, Dept Genet, Div Stat Genom, St Louis, MO 63108 USA.;Washington Univ, Sch Med, Ctr Genome Sci & Syst Biol, St Louis, MO 63108 USA..
    den Hoed, Marcel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Dunn, Janet A.
    Univ Warwick, Warwick Clin Trials Unit, Gibbet Hill Rd, Coventry CV4 7AL, W Midlands, England..
    Earl, Helena M.
    Univ Cambridge, Cambridge CB2 0QQ, England.;Cambridge Univ Hosp Natl Hlth Serv Fdn Trust, Natl Inst Hlth Res, Cambridge Biomed Res Ctr, Cambridge CB2 0QQ, England..
    Ehret, Georg B.
    Johns Hopkins Univ, McKusick Nathans Inst Genet Med, Baltimore, MD 21205 USA..
    Ferrannini, Ele
    CNR, Inst Clin Physiol, I-56124 Pisa, Italy..
    Ferrieres, Jean
    Ctr Hosp Univ CHU Toulouse, Dept Epidemiol, INSERM, UMR 1027, F-31000 Toulouse, France..
    Foltynie, Thomas
    UCL Inst Neurol, Sobell Partment Motor Neurosci, London WC1N 3BG, England..
    Ford, Ian
    Univ Glasgow, Glasgow G12 8QQ, Lanark, Scotland..
    Forouhi, Nita G.
    Univ Cambridge, Sch Clin Med, MRC, Epidemiol Unit,Inst Metab Sci, Cambridge Biomedical Campus, Cambridge CB2 0QQ, England..
    Gianfagna, Francesco
    Univ Insubria, Dept Clin & Expt Med, Res Ctr Epidemiol & Prevent Med, I-21100 Varese, Italy.;IRCCS, Dept Epidemiol & Prevent, Ist Neurol Mediterraneo Neuromed, I-86077 Pozzilli, Italy..
    Gonzalez, Carlos
    Catalan Inst Oncol ICO, Barcelona 08908, Spain..
    Grioni, Sara
    Epidemiol & Prevent Unit, I-20133 Milan, Italy..
    Hiller, Louise
    Univ Warwick, Warwick Clin Trials Unit, Gibbet Hill Rd, Coventry CV4 7AL, W Midlands, England..
    Jansson, Jan-Hakan
    Res Unit, S-93141 Skelleftea, Sweden.;Umea Univ, Dept Publ Hlth & Clin Med, S-90185 Umea, Sweden..
    Jorgensen, Marit E.
    Steno Diabet Ctr, DK-2820 Gentofte, Denmark.;Southern Denmark Univ, Natl Inst Publ Hlth, DK-1353 Odense, Denmark..
    Jukema, J. Wouter
    Umea Univ, Dept Publ Hlth & Clin Med, S-90185 Umea, Sweden..
    Kaaks, Rudolf
    German Canc Res Ctr, D-69120 Heidelberg, Germany..
    Kee, Frank
    Queens Univ Belfast, UK Clin Res Collaborat UKCRC, Ctr Excellence Publ Hlth, Belfast BT12 6BJ, Antrim, North Ireland..
    Kerrison, Nicola D.
    Univ Cambridge, Sch Clin Med, MRC, Epidemiol Unit,Inst Metab Sci, Cambridge Biomedical Campus, Cambridge CB2 0QQ, England..
    Key, Timothy J.
    Univ Oxford, S Parks Rd, Oxford OX1 2JD, England..
    Kontto, Jukka
    Natl Inst Hlth & Welfare, FI-00271 Helsinki, Finland..
    Kote-Jarai, Zsofia
    Inst Canc Res, Sutton SM2 5NG, Surrey, England..
    Kraja, Aldi T.
    Washington Univ, Sch Med, Dept Genet, Div Stat Genom, St Louis, MO 63108 USA.;Washington Univ, Sch Med, Ctr Genome Sci & Syst Biol, St Louis, MO 63108 USA..
    Kuulasmaa, Kari
    Natl Inst Hlth & Welfare, FI-00271 Helsinki, Finland..
    Kuusisto, Johanna
    Univ Eastern Finland, Inst Clin Med, Internal Med, FI-70211 Kuopio, Finland..
    Linneberg, Allan
    Res Ctr Prevent & Hlth, DK-2600 Copenhagen, Denmark.;Rigshosp, Dept Clin Expt, DK-2100 Copenhagen, Denmark.;Univ Copenhagen, Fac Hlth & Med Sci, Dept Clin Med, DK-2200 Copenhagen, Denmark..
    Liu, Chunyu
    NHLBI, Framingham Heart Study, Populat Sci Branch, NIH, Bethesda, MD 20892 USA..
    Marenne, Galle
    Wellcome Trust Sanger Inst, Cambridge CB10 1SA, England..
    Mohlke, Karen L.
    Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA..
    Morris, Andrew P.
    Univ Liverpool, Dept Biostat, Liverpool L69 3GL, Merseyside, England.;Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England..
    Muir, Kenneth
    Univ Manchester, Inst Populat Hlth, Ctr Epidemiol, Oxford Rd, Manchester M13 9PT, Lancs, England.;Univ Warwick, Coventry CV4 7AL, W Midlands, England..
    Mueller-Nurasyid, Martina
    German Res Ctr Environm Hlth, Inst Genet Epidemiol, Helmholtz Zentrum Munchen, D-85764 Neuherberg, Germany.;Univ Munich, Dept Med 1, D-80336 Munich, Germany.;DZHK German Ctr Cardiovasc Res, Partner Site Munich Heart Alliance, D-80802 Munich, Germany..
    Munroe, Patricia B.
    Queen Mary Univ London, Barts & London Sch Med & Dent, William Harvey Res Inst, Clin Pharmacol, London EC1M 6BQ, England..
    Navarro, Carmen
    CIBER Epidemiol & Salud Publ CIBERESP, Madrid 28029, Spain.;Murcia Reg Hlth Council, Dept Epidemiol, IMIB Arrixaca, Murcia 30008, Spain..
    Nielsen, Sune F.
    Univ Copenhagen, Copenhagen Univ Hosp, Herlev Hosp, Dept Clin Biochem, DK-2730 Copenhagen, Denmark..
    Nilsson, Peter M.
    Lund Univ, S-20502 Malmo, Sweden..
    Nordestgaard, Borge G.
    Univ Copenhagen, Copenhagen Univ Hosp, Herlev Hosp, Dept Clin Biochem, DK-2730 Copenhagen, Denmark..
    Packard, Chris J.
    Univ Glasgow, Glasgow G12 8QQ, Lanark, Scotland..
    Palli, Domenico
    Canc Res & Prevent Inst ISPO, I-50141 Florence, Italy..
    Panico, Salvatore
    Univ Naples Federico II, Dipartimento Med Clin & Chirurg, I-80131 Naples, Italy..
    Peloso, Gina M.
    Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA.;Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA.;Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA..
    Perola, Markus
    Canc Res & Prevent Inst ISPO, I-50141 Florence, Italy.;Univ Helsinki, Inst Mol Med Finland FIMM, FI-00014 Helsinki, Finland..
    Peters, Annette
    DZHK German Ctr Cardiovasc Res, Partner Site Munich Heart Alliance, D-80802 Munich, Germany.;German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol 2, D-85764 Neuherberg, Germany..
    Poole, Christopher J.
    Univ Warwick, Coventry CV4 7AL, W Midlands, England.;Univ Hosp Coventry & Warwickshire, Arden Canc Ctr, Dept Med Oncol, Coventry CV2 2DX, W Midlands, England..
    Quiros, J. Ramn
    Publ Hlth Directorate, Oviedo 33006, Asturias, Spain..
    Rolandsson, Olov
    Umea Univ, S-90187 Umea, Sweden..
    Sacerdote, Carlotta
    Univ Turin, Citta Salute & Sci Hosp, Unit Canc Epidemiol, I-10126 Turin, Italy.;Ctr Canc Prevent CPO, I-10126 Turin, Italy.;Human Genet Fdn, I-10126 Turin, Italy..
    Salomaa, Veikko
    Natl Inst Hlth & Welfare, FI-00271 Helsinki, Finland..
    Sanchez, Mara-Jose
    CIBER Epidemiol & Salud Publ CIBERESP, Madrid 28029, Spain.;Univ Granada, Hosp Univ Granada, Inst Invest Biosanitaria Ibs GRANADA, Escuela Andaluza Salud Publ, Granada 18012, Spain..
    Sattar, Naveed
    Univ Glasgow, Glasgow G12 8QQ, Lanark, Scotland..
    Sharp, Stephen J.
    Univ Cambridge, Sch Clin Med, MRC, Epidemiol Unit,Inst Metab Sci, Cambridge Biomedical Campus, Cambridge CB2 0QQ, England..
    Sims, Rebecca
    Cardiff Univ, MRC Ctr, Inst Psychol Med & Clin Neurosci, Cardiff CF24 4HQ, S Glam, Wales..
    Slimani, Nadia
    Int Agcy Res Canc, F-69372 Lyon, France..
    Smith, Jennifer A.
    Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA..
    Thompson, Deborah J.
    Univ Cambridge, Ctr Canc Genet Epidemiol, Dept Publ Hlth & Primary Care, Strangeways Lab, Cambridge CB1 8RN, England..
    Trompet, Stella
    Leiden Univ, Med Ctr, NL-2333 AA Leiden, Netherlands..
    Tumino, Rosario
    ASP Ragusa, Civ MP Arezzo Hosp, Canc Registry & Histopathol Unit, I-97100 Ragusa, Italy..
    van der A, Daphne L.
    Natl Inst Publ Hlth & Environm RIVM, NL-3720 BA Bilthoven, Netherlands..
    van der Schouw, Yvonne T.
    Univ Med Ctr Utrecht, NL-3508 GA Utrecht, Netherlands..
    Virtamo, Jarmo
    Natl Inst Hlth & Welfare, FI-00271 Helsinki, Finland..
    Walker, Mark
    Newcastle Univ, Inst Cellular Med, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England..
    Walter, Klaudia
    Wellcome Trust Sanger Inst, Cambridge CB10 1SA, England..
    Abraham, Jean E.
    Univ Cambridge, Dept Oncol, Strangeways Lab, Ctr Canc Genet Epidemiol, Worts Causeway, Cambridge CB1 8RN, England..
    Amundadottir, Laufey T.
    NCI, Lab Translat Genom, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA..
    Aponte, Jennifer L.
    GlaxoSmithKline, PCPS, Genet, Res Triangle Pk, NC 27709 USA..
    Butterworth, Adams.
    Univ Cambridge, Strangeways Res Lab, Dept Publ Hlth & Primary Care, Cambridge CB1 8RN, England..
    Dupuis, Josee
    Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA..
    Easton, Douglas F.
    Univ Cambridge, Ctr Canc Genet Epidemiol, Dept Publ Hlth & Primary Care, Strangeways Lab, Cambridge CB1 8RN, England.;Univ Cambridge, Dept Oncol, Strangeways Lab, Ctr Canc Genet Epidemiol, Worts Causeway, Cambridge CB1 8RN, England..
    Eeles, Rosalind A.
    Inst Canc Res, Sutton SM2 5NG, Surrey, England.;Royal Marsden NHS Fdn Trust, London SW3 6JJ, England.;Royal Marsden NHS Fdn Trust, Surrey SW3 6JJ, England..
    Erdmann, Jeanette
    Med Univ Lubeck, Inst Integrat & Expt Genom, D-23562 Lubeck, Germany..
    Franks, Paul W.
    Lund Univ, Genet & Mol Epidemiol Unit, Dept Clin Sci, SE-205 Malmo, Sweden.;Umea Univ, Dept Publ Hlth & Clin Med, S-90185 Umea, Sweden.;Harvard Univ, TH Chan Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA..
    Frayling, Timothy M.
    Univ Exeter, Sch Med, Genet Complex Traits, Exeter EX1 2LU, Devon, England..
    Hansen, Torben
    Univ Copenhagen, NovoNordisk Fdn, Fac Hlth & Med Sci, Ctr Basic Metab Res, DK-2200 Copenhagen, Denmark..
    Howson, Joanna M. M.
    Univ Cambridge, Strangeways Res Lab, Dept Publ Hlth & Primary Care, Cambridge CB1 8RN, England..
    Jorgensen, Torben
    Res Ctr Prevent & Hlth, DK-2600 Capital Region, Denmark.;Univ Copenhagen, Inst Hlth Sci, Dept Publ Hlth, DK-1014 Copenhagen, Denmark.;Aalborg Univ, Fac Med, DK-9220 Aalborg, Denmark..
    Kooner, Jaspal
    Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, London SW3 6LY, England.;Imperial Coll Healthcare NHS Trust, London W2 1NY, England.;Ealing Hosp NHS Trust, Southall UB1 3HW, Middx, England..
    Laakso, Markku
    Univ Kuopio, Dept Med, FI-70211 Kuopio, Finland..
    Langenberg, Claudia
    Univ Cambridge, Sch Clin Med, MRC, Epidemiol Unit,Inst Metab Sci, Cambridge Biomedical Campus, Cambridge CB2 0QQ, England..
    McCarthy, Mark I.
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England.;Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab OCDEM, Oxford OX3 7LE, England..
    Pankow, James S.
    Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN 55455 USA..
    Pedersen, Oluf
    Univ Copenhagen, NovoNordisk Fdn, Fac Hlth & Med Sci, Ctr Basic Metab Res, DK-2200 Copenhagen, Denmark..
    Riboli, Elio
    Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, London W2 1PG, England..
    Rotter, Jerome I.
    Harbor Univ Calif Los Angeles, Med Ctr, Los Angeles Biomed Res Inst, Inst Translat Genom & Populat Sci, Torrance, CA 90502 USA..
    Saleheen, Danish
    Univ Penn, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA..
    Samani, Nilesh J.
    Univ Leicester, Glenfield Hosp, Dept Cardiovasc Sci, Leicester LE3 9QP, Leics, England.;Glenfield Hosp, Natl Inst Hlth Res, Leicester Cardiovasc Biomed Res Unit, Leicester LE3 9QP, Leics, England..
    Schunkert, Heribert
    DZHK German Ctr Cardiovasc Res, Partner Site Munich Heart Alliance, D-80802 Munich, Germany.;Tech Univ Munich, Deutsch Herzzentrum Munchen, D-80636 Munich, Germany..
    Vollenweider, Peter
    Lausanne Univ Hosp CHUV, Dept Internal Med, Internal Med, BH10-462, CH-1011 Lausanne, Switzerland..
    O'Rahilly, Stephen
    Univ Cambridge, Wellcome Trust MRC Inst Metab Sci, Metab Res Labs, Cambridge CB2 0QQ, England.;MRC Metab Dis Unit, Cambridge CB2 0QQ, England.;Natl Inst Hlth Res, Cambridge Biomed Res Ctr, Cambridge CB2 0QQ, England..
    Deloukas, Panos
    Queen Mary Univ London, Barts & London Sch Med & Dent, William Harvey Res Inst, London EC1M 6BQ, England..
    Danesh, John
    Univ Cambridge, Strangeways Res Lab, Dept Publ Hlth & Primary Care, Cambridge CB1 8RN, England.;Wellcome Trust Sanger Inst, Cambridge CB10 1SA, England..
    Goodarzi, Mark O.
    Cedars Sinai Med Ctr, Div Endocrinol Diabet & Metab, Los Angeles, CA 90048 USA..
    Kathiresan, Sekar
    Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA.;Broad Inst Harvard & MIT, Cambridge, MA 02142 USA.;Massachusetts Gen Hosp, Ctr Human Genet Res, Cardiol Div, Boston, MA 02114 USA.;Harvard Univ, Sch Med, Boston, MA 02114 USA..
    Meigs, James B.
    Massachusetts Gen Hosp, Dept Med, Div Gen Internal Med, Boston, MA 02114 USA.;Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA..
    Ehm, Margaret G.
    GlaxoSmithKline, PCPS, Genet, Res Triangle Pk, NC 27709 USA..
    Wareham, Nicholas J.
    Univ Cambridge, Sch Clin Med, MRC, Epidemiol Unit,Inst Metab Sci, Cambridge Biomedical Campus, Cambridge CB2 0QQ, England..
    Waterworth, Dawn M.
    GlaxoSmithKline, PCPS, Genet, Philadelphia, PA 19104 USA..
    A genomic approach to therapeutic target validation identifies a glucose-lowering GLP1R variant protective for coronary heart disease2016In: Science Translational Medicine, ISSN 1946-6234, E-ISSN 1946-6242, Vol. 8, no 341, article id 341ra76Article in journal (Refereed)
    Abstract [en]

    Regulatory authorities have indicated that new drugs to treat type 2 diabetes (T2D) should not be associated with an unacceptable increase in cardiovascular risk. Human genetics may be able to guide development of antidiabetic therapies by predicting cardiovascular and other health endpoints. We therefore investigated the association of variants in six genes that encode drug targets for obesity or T2D with a range of metabolic traits in up to 11,806 individuals by targeted exome sequencing and follow-up in 39,979 individuals by targeted genotyping, with additional in silico follow-up in consortia. We used these data to first compare associations of variants in genes encoding drug targets with the effects of pharmacological manipulation of those targets in clinical trials. We then tested the association of those variants with disease outcomes, including coronary heart disease, to predict cardiovascular safety of these agents. A low-frequency missense variant (Ala316Thr; rs10305492) in the gene encoding glucagon-like peptide-1 receptor (GLP1R), the target of GLP1R agonists, was associated with lower fasting glucose and T2D risk, consistent with GLP1R agonist therapies. The minor allele was also associated with protection against heart disease, thus providing evidence that GLP1R agonists are not likely to be associated with an unacceptable increase in cardiovascular risk. Our results provide an encouraging signal that these agents may be associated with benefit, a question currently being addressed in randomized controlled trials. Genetic variants associated with metabolic traits and multiple disease outcomes can be used to validate therapeutic targets at an early stage in the drug development process.

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