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  • 101.
    Helmersson-Karlqvist, Johanna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Ärnlöv, Johan
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Dalarna Univ, Sch Hlth & Social Studies, Falun, Sweden.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Cystatin C-based glomerular filtration rate associates more closely with mortality than creatinine-based or combined glomerular filtration rate equations in unselected patients.2016In: European Journal of Preventive Cardiology, ISSN 2047-4873, E-ISSN 2047-4881, Vol. 23, no 15, p. 1649-1657Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Decreased glomerular filtration rate (GFR) is an important cardiovascular risk factor, but estimated GFR (eGFR) may differ depending on whether it is based on creatinine or cystatin C. A combined creatinine/cystatin C equation has recently been shown to best estimate GFR; however, the benefits of using the combined equation for risk prediction in routine clinical care have been less studied. This study compares mortality risk prediction by eGFR using the combined creatinine/cystatin C equation (CKD-EPI), a sole creatinine equation (CKD-EPI) and a sole cystatin C equation (CAPA), respectively, using assays that are traceable to international calibrators.

    METHODS AND RESULTS: All patients analysed for both creatinine and cystatin C from the same blood sample tube (n = 13,054) during 2005-2007 in Uppsala University Hospital Laboratory were divided into eGFR risk categories>60, 30-60 and <30 mL/min/1.73 m(2) by each eGFR equation. During follow-up (median 4.6 years), 4398 participants died, of which 1396 deaths were due to cardiovascular causes. Reduced eGFR was significantly associated with death as assessed by all eGFR equations. The net reclassification improvement (NRI) for the combination equation compared with the sole creatinine equation was 0.10 (p < 0.001) for all-cause mortality and 0.08 (p < 0.001) for cardiovascular mortality, indicating improved reclassification. In contrast, NRI for the combination equation, compared with the sole cystatin C equation, was -0.06 (p < 0.001) for all-cause mortality and -0.02 (p = 0.032) for cardiovascular mortality, indicating a worsened reclassification.

    CONCLUSIONS: In routine clinical care, cystatin C-based eGFR was more closely associated with mortality compared with both creatinine-based eGFR and creatinine/cystatin C-based eGFR.

  • 102. Hemani, Gibran
    et al.
    Yang, Jian
    Vinkhuyzen, Anna
    Powell, Joseph E.
    Willemsen, Gonneke
    Hottenga, Jouke-Jan
    Abdellaoui, Abdel
    Mangino, Massimo
    Valdes, Ana M.
    Medland, Sarah E.
    Madden, Pamela A.
    Heath, Andrew C.
    Henders, Anjali K.
    Nyholt, Dale R.
    de Geus, Eco J. C.
    Magnusson, Patrik K. E.
    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.
    Montgomery, Grant W.
    Spector, Timothy D.
    Boomsma, Dorret I.
    Pedersen, Nancy L.
    Martin, Nicholas G.
    Visscher, Peter M.
    Inference of the Genetic Architecture Underlying BMI and Height with the Use of 20,240 Sibling Pairs2013In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 93, no 5, p. 865-875Article in journal (Refereed)
    Abstract [en]

    Evidence that complex traits are highly polygenic has been presented by population-based genome-wide association studies (GWASs) through the identification of many significant variants, as well as by family-based de novo sequencing studies indicating that several traits have a large mutational target size. Here, using a third study design, we show results consistent with extreme polygenicity for body mass index (BMI) and height. On a sample of 20,240 siblings (from 9,570 nuclear families), we used a within-family method to obtain narrow-sense heritability estimates of 0.42 (SE = 0.17, p = 0.01) and 0.69 (SE = 0.14, p = 6 x 10(-7)) for BMI and height, respectively, after adjusting for covariates. The genomic inflation factors from locus-specific-linkage analysis were 1.69 (SE = 0.21, p = 0.04) for BMI and 2.18 (SE = 0.21, p = 2 x 10(-10)) for height. This inflation is free of confounding and congruent with polygenicity, consistent with observations of ever-increasing genomic-inflation factors from GWASs with large sample sizes, implying that those signals are due to true genetic signals across the genome rather than population stratification. We also demonstrate that the distribution of the observed test statistics is consistent with both rare and common variants underlying a polygenic architecture and that previous reports of linkage signals in complex traits are probably a consequence of polygenic architecture rather than the segregation of variants with large effects. The convergent empirical evidence from GWASs, de novo studies, and within-family segregation implies that family-based sequencing studies for complex traits require very large sample sizes because the effects of causal variants are small on average.

  • 103.
    Henriksson, Catrin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Wernroth, Lisa
    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.
    Christersson, Christina
    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. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science.
    An Observational Study of the Occurence of Anxiety, Depression and self-reported Quality of Life 2 Years after Myocardial Infarction2018In: Journal of Cardiology and Cardiovascular Medicine, ISSN ISSN: 2575-0143, no 3, p. 052-063Article in journal (Refereed)
    Abstract [en]

    Background: Patients with myocardial infarction (MI) often experience anxiety, depression and poor quality of life (QoL) compared with a normative population. Mood disturbances and QoL have been extensively investigated, but only a few studies have examined the long-term effects of MI on these complex phenomena.

    Aims: To examine the levels and associated predictors of anxiety, depression, and QoL in patients 2 years after MI.

    Methods: This was a single center, observational study of patients with MI (n=377, 22% women, median age 66 years). Two years after MI (2012-2014), the patients were asked to answer the Hospital Anxiety and Depression Scale (HADS) and EuroQol 5-dimension (EQ-5D-3L) questionnaires.

    Results: Most patients experienced neither anxiety (87%, 95% confidence interval [CI]: 83-90%) nor depression (94%, 95% CI: 92-97%) 2 years post-MI. Elderly patients experienced more depression than younger patients (p=0.003) and women had higher anxiety levels than men (p=0.009).

    Most patients had “no problems” with any of the EQ-5D-3L dimensions (72-98%), but 48% (95% CI: 43%-53%) self-reported at least “some problems” with pain/discomfort. In a multiple logistic regression model (EQ-5D-3L) higher age (p<0.001) and female sex (p<0.001) were associated with more pain/discomfort. Female sex (p=0.047) and prior MI (p=0.038) were associated with anxiety/depression. History of heart failure was associated with worse mobility (p=0.005) and problems with usual activities (p=0.006). The median total health status of the patients (EQ-VAS) was 78 (95% CI: 75-80)

  • 104.
    Henrohn, Dan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Björkstrand, Kristoffer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Lundberg, Jon O
    Granstam, Sven-Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Baron, Tomasz
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ingimarsdóttir, Inga J
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Hedenström, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Malinovschi, Andrei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Wernroth, Lisa
    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.
    Jansson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Hedeland, Mikael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Science.
    Wikström, Gerhard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Effects of Oral Supplementation With Nitrate-Rich Beetroot Juice in Patients With Pulmonary Arterial Hypertension-Results From BEET-PAH, an Exploratory Randomized, Double-Blind, Placebo-Controlled, Crossover Study.2018In: Journal of Cardiac Failure, ISSN 1071-9164, E-ISSN 1532-8414, Vol. 24, no 10, p. 640-653Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The nitrate-nitrite-nitric oxide (NO) pathway may represent a potential therapeutic target in patients with pulmonary arterial hypertension (PAH). We explored the effects of dietary nitrate supplementation, with the use of nitrate-rich beetroot juice (BRJ), in patients with PAH.

    METHODS AND RESULTS: We prospectively studied 15 patients with PAH in an exploratory randomized, double-blind, placebo-controlled, crossover trial. The patients received nitrate-rich beetroot juice (∼16 mmol nitrate per day) and placebo in 2 treatment periods of 7 days each. The assessments included; exhaled NO and NO flow-independent parameters (alveolar NO and bronchial NO flux), plasma and salivary nitrate and nitrite, biomarkers and metabolites of the NO-system, N-terminal pro-B-type natriuretic peptide, echocardiography, ergospirometry, diffusing capacity of the lung for carbon monoxide, and the 6-minute walk test. Compared with placebo ingestion of BRJ resulted in increases in; fractional exhaled NO at all flow-rates, alveolar NO concentrations and bronchial NO flux, and plasma and salivary levels of nitrate and nitrite. Plasma ornithine levels decreased and indices of relative arginine availability increased after BRJ compared to placebo. A decrease in breathing frequency was observed during ergospirometry after BRJ. A tendency for an improvement in right ventricular function was observed after ingestion of BRJ. In addition a tendency for an increase in the peak power output to peak oxygen consumption ratio (W peak/VO2 peak) was observed, which became significant in patients reaching an increase of plasma nitrite >30% (responders).

    CONCLUSIONS: BRJ administered for 1 week increases pulmonary NO production and the relative arginine bioavailability in patients with PAH, compared with placebo. An increase in the W peak/VO2 peak ratio was observed after BRJ ingestion in plasma nitrite responders. These findings indicate that supplementation with inorganic nitrate increase NO synthase-independent NO production from the nitrate-nitrite-NO pathway.

  • 105.
    Hillström, Anna
    et al.
    Swedish Univ Agr Sci, Dept Clin Sci, Uppsala, Sweden..
    Bylin, Jonas
    Evidensia Sodra Djursjukhuset, Stockholm, Sweden..
    Hagman, Ragnvi
    Swedish Univ Agr Sci, Dept Clin Sci, Uppsala, Sweden..
    Björhall, Karin
    AstraZeneca R&D, RIA IMed, Dept Translat Sci, Molndal, Sweden..
    Tvedten, Harold
    Swedish Univ Agr Sci, Dept Clin Sci, Uppsala, Sweden..
    Königsson, Kristian
    AstraZeneca R&D Sodertalje, Safety Assessment, Sodertalje, 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.
    Kjelgaard-Hansen, Mads
    Novo Nordisk, Translat Haemophilia Pharmacol, Malov, Denmark..
    Measurement of serum C-reactive protein concentration for discriminating between suppurative arthritis and osteoarthritis in dogs2016In: BMC Veterinary Research, ISSN 1746-6148, E-ISSN 1746-6148, Vol. 12, article id 240Article in journal (Refereed)
    Abstract [en]

    Background: In a dog with joint pain, it is important to determine whether it has suppurative joint disease, characterized by exudation of neutrophils in the synovial fluid, or not, as this affects choice of diagnostic tests and treatments. The aim of this study was to evaluate whether measurement of serum C-reactive protein (CRP) concentration could be used to discriminate between dogs with suppurative arthritis and osteoarthritis (OA). Furthermore, the concentrations of serum and synovial fluid interleukin (IL) 6 concentrations were measured in dogs with joint disease and in healthy dogs, and were correlated to serum CRP concentrations. Methods: Dogs with joint pain were enrolled prospectively and were classified to have suppurative arthritis or OA based on synovial fluid analysis and radiographic/arthroscopic findings. Healthy Beagles were enrolled as a comparative group. CRP and IL-6 concentrations were measured with canine-specific immunoassays. The performance of CRP concentration in discriminating between dogs with suppurative arthritis and OA was evaluated using a previously established clinical decision limit for CRP (20 mg/l), and by receiver operator characteristic (ROC) curve and logistic regression analysis. Comparisons of CRP and IL-6 concentrations between groups were performed using t-tests, and correlations by Spearman rank correlation coefficients. Results: Samples were obtained from 31 dogs with suppurative arthritis, 34 dogs with OA, and 17 healthy dogs. Sixty-two out of 65 dogs with joint disease were correctly classified using the clinical decision limit for CRP. Evaluation of ROC curve and regression analysis indicated that serum CRP concentrations could discriminate between suppurative arthritis and OA. Dogs with suppurative arthritis had higher serum CRP and serum and synovial fluid IL-6 concentrations compared to dogs with OA (p < 0.001). Dogs with OA had higher synovial fluid IL-6 concentrations (p < 0.001), but not higher serum CRP (p = 0.29) or serum IL-6 (p = 0.07) concentrations, compared to healthy dogs. There was a positive correlation between synovial fluid IL-6 and serum CRP concentrations (r(s) = 0.733, p < 0.001), and between serum IL-6 and serum CRP concentrations (r(s) = 0.729, p < 0.001). Conclusion: CRP concentration was found to discriminate well between dogs with suppurative arthritis and OA.

  • 106.
    Holzmann, Martin J.
    et al.
    Karolinska Univ Hosp, Dept Emergency Med, Huddinge, Sweden.;Karolinska Inst, Dept Internal Med, Huddinge, Sweden..
    Carlsson, Axel C.
    Karolinska Inst, Div Family Med, Dept Neurobiol Care Sci & Soc, Huddinge, Sweden.;Karolinska Inst, Inst Environm Med, Div Cardiovasc Epidemiol, Huddinge, Sweden..
    Hammar, Niklas
    Karolinska Inst, Inst Environm Med, Div Cardiovasc Epidemiol, Huddinge, Sweden..
    Ivert, Torbjorn
    Karolinska Univ Hosp, Dept Cardiothorac Surg & Anesthesiol, Stockholm, Sweden.;Karolinska Inst, Dept Mol Med & Surg, Huddinge, Sweden..
    Walldius, Goran
    Karolinska Inst, Inst Environm Med, Div Cardiovasc Epidemiol, Huddinge, Sweden..
    Jungner, Ingmar
    Karolinska Inst, Inst Environm Med, Div Cardiovasc Epidemiol, Huddinge, Sweden..
    Wandell, Per
    Karolinska Inst, Div Family Med, Dept Neurobiol Care Sci & Soc, Huddinge, Sweden..
    Ärnlöv, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Dalarna Univ, Sch Hlth & Social Studies, Falun, Sweden..
    Chronic kidney disease and 10-year risk of cardiovascular death2016In: European Journal of Preventive Cardiology, ISSN 2047-4873, E-ISSN 2047-4881, Vol. 23, no 11, p. 1187-1194Article in journal (Refereed)
    Abstract [en]

    Background In recent clinical guidelines, individuals with chronic kidney disease are considered to have a similar 10-year absolute risk of cardiovascular death as individuals with diabetes or established cardiovascular disease. There is limited evidence to support this claim. Methods We investigated the 10-year risk for cardiovascular death in individuals with moderate or severe chronic kidney disease (glomerular filtration rate of 30-60 or <30mL/min/1.73m(2), respectively) in a cohort of primary care health check-ups in Stockholm, Sweden (n=295,191, 46% women, 4290 cardiovascular deaths during 10 years follow-up). We also assessed the risk associated with diabetes or cardiovascular disease. The inclusion criteria, exposure, study outcome and follow-up period adhered strictly to the definitions of the European Society of Cardiology guidelines. Results The absolute 10-year risk of cardiovascular death was 3.9% and 14.0% in individuals with moderate and severe chronic kidney disease, respectively, but was substantially lower in women and in younger individuals. The risk in individuals with prevalent diabetes and cardiovascular disease was approximately two and three times higher compared to the risk estimate for moderate chronic kidney disease (hazard ratio (HR) 4.1, 95% confidence interval (CI) 3.8-4.5 and HR 6.2, 95% CI 5.7-6.7 vs. HR 2.3 95% CI 2.0-2.6, respectively) while the risk for individuals with severe chronic kidney disease appeared more congruent to that of diabetes and cardiovascular disease (HR 5.5, 95% CI 3.3-8.9). Conclusions Although moderate chronic kidney disease is an independent predictor for an increased 10-year risk of cardiovascular death, only those with severe chronic kidney disease had similar risk to those with diabetes or cardiovascular disease.

  • 107.
    Horikoshi, Momoko
    et al.
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England..
    Maegi, Reedik
    Univ Tartu, Estonian Genome Ctr, EE-50090 Tartu, Estonia..
    van de Bunt, Martijn
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England..
    Surakka, Ida
    Univ Helsinki, Inst Mol Med Finland FIMM, Helsinki, Finland.;Natl Inst Hlth & Welf, Helsinki, Finland..
    Sarin, Antti-Pekka
    Univ Helsinki, Inst Mol Med Finland FIMM, Helsinki, Finland.;Natl Inst Hlth & Welf, Helsinki, Finland..
    Mahajan, Anubha
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England..
    Marullo, Letizia
    Univ Ferrara, Dept Life Sci & Biotechnol, I-44100 Ferrara, Italy..
    Thorleifsson, Gudmar
    deCode Genet Amgen Inc, Reykjavik, Iceland..
    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. Karolinska Inst, Dept Med Epidemiol & Biostatist, Stockholm, Sweden..
    Hottenga, Jouke-Jan
    Vrije Univ Amsterdam, Dept Biol Psychol, Amsterdam, Netherlands..
    Ladenvall, Claes
    Skane Univ Hosp, Lund Univ Diabet Ctr, Dept Clin Sci Diabet & Endocrinol, Malmo, Sweden..
    Ried, Janina S.
    Helmholtz Zentrum Munchen, Inst Genet Epidemiol, German Res Ctr Environm Hlth, Neuherberg, Germany..
    Winkler, Thomas W.
    Univ Regensburg, Dept Genet Epidemiol, Inst Epidemiol & Prevent Med, D-93053 Regensburg, Germany..
    Willems, Sara M.
    Erasmus Univ, Med Ctr, Dept Epidemiol, Genet Epidemiol Unit, Rotterdam, Netherlands..
    Pervjakova, Natalia
    Univ Tartu, Estonian Genome Ctr, EE-50090 Tartu, Estonia..
    Esko, Tonu
    Univ Tartu, Estonian Genome Ctr, EE-50090 Tartu, Estonia.;Childrens Hosp, Div Endocrinol, Boston, MA 02115 USA.;Childrens Hosp, Ctr Basic & Translat Obes Res, Boston, MA 02115 USA.;Broad Inst, Program Med & Populat Genet, Cambridge, MA USA.;Harvard Univ, Sch Med, Dept Genet, Boston, MA USA..
    Beekman, Marian
    Leiden Univ, Med Ctr, Dept Mol Epidemiol, Leiden, Netherlands.;Netherlands Consortium Hlth Ageing, Leiden, Netherlands..
    Nelson, Christopher P.
    Univ Leicester, Dept Cardiovasc Sci, Leicester, Leics, England.;Natl Inst Hlth Res, Leicester Cardiovasc Dis Biomed Res Unit, Glenfield Hosp, Leicester, Leics, England..
    Willenborg, Christina
    Univ Lubeck, Inst Integrat & Expt Gen, Lubeck, Germany.;DZHK German Ctr Cardiovascular Res, Lubeck, Germany..
    Wiltshire, Steven
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England..
    Ferreira, Teresa
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England..
    Fernandez, Juan
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England..
    Gaulton, Kyle J.
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England..
    Steinthorsdottir, Valgerdur
    deCode Genet Amgen Inc, Reykjavik, Iceland..
    Hamsten, Anders
    Karolinska Inst, Atherosclerosis Res Unit, Dept Med Solna, Cardiovascular Genet & Genom Grp, Stockholm, Sweden..
    Magnusson, Patrik K. E.
    Karolinska Inst, Dept Med Epidemiol & Biostatist, Stockholm, Sweden..
    Willemsen, Gonneke
    Vrije Univ Amsterdam, Dept Biol Psychol, Amsterdam, Netherlands..
    Milaneschi, Yuri
    Vrije Univ Amsterdam, Dept Psychiat, Med Ctr, Amsterdam, Netherlands..
    Robertson, Neil R.
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England..
    Groves, Christopher J.
    Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England..
    Bennett, Amanda J.
    Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England..
    Lehtimaeki, Terho
    Univ Tampere, Dept Clin Chem, Fimlab Labs, FIN-33101 Tampere, Finland.;Univ Tampere, Sch Med, FIN-33101 Tampere, Finland..
    Viikari, Jorma S.
    Univ Turku, Dept Med, Turku, Finland.;Turku Univ Hosp, Div Med, FIN-20520 Turku, Finland..
    Rung, Johan
    European Bioinformat Inst, European Mol Biol Lab, Hinxton, England..
    Lyssenko, Valeriya
    Skane Univ Hosp, Lund Univ Diabet Ctr, Dept Clin Sci Diabet & Endocrinol, Malmo, Sweden.;Steno Diabet Ctr AS, Gentofte, Denmark..
    Perola, Markus
    Univ Helsinki, Inst Mol Med Finland FIMM, Helsinki, Finland.;Natl Inst Hlth & Welf, Helsinki, Finland..
    Heid, Iris M.
    Univ Regensburg, Dept Genet Epidemiol, Inst Epidemiol & Prevent Med, D-93053 Regensburg, Germany..
    Herder, Christian
    Univ Dusseldorf, Leibniz Inst Diabet Res, German Diabet Ctr, Inst Clin Diabetol, Dusseldorf, Germany.;German Ctr Diabet Res DZD eV, Partner Dusseldorf, Dusseldorf, Germany..
    Grallert, Harald
    Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Res Unit Mol Epidemiol, Neuherberg, Germany.;Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Epidemiol 2, Neuherberg, Germany..
    Mueller-Nurasyid, Martina
    Helmholtz Zentrum Munchen, Inst Genet Epidemiol, German Res Ctr Environm Hlth, Neuherberg, Germany.;Univ Munich, Univ Hosp Grosshadern, Dept Med 1, Munich, Germany.;Univ Munich, Inst Med Informat,Biometry & Epidemiol, Chair Genet Epidemiol, Munich, Germany..
    Roden, Michael
    Univ Dusseldorf, Leibniz Inst Diabet Res, German Diabet Ctr, Inst Clin Diabetol, Dusseldorf, Germany.;German Ctr Diabet Res DZD eV, Partner Dusseldorf, Dusseldorf, Germany.;Univ Hosp Dusseldorf, Dept Endocrinol & Diabetol, Dusseldorf, Germany..
    Hypponen, Elina
    Univ S Australia, Sch Populat Hlth, Adelaide, SA 5001, Australia.;UCL, Inst Child Hlth, Ctr Paediat Epidemiol & Biostat, London, England..
    Isaacs, Aaron
    Erasmus Univ, Med Ctr, Dept Epidemiol, Genet Epidemiol Unit, Rotterdam, Netherlands.;Ctr Med Syst Biol, Leiden, Netherlands..
    van Leeuwen, Elisabeth M.
    Erasmus Univ, Med Ctr, Dept Epidemiol, Genet Epidemiol Unit, Rotterdam, Netherlands..
    Karssen, Lennart C.
    Erasmus Univ, Med Ctr, Dept Epidemiol, Genet Epidemiol Unit, Rotterdam, Netherlands..
    Mihailov, Evelin
    Univ Tartu, Estonian Genome Ctr, EE-50090 Tartu, Estonia..
    Houwing-Duistermaat, Jeanine J.
    Leiden Univ, Med Ctr, Dept Med Stat & Bioinformat, Leiden, Netherlands..
    de Craen, Anton J. M.
    Netherlands Consortium Hlth Ageing, Leiden, Netherlands.;Leiden Univ, Med Ctr, Dept Gerontol & Geriatr, Leiden, Netherlands..
    Deelen, Joris
    Leiden Univ, Med Ctr, Dept Mol Epidemiol, Leiden, Netherlands.;Netherlands Consortium Hlth Ageing, Leiden, Netherlands..
    Havulinna, Aki S.
    Natl Inst Hlth & Welf, Unit Chron Dis Epidemiol & Prevent, Helsinki, Finland..
    Blades, Matthew
    Univ Leicester, Bioinformat & Biostatist Support Hub, Leicester, Leics, England..
    Hengstenberg, Christian
    Tech Univ Munich, Deutsch Herzzentrum Munchen, D-80290 Munich, Germany.;DZHK German Ctr Cardiovasc Res, Munich, Germany..
    Erdmann, Jeanette
    Univ Lubeck, Inst Integrat & Expt Gen, Lubeck, Germany.;DZHK German Ctr Cardiovascular Res, Lubeck, Germany..
    Schunkert, Heribert
    Tech Univ Munich, Deutsch Herzzentrum Munchen, D-80290 Munich, Germany.;DZHK German Ctr Cardiovasc Res, Munich, Germany..
    Kaprio, Jaakko
    Univ Helsinki, Inst Mol Med Finland FIMM, Helsinki, Finland.;Natl Inst Hlth & Welf, Helsinki, Finland.;Univ Helsinki, Dept Publ Hlth, Helsinki, Finland..
    Tobin, Martin D.
    Univ Leicester, Dept Hlth Sci, Genet Epidemiol Grp, Leicester, Leics, England.;Natl Inst Hlth Res, Leicester Resp Biomed Res Unit, Glenfield Hosp, Leicester, Leics, England..
    Samani, Nilesh J.
    Univ Leicester, Dept Cardiovasc Sci, Leicester, Leics, England.;Natl Inst Hlth Res, Leicester Cardiovasc Dis Biomed Res Unit, Glenfield Hosp, Leicester, Leics, England..
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Salomaa, Veikko
    Natl Inst Hlth & Welf, Unit Chron Dis Epidemiol & Prevent, Helsinki, Finland..
    Lindgren, Cecilia M.
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.;Broad Inst Harvard & MIT, Broad Inst, Cambridge, MA USA..
    Slagboom, P. Eline
    Leiden Univ, Med Ctr, Dept Mol Epidemiol, Leiden, Netherlands.;Netherlands Consortium Hlth Ageing, Leiden, Netherlands..
    Metspalu, Andres
    Univ Tartu, Estonian Genome Ctr, EE-50090 Tartu, Estonia.;Univ Tartu, Inst Mol & Cell Biol, EE-50090 Tartu, Estonia..
    van Duijn, Cornelia M.
    Erasmus Univ, Med Ctr, Dept Epidemiol, Genet Epidemiol Unit, Rotterdam, Netherlands.;Ctr Med Syst Biol, Leiden, Netherlands..
    Eriksson, Johan G.
    Univ Helsinki, Dept Gen Practice & Primary Hlth Care, Helsinki, Finland.;Folkhalsan Res Ctr, Helsinki, Finland.;Vasa Cent Hosp, Vaasa, Finland.;Natl Inst Hlth & Welf, Dept Hlth Promot & Chron Dis Prevent, Helsinki, Finland..
    Peters, Annette
    Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Res Unit Mol Epidemiol, Neuherberg, Germany.;Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Epidemiol 2, Neuherberg, Germany..
    Gieger, Christian
    Helmholtz Zentrum Munchen, Inst Genet Epidemiol, German Res Ctr Environm Hlth, Neuherberg, Germany.;Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Res Unit Mol Epidemiol, Neuherberg, Germany.;Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Epidemiol 2, Neuherberg, Germany..
    Jula, Antti
    Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Turku, Finland..
    Groop, Leif
    Univ Helsinki, Inst Mol Med Finland FIMM, Helsinki, Finland.;Skane Univ Hosp, Lund Univ Diabet Ctr, Dept Clin Sci Diabet & Endocrinol, Malmo, Sweden..
    Raitakari, Olli T.
    Univ Turku, Res Ctr Appl & Prevent Cardiovasc Med, Turku, Finland.;Univ Turku, Dept Clin Physiol & Nucl Med, Turku, Finland.;Turku Univ Hosp, FIN-20520 Turku, Finland..
    Power, Chris
    UCL, Inst Child Hlth, Ctr Paediat Epidemiol & Biostat, London, England..
    Penninx, Brenda W. J. H.
    Vrije Univ Amsterdam, Dept Psychiat, Med Ctr, Amsterdam, Netherlands..
    de Geus, Eco
    Vrije Univ Amsterdam, Dept Biol Psychol, Amsterdam, Netherlands.;Vrije Univ Amsterdam, EMGO Inst Hlth & Care Res, Amsterdam, Netherlands.;Vrije Univ Amsterdam, Med Ctr, Amsterdam, Netherlands..
    Smit, Johannes H.
    Vrije Univ Amsterdam, Dept Psychiat, Med Ctr, Amsterdam, Netherlands..
    Boomsma, Dorret I.
    Vrije Univ Amsterdam, Dept Biol Psychol, Amsterdam, Netherlands..
    Pedersen, Nancy L.
    Karolinska Inst, Dept Med Epidemiol & Biostatist, Stockholm, 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. Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England..
    Thorsteinsdottir, Unnur
    deCode Genet Amgen Inc, Reykjavik, Iceland.;Univ Iceland, Fac Med, Reykjavik, Iceland..
    Stefansson, Kari
    deCode Genet Amgen Inc, Reykjavik, Iceland.;Univ Iceland, Fac Med, Reykjavik, Iceland..
    Ripatti, Samuli
    Univ Helsinki, Inst Mol Med Finland FIMM, Helsinki, Finland.;Natl Inst Hlth & Welf, Helsinki, Finland.;Univ Helsinki, Dept Publ Hlth, Helsinki, Finland.;Wellcome Trust Sanger Inst, Cambridge, England..
    Prokopenko, Inga
    Univ London Imperial Coll Sci Technol & Med, Dept Genom Common Dis, Sch Publ Hlth, London, England..
    McCarthy, Mark I.
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England.;Churchill Hosp, Biomed Res Ctr, Oxford Natl Inst Hlth Res, Oxford OX3 7LJ, England..
    Morris, Andrew P.
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Tartu, Estonian Genome Ctr, EE-50090 Tartu, Estonia.;Univ Liverpool, Dept Biostat, Liverpool L69 3BX, Merseyside, England.;Univ Liverpool, Dept Mol & Clin Pharmacol, Liverpool, Merseyside, England..
    Discovery and Fine-Mapping of Glycaemic and Obesity-Related Trait Loci Using High-Density Imputation2015In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 11, no 7, article id e1005230Article in journal (Refereed)
    Abstract [en]

    Reference panels from the 1000 Genomes (1000G) Project Consortium provide near complete coverage of common and low-frequency genetic variation with minor allele frequency >= 0.5% across European ancestry populations. Within the European Network for Genetic and Genomic Epidemiology (ENGAGE) Consortium, we have undertaken the first large-scale meta-analysis of genome-wide association studies (GWAS), supplemented by 1000G imputation, for four quantitative glycaemic and obesity-related traits, in up to 87,048 individuals of European ancestry. We identified two loci for body mass index (BMI) at genome-wide significance, and two for fasting glucose (FG), none of which has been previously reported in larger meta-analysis efforts to combine GWAS of European ancestry. Through conditional analysis, we also detected multiple distinct signals of association mapping to established loci for waist-hip ratio adjusted for BMI (RSPO3) and FG (GCK and G6PC2). The index variant for one association signal at the G6PC2 locus is a low-frequency coding allele, H177Y, which has recently been demonstrated to have a functional role in glucose regulation. Fine-mapping analyses revealed that the non-coding variants most likely to drive association signals at established and novel loci were enriched for overlap with enhancer elements, which for FG mapped to promoter and transcription factor binding sites in pancreatic islets, in particular. Our study demonstrates that 1000G imputation and genetic fine-mapping of common and low-frequency variant association signals at GWAS loci, integrated with genomic annotation in relevant tissues, can provide insight into the functional and regulatory mechanisms through which their effects on glycaemic and obesity-related traits are mediated.

  • 108.
    Huang, Biying
    et al.
    Stanford Univ, Sch Med, Dept Med, Div Cardiovasc Med, 300 Pasteur Dr, Stanford, CA 94304 USA.;Karolinska Inst, Dept Med, S-17176 Stockholm, Sweden..
    Svensson, Per
    Karolinska Inst, Dept Med, S-17176 Stockholm, Sweden..
    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, S-79188 Falun, Sweden..
    Sundstrom, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    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. Stanford Univ, Sch Med, Dept Med, Div Cardiovasc Med, 300 Pasteur Dr, Stanford, CA 94304 USA.
    Effects of cigarette smoking on cardiovascular-related protein profiles in two community-based cohort studies2016In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 254, p. 52-58Article in journal (Refereed)
    Abstract [en]

    Background and aims: Cardiovascular diseases account for the largest fraction of smoking-induced deaths. Studies of smoking in relation to cardiovascular-related protein markers can provide novel insights into the biological effects of smoking. We investigated the associations between cigarette smoking and 80 protein markers known to be related to cardiovascular diseases in two community-based cohorts, the Prospective Study of the Vasculature in Uppsala Seniors (PIVUS, n = 969, 50% women, all aged 70 years) and the Uppsala Longitudinal Study of Adult Men (ULSAM, n = 717, all men aged 77 years). Methods: Smoking status was self-reported and defined as current smoker, former smoker or never-smoker. Levels of the 80 proteins were measured using the proximity extension assay, a novel PCR-based proteomics technique. Results: We found 30 proteins to be significantly associated with current cigarette smoking in PIVUS (FDR<5%); and ten were replicated in ULSAM (p<0.05). Matrix metalloproteinase-12 (MMP-12), growth/differentiation factor 15 (GDF-15), urokinase plasminogen activator surface receptor (uPAR), TNF-related apoptosis-inducing ligand receptor 2 (TRAIL-R2), lectin-like oxidized LDL receptor 1 (LOX-1), hepatocyte growth factor (HGF), matrix metalloproteinase-10 (MMP-10) and matrix metalloproteinase-1 (MMP-1) were positively associated, while endothelial cell-specific molecule 1 (ESM-1) and interleukin-27 subunit alpha (IL27-A) showed inverse associations. All of them remained significant in a subset of individuals without manifest cardiovascular disease. Conclusions: The findings of the present study suggest that cigarette smoking may interfere with several essential parts of the atherosclerosis process, as evidenced by associations with protein markers representing endothelial dysfunction, inflammation, neointimal formation, foam cell formation and plaque instability. (C) 2016 Elsevier Ireland Ltd. All rights reserved.

  • 109.
    Hägg, Sara
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. 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. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ploner, Alexander
    Maegi, Reedik
    Fischer, Krista
    Draisma, Harmen H. M.
    Kals, Mart
    de Vries, Paul S.
    Dehghan, Abbas
    Willems, Sara M.
    Sarin, Antti-Pekka
    Kristiansson, Kati
    Nuotio, Marja-Liisa
    Havulinna, Aki S.
    de Bruijn, Renee F. A. G.
    Ikram, M. Arfan
    Kuningas, Maris
    Stricker, Bruno H.
    Franco, Oscar H.
    Benyamin, Beben
    Gieger, Christian
    Hall, Alistair S.
    Huikari, Ville
    Jula, Antti
    Jarvelin, Marjo-Riitta
    Kaakinen, Marika
    Kaprio, Jaakko
    Kobl, Michael
    Mangino, Massimo
    Nelson, Christopher P.
    Palotie, Aarno
    Samani, Nilesh J.
    Spector, Tim D.
    Strachan, David P.
    Tobin, Martin D.
    Whitfield, John B.
    Uitterlinden, Andre G.
    Salomaa, Veikko
    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.
    Kuulasmaa, Kari
    Magnusson, Patrik K.
    Esko, Tonu
    Hofman, Albert
    de Geus, Eco J. C.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Giedraitis, Vilmantas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Perola, Markus
    Evans, Alun
    Ferrieres, Jean
    Virtamo, Jarmo
    Kee, Frank
    Tregouet, David-Alexandre
    Arveiler, Dominique
    Amouyel, Philippe
    Gianfagna, Francesco
    Brambilla, Paolo
    Ripatti, Samuli
    van Duijn, Cornelia M.
    Metspalu, Andres
    Prokopenko, Inga
    McCarthy, Mark I.
    Pedersen, Nancy L.
    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.
    Adiposity as a cause of cardiovascular disease: a Mendelian randomization study2015In: International Journal of Epidemiology, ISSN 0300-5771, E-ISSN 1464-3685, Vol. 44, no 2, p. 578-586Article in journal (Refereed)
    Abstract [en]

    Background: Adiposity, as indicated by body mass index (BMI), has been associated with risk of cardiovascular diseases in epidemiological studies. We aimed to investigate if these associations are causal, using Mendelian randomization (MR) methods. Methods: The associations of BMI with cardiovascular outcomes [coronary heart disease (CHD), heart failure and ischaemic stroke], and associations of a genetic score (32 BMI single nucleotide polymorphisms) with BMI and cardiovascular outcomes were examined in up to 22 193 individuals with 3062 incident cardiovascular events from nine prospective follow-up studies within the ENGAGE consortium. We used random-effects meta-analysis in an MR framework to provide causal estimates of the effect of adiposity on cardiovascular outcomes. Results: There was a strong association between BMI and incident CHD (HR = 1.20 per SD-increase of BMI, 95% CI, 1.12-1.28, P = 1.9.10(-7)), heart failure (HR = 1.47, 95% CI, 1.35-1.60, P = 9.10(-19)) and ischaemic stroke (HR = 1.15, 95% CI, 1.06-1.24, P = 0.0008) in observational analyses. The genetic score was robustly associated with BMI (beta = 0.030 SD-increase of BMI per additional allele, 95% CI, 0.028-0.033, P = 3.10(-107)). Analyses indicated a causal effect of adiposity on development of heart failure (HR = 1.93 per SD-increase of BMI, 95% CI, 1.12-3.30, P = 0.017) and ischaemic stroke (HR = 1.83, 95% CI, 1.05-3.20, P = 0.034). Additional cross-sectional analyses using both ENGAGE and CARDIoGRAMplusC4D data showed a causal effect of adiposity on CHD. Conclusions: Using MR methods, we provide support for the hypothesis that adiposity causes CHD, heart failure and, previously not demonstrated, ischaemic stroke.

  • 110.
    Hägg, Sara
    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.
    Ganna, Andrea
    Van Der Laan, Sander W
    Esko, Tonu
    Pers, Tune H
    Locke, Adam E
    Berndt, Sonja I
    Justice, Anne E
    Kahali, Bratati
    Siemelink, Marten A
    Pasterkamp, Gerard
    Strachan, David P
    Speliotes, Elizabeth K
    North, Kari E
    Loos, Ruth J F
    Hirschhorn, Joel N
    Pawitan, Yudi
    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.
    Gene-based meta-analysis of genome-wide association studies implicates new loci involved in obesity2015In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 24, no 23, p. 6849-6860Article in journal (Refereed)
    Abstract [en]

    To date, genome-wide association studies (GWASs) have identified >100 loci with single variants associated with body mass index (BMI). This approach may miss loci with high allelic heterogeneity; therefore, the aim of the present study was to use gene-based meta-analysis to identify regions with high allelic heterogeneity to discover additional obesity susceptibility loci. We included GWAS data from 123 865 individuals of European descent from 46 cohorts in Stage 1 and Metabochip data from additional 103 046 individuals from 43 cohorts in Stage 2, all within the Genetic Investigation of ANthropometric Traits (GIANT) consortium. Each cohort was tested for association between ∼2.4 million (Stage 1) or ∼200 000 (Stage 2) imputed or genotyped single variants and BMI, and summary statistics were subsequently meta-analyzed in 17 941 genes. We used the 'VErsatile Gene-based Association Study' (VEGAS) approach to assign variants to genes and to calculate gene-based P-values based on simulations. The VEGAS method was applied to each cohort separately before a gene-based meta-analysis was performed. In Stage 1, two known (FTO and TMEM18) and six novel (PEX2, MTFR2, SSFA2, IARS2, CEP295 and TXNDC12) loci were associated with BMI (P < 2.8 × 10(-6) for 17 941 gene tests). We confirmed all loci, and six of them were gene-wide significant in Stage 2 alone. We provide biological support for the loci by pathway, expression and methylation analyses. Our results indicate that gene-based meta-analysis of GWAS provides a useful strategy to find loci of interest that were not identified in standard single-marker analyses due to high allelic heterogeneity.

  • 111.
    Iggman, David
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Rosqvist, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Ärnlöv, Johan
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Beckman, Lena
    Rudling, Mats
    Risérus, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Role of Dietary Fats in Modulating Cardiometabolic Risk During Moderate Weight Gain: A Randomized Double-Blind Overfeeding Trial (LIPOGAIN Study)2014In: Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease, ISSN 2047-9980, E-ISSN 2047-9980, Vol. 3, no 5, article id e001095Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Whether the type of dietary fat could alter cardiometabolic responses to a hypercaloric diet is unknown. In addition, subclinical cardiometabolic consequences of moderate weight gain require further study.

    METHODS AND RESULTS: In a 7-week, double-blind, parallel-group, randomized controlled trial, 39 healthy, lean individuals (mean age of 27±4) consumed muffins (51% of energy [%E] from fat and 44%E refined carbohydrates) providing 750 kcal/day added to their habitual diets. All muffins had identical contents, except for type of fat; sunflower oil rich in polyunsaturated fatty acids (PUFA diet) or palm oil rich in saturated fatty acids (SFA diet). Despite comparable weight gain in the 2 groups, total: high-density lipoprotein (HDL) cholesterol, low-density lipoprotein:HDL cholesterol, and apolipoprotein B:AI ratios decreased during the PUFA versus the SFA diet (-0.37±0.59 versus +0.07±0.29, -0.31±0.49 versus +0.05±0.28, and -0.07±0.11 versus +0.01±0.07, P=0.003, P=0.007, and P=0.01 for between-group differences), whereas no significant differences were observed for other cardiometabolic risk markers. In the whole group (ie, independently of fat type), body weight increased (+2.2%, P<0.001) together with increased plasma proinsulin (+21%, P=0.007), insulin (+17%, P=0.003), proprotein convertase subtilisin/kexin type 9, (+9%, P=0.008) fibroblast growth factor-21 (+31%, P=0.04), endothelial markers vascular cell adhesion molecule-1, intercellular adhesion molecule-1, and E-selectin (+9, +5, and +10%, respectively, P<0.01 for all), whereas nonesterified fatty acids decreased (-28%, P=0.001).

    CONCLUSIONS: Excess energy from PUFA versus SFA reduces atherogenic lipoproteins. Modest weight gain in young individuals induces hyperproinsulinemia and increases biomarkers of endothelial dysfunction, effects that may be partly outweighed by the lipid-lowering effects of PUFA.

    CLINICAL TRIAL REGISTRATION URL: http://ClinicalTrials.gov. Unique identifier: NCT01427140.

  • 112.
    Iggman, David
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Ärnlöv, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab. School of Health and Social Studies, Dalarna University.
    Cederholm, Tommy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Risérus, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Association of Adipose Tissue Fatty Acids With Cardiovascular and All-Cause Mortality in Elderly Men2016In: JAMA cardiology, ISSN 2380-6591, Vol. 1, no 7, p. 745-753Article in journal (Refereed)
    Abstract [en]

    Importance: The major polyunsaturated fatty acids in adipose tissue objectively reflect long-term dietary intake, and may provide more reliable information than would self-reported intake. Whether adipose tissue fatty acids predict cardiovascular and all-cause mortality needs investigation.

    Objective: To investigate associations between adipose tissue fatty acids and cardiovascular and overall mortality in a cohort of elderly men.

    Design, Setting, and Participants: We hypothesized that polyunsaturated fatty acids reflecting dietary intake, are inversely associated with cardiovascular and all-cause mortality. In the Swedish cohort study Uppsala Longitudinal Cohort of Adult Men, buttock fatty acid composition was analyzed by gas-liquid chromatography in 1992 to 1993 and 2008. The study participants were followed during 11 311 person-years, between 1991 and 2011 (median follow-up, 14.8 years). In this community-based study that took place from 1970 to 1973, all men born in 1920 to 1924 in Uppsala, Sweden, were invited and 2322 (82%) were included (at age 50 years). At the reinvestigation at age 71 years, 1221 (73%) of the 1681 invited men participated. Adipose tissue biopsy specimens were taken in a subsample of 853 men. There was no loss to follow-up.

    Exposures: Adipose tissue proportions of 4 polyunsaturated fatty acids that were considered to mainly reflect dietary intake (linoleic acid, 18:2n-6; α-linolenic acid, 18:3n-3; eicosapentaenoic acid, 20:5n-3; and docosahexaenoic acid, 22:6n-3) comprised primary analyses, and all other available fatty acids were secondary analyses.

    Main Outcomes and Measures: Hazard ratios (HRs) for cardiovascular and all-cause mortality using Cox proportional hazards regression analyses, performed in 2015.

    Results: Among the 853 Swedish men, there were 605 deaths, of which 251 were cardiovascular deaths. After adjusting for risk factors, none of the 4 primary fatty acids were associated with cardiovascular mortality (HR, 0.92-1.05 for each standard deviation increase; P ≥ .27). Linoleic acid was inversely associated with all-cause mortality (HR, 0.90; 95% CI, 0.82-0.98; P = .02) and directly associated with intake (P < .001). In secondary analyses, palmitoleic acid, 16:1n-7 (HR, 1.11; 95% CI, 1.02-1.21; P = .02) was associated with higher all-cause mortality, whereas heptadecanoic acid, 17:0, tended to be associated with lower all-cause mortality (HR, 0.89; 95% CI, 0.79-1.00; P = .05). Arachidonic:linoleic acid ratio was associated with both cardiovascular (HR, 1.15; 95% CI, 1.05-1.31; P = .04) and all-cause (HR, 1.13; 95% CI, 1.04-1.23; P = .005) mortality.

    Conclusions and Relevance: Adipose tissue linoleic acid was inversely associated with all-cause mortality in elderly men, although not significantly with cardiovascular mortality.

  • 113. Iglesias, M. J.
    et al.
    Bruzelius, M.
    Hong, M-G
    Tregouet, D. A.
    Perisic, L.
    Franberg, M.
    Parini, P.
    Ganna, A.
    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.
    Nilsson, P.
    Hedin, U.
    Uhlen, M.
    Silveira, A.
    Morange, P. E.
    Hamsten, A.
    Schwenk, J. M.
    Odeberg, J.
    An affinity proteomics study for plasma biomarker candidates of cardiovascular disease in venous thromboembolism2015In: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, E-ISSN 1538-7836, Vol. 13, no S2, p. 956-956, article id PO564-WEDArticle in journal (Other academic)
  • 114.
    Imgenberg-Kreuz, Juliana
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Almlöf, Jonas Carlsson
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Leonard, Dag
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Alexsson, Andrei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Nordmark, Gunnel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Eloranta, Maija-Leena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Umeå, Sweden.
    Bengtsson, Anders A
    Lund University, Skane University Hospital, Lund, Sweden.
    Jönsen, Andreas
    Lund University, Skane University Hospital, Lund, Sweden.
    Padyukov, Leonid
    Karolinska University Hospital, Stockholm, Sweden.
    Gunnarsson, Iva
    Karolinska University Hospital, Stockholm, Sweden.
    Svenungsson, Elisabet
    Karolinska University Hospital, Stockholm, Sweden.
    Sjöwall, Christopher
    Linköping University, Linköping, Sweden.
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Sandling, Johanna K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    DNA methylation mapping identifies gene regulatory effects in patients with systemic lupus erythematosus2018In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 77, no 5, p. 736-743Article in journal (Refereed)
    Abstract [en]

    Objectives: Systemic lupus erythematosus (SLE) is a chronic autoimmune condition with heterogeneous presentation and complex aetiology where DNA methylation changes are emerging as a contributing factor. In order to discover novel epigenetic associations and investigate their relationship to genetic risk for SLE, we analysed DNA methylation profiles in a large collection of patients with SLE and healthy individuals.

    Methods: DNA extracted from blood from 548 patients with SLE and 587 healthy controls were analysed on the Illumina HumanMethylation 450 k BeadChip, which targets 485 000 CpG sites across the genome. Single nucleotide polymorphism (SNP) genotype data for 196 524 SNPs on the Illumina ImmunoChip from the same individuals were utilised for methylation quantitative trait loci (cis-meQTLs) analyses.

    Results: We identified and replicated differentially methylated CpGs (DMCs) in SLE at 7245 CpG sites in the genome. The largest methylation differences were observed at type I interferon-regulated genes which exhibited decreased methylation in SLE. We mapped cis-meQTLs and identified genetic regulation of methylation levels at 466 of the DMCs in SLE. The meQTLs for DMCs in SLE were enriched for genetic association to SLE, and included seven SLE genome-wide association study (GWAS) loci: PTPRC (CD45), MHC-class III, UHRF1BP1, IRF5, IRF7, IKZF3 and UBE2L3. In addition, we observed association between genotype and variance of methylation at 20 DMCs in SLE, including at the HLA-DQB2 locus.

    Conclusions: Our results suggest that several of the genetic risk variants for SLE may exert their influence on the phenotype through alteration of DNA methylation levels at regulatory regions of target genes.

  • 115.
    Ingelsson, Erik
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California, USA.
    Kilpeläinen, Tuomas O.
    The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
    Genome-wide association studies (GWAS) of adiposity2016In: The Genetics of Type 2 Diabetes and Related Traits: Biology, Physiology and Translation / [ed] Jose C. Florez, Cham: Springer Publishing Company, 2016, p. 91-109Chapter in book (Refereed)
    Abstract [en]

    Adiposity is strongly heritable and one of the leading risk factors for type 2 diabetes, cardiovascular disease, cancer, and premature death. In the past 8 years, genome-wide association studies (GWAS) have greatly increased our understanding of the genes and biological pathways that regulate adiposity by identifying more than 100 novel susceptibility loci for overall adiposity and more than 70 loci for body fat distribution. The results for overall adiposity highlight a significant neuronal component, whereas loci regulating body fat distribution demonstrate a central role for adipocyte biology and insulin resistance in the pathophysiology. The effect sizes of all identified loci are small, and even in aggregate, they explain <3 % of the variance in each adiposity trait. This and other evidence suggest that numerous new loci will be identified in extended meta-analyses in the future. The translation of the new discoveries into clinical care remains a major challenge. As the first step, further studies are required to establish the causal genes and variants and to disentangle the exact physiological mechanisms underlying each genotype-phenotype association.

  • 116. Jallow, Amadou
    et al.
    Ljunggren, Gunnar
    Wandell, Per
    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.
    Prevalence, incidence, mortality and co-morbidities amongst human immunodeficiency virus ( HIV) patients in Stockholm County, Sweden - The Greater Stockholm HIV Cohort Study2015In: AIDS Care, ISSN 0954-0121, E-ISSN 1360-0451, Vol. 27, no 2, p. 142-149Article in journal (Refereed)
    Abstract [en]

    The objective of this study was to develop a multidisciplinary guideline that supports the care and vocational rehabilitation of HIV-infected people with employment-related problems. The guideline was developed according to the "evidence-based guideline development" method developed by the Dutch Institute for Health Care Improvement. This method consists of the following steps: forming a multidisciplinary core group and an expert panel, formulating key questions, searching and appraising the available literature, formulating considerations and recommendations, peer reviewing the draft guideline, and authorizing the final guideline. All relevant professional associations were represented in the core group that was assembled to develop the guideline, i.e., HIV doctors, HIV nurses, general practitioners, occupational health physicians, psychologists, social workers, occupational health nurses, vocational experts, and insurance physicians. Five key questions for the guideline were formulated with the following themes: determinants of employment, disclosure and stigma, self-management, interventions, and the organization of care. In the literature review on these topics, 45 studies met the inclusion criteria. The methodological quality of the included articles was poor. Factors such as patient preferences and medical/ethical issues were considered. The recommendations in the guideline are a weighting of the scientific evidence and the considerations of the core group. The guideline, as well as its summary for daily practice, clarifies the most important barriers and facilitators to people with HIV either staying at work or returning to work, and it constitutes a clinical, easy-to-use guideline for health-care providers and how they can support people with HIV who want to work.

  • 117. Jayasinghe, Saroj
    et al.
    Lind, Lars
    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. Uppsala University, Science for Life Laboratory, SciLifeLab. MTM Research Centre, School of Science and Technology, Örebro University, Örebro, Sweden.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Lind, P. Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    DDT and its metabolites could contribute to the aetiology of chronic kidney disease of unknown aetiology (CKDu) and more studies are a priority2019In: Science of the Total Environment, ISSN 0048-9697, E-ISSN 1879-1026, Vol. 649, p. 1638-1639Article in journal (Refereed)
  • 118. Jayasinghe, Saroj
    et al.
    Lind, Lars
    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. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Lind, P. Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    High serum levels of p,p'-DDE are associated with an accelerated decline in GFR during 10 years follow-up.2018In: Science of the Total Environment, ISSN 0048-9697, E-ISSN 1879-1026, Vol. 644, p. 371-374Article in journal (Refereed)
    Abstract [en]

    Over the past 20 years, the global incidence of chronic kidney disease (CKD) has been increasing and organochlorine pesticides (such as DDT) is a suspected etiological factor. The present study examines the associations between low level background exposure to p,p'-DDE (1-dichloro-2,2-bis (p-chlorophenyl) ethylene), the main DDT metabolite, and kidney function during a 10-year follow-up. Data was analysed from the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study (n = 1016, 50% women, all aged 70 years). Serum levels of p,p'-DDE was measured by gas chromatography coupled to high-resolution mass spectrometry (GC/HRMS) at baseline (i.e. age of 70 years). Glomerular filtration rate (GFR) was estimated using serum creatinine and cystatin C at 70, 75 and 80 years of age. A significant decline in GFR was seen during the 10-year follow-up (-24 ml/min/1.73 m2, p < 0.0001). A significant negative interaction was seen between baseline p,p'-DDE levels and change in GFR over time (p < 0.0001) following adjustment for sex, systolic blood pressure, diabetes, BMI, smoking and education level at age 70. Subjects with the lowest levels of p,p'-DDE levels at age 70 showed the lowest decline in GFR over 10 years, while subjects with the highest p,p'-DDE levels showed the greatest decline. Baseline levels of p,p'-DDE were related to an accelerated reduction in GFR over 10 years suggesting a nephrotoxic effect of DDT/p,p'-DDE. These findings support a potential role for DDT in the epidemic of CKD of unknown etiology (CKDu) in agricultural communities of Sri Lanka and Central America where DDT was previously used.

  • 119. Jia, Ting
    et al.
    Huang, Xiaoyan
    Qureshi, Abdul R.
    Xu, Hong
    Ärnlöv, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Lindholm, Bengt
    Cederholm, Tommy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Stenvinkel, Peter
    Risérus, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Carrero, Juan J.
    Validation of insulin sensitivity surrogate indices and prediction of clinical outcomes in individuals with and without impaired renal function2014In: Kidney International, ISSN 0085-2538, E-ISSN 1523-1755, Vol. 86, no 2, p. 383-391Article in journal (Refereed)
    Abstract [en]

    As chronic kidney disease (CKD) progresses with abnormalities in glucose and insulin metabolism, commonly used insulin sensitivity indices (151s) may not be applicable in individuals with CKD. Here we sought to validate surrogate ISls against the glucose disposal rate by the gold-standard hyperinsulinemic euglycemic glucose clamp (HEGC) technique in 1074 elderly men of similar age (70 years) of whom 495 had and 579 did not have CKD (estimated glomerular filtration rate (eGFR) under 60 ml/min per 1.73 m2 (median eGFR of 46 ml/min per 1.73 m2)). All ISls provided satisfactory (weighted K over 0.6) estimates of the glucose disposal rate in patients with CKD. ISls derived from oral glucose tolerance tests (OGTTs) agreed better with HEGC than those from fasting samples (higher predictive accuracy). Regardless of CKD strata, all ISls allowed satisfactory clinical discrimination between the presence and absence of insulin resistance (glucose disposal rate under 4 mg/kg/min). We also assessed the ability of both HEGC and ISls to predict all-cause and cardiovascular mortality during a 10-year follow-up. Neither HEGC nor ISIs independently predicted mortality. Adjustment for renal function did not materially change these associations. Thus, ISls can be applied in individuals with moderately impaired renal function for diagnostic purposes. For research matters, OGTT-derived ISls may be preferred. Our data do not support the hypothesis of kidney function mediating insulin sensitivity (I5)-associated outcomes nor a role for IS as a predictor of mortality

  • 120.
    Jiang, Xia
    et al.
    Harvard TH Chan Sch Publ Hlth, Program Genet Epidemiol & Stat Genet, Dept Epidemiol, 677 Huntington Ave, Boston, MA USA.;Karolinska Inst, Inst Environm Med, Unit Cardiovasc Epidemiol, Nobels Vagen 13, S-17177 Stockholm, Sweden..
    O'Reilly, Paul F.
    Kings Coll London, Inst Psychiat, Dept Social Genet & Dev Psychiat, De Crespigny Pk, London SE5 8AF, England..
    Aschard, Hugues
    Harvard TH Chan Sch Publ Hlth, Program Genet Epidemiol & Stat Genet, Dept Epidemiol, 677 Huntington Ave, Boston, MA USA.;Inst Pasteur, Ctr Bioinformat Biostat & Biol Integrat C3BI, F-75724 Paris, France..
    Hsu, Yi-Hsiang
    Hebrew SeniorLife, Inst Aging Res, 1200 Ctr St, Boston, MA 02131 USA.;Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02115 USA.;Harvard Med Sch, Boston, MA 02115 USA.;Broad Inst Harvard & Massachusetts Inst Technol, Boston, MA 02142 USA..
    Richards, J. Brent
    Dept Med, 3755 Cote Ste Catherine Rd,Suite H-413, Montreal, PQ H3T 1E2, Canada.;Dept Human Genet, 3755 Cote Ste Catherine Rd,Suite H-413, Montreal, PQ H3T 1E2, Canada.;Dept Epidemiol, 3755 Cote Ste Catherine Rd,Suite H-413, Montreal, PQ H3T 1E2, Canada.;Dept Biostat, 3755 Cote Ste Catherine Rd,Suite H-413, Montreal, PQ H3T 1E2, Canada..
    Dupuis, Josee
    Boston Univ, Dept Biostat, Sch Publ Hlth, Crosstown Ctr, 801 Massachusetts Ave,3rd Floor, Boston, MA 02118 USA.;Framingham Heart Dis Epidemiol Study, 73 Mt Wayte Ave, Framingham, MA 01702 USA..
    Ingelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Stanford Univ, Sch Med, Div Cardiovasc Med, Dept Med, Stanford, USA.
    Karasik, David
    Hebrew SeniorLife, Inst Aging Res, 1200 Ctr St, Boston, MA 02131 USA..
    Pilz, Stefan
    Med Univ Graz, Div Endocrinol & Diabetol, Dept Internal Med, Auenbruggerpl 15, A-8036 Graz, Austria..
    Berry, Diane
    UCL, Populat Policy & Practice, Inst Child Hlth, Great Ormond St, London WC1E 6BT, England..
    Kestenbaum, Bryan
    Kidney Res Inst, Div Nephrol, 325 Ninth Ave, Seattle, WA 98104 USA..
    Zheng, Jusheng
    Univ Cambridge, MRC Epidemiol Unit, Sch Clin Med, Cambridge Biomed Campus, Cambridge CB2 0QQ, England..
    Luan, Jianan
    Univ Cambridge, MRC Epidemiol Unit, Sch Clin Med, Cambridge Biomed Campus, Cambridge CB2 0QQ, England..
    Sofianopoulou, Eleni
    Univ Cambridge, Strangeways Res Lab, Dept Publ Hlth & Primary Care, Worts Causeway, Cambridge CB1 8RN, England..
    Streeten, Elizabeth A.
    Univ Maryland, Genet & Personalized Med Program, Sch Med, Howard Hall Room 567, Baltimore, MD 21201 USA..
    Albanes, Demetrius
    NCI, Metabol Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, 9609 Med Ctr Dr, Bethesda, MD 20892 USA..
    Lutsey, Pamela L.
    Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, 1300S 2nd St,Suite 300, Minneapolis, MN 55454 USA..
    Yao, Lu
    Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, 1300S 2nd St,Suite 300, Minneapolis, MN 55454 USA..
    Tang, Weihong
    Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, 1300S 2nd St,Suite 300, Minneapolis, MN 55454 USA..
    Econs, Michael J.
    Indiana Univ, Dept Med, Endocrinol, 1120W Michigan St, Indianapolis, IN 46202 USA..
    Wallaschofski, Henri
    Univ Med Greifswald, Inst Clin Chem & Lab Med, D-17489 Greifswald, Germany.;DZHK German Ctr Cardiovasc Res, Partner Site, D-13316 Greifswald, Germany..
    Voelzke, Henry
    DZHK German Ctr Cardiovasc Res, Partner Site, D-13316 Greifswald, Germany.;Univ Med Greifswald, Inst Community Med, SHIP Klinisch Epidemiol Forsch, Walther Rathenau Str 48, D-17475 Greifswald, Germany..
    Zhou, Ang
    Univ South Australia, Ctr Populat Hlth Res, Sansom Inst Hlth Res, Adelaide, SA 5001, Australia..
    Power, Chris
    UCL, Populat Policy & Practice, Inst Child Hlth, Great Ormond St, London WC1E 6BT, England..
    McCarthy, Mark I.
    Univ Oxford, Churchill Hosp, Oxford Ctr Diabet Endocrinol & Metab, Old Rd, Oxford OX3 7LJ, England.;Univ Oxford, Wellcome Ctr Human Genet, Roosevelt Dr, Oxford OX3 7BN, England.;Churchill Hosp, Oxford NIHR Biomed Res Ctr, Old Rd, Oxford OX3 7LJ, England..
    Michos, Erin D.
    Johns Hopkins Sch Med, Ciccarone Ctr Prevent Heart Dis, Div Cardiol, Baltimore, MD 21287 USA.;Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA..
    Boerwinkle, Eric
    Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Houston, TX 77030 USA..
    Weinstein, Stephanie J.
    NCI, Metabol Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, 9609 Med Ctr Dr, Bethesda, MD 20892 USA..
    Freedman, Neal D.
    NCI, Metabol Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, 9609 Med Ctr Dr, Bethesda, MD 20892 USA..
    Huang, Wen-Yi
    NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, 9609 Med Ctr Dr, Bethesda, MD 20892 USA..
    Van Schoor, Natasja M.
    Vrije Univ Amsterdam Med Ctr, Dept Epidemiol & Biostat, Amsterdam Publ Hlth Res Inst, Boelelaan 1089a, NL-1081 HV Amsterdam, Netherlands..
    van der Velde, Nathalie
    Erasmus MC, Dept Epidemiol, Postbus 2040, NL-3000 CA Rotterdam, Netherlands.;AMC, Internal Med, Dept Geriatr, POB 22700, NL-1100 DE Amsterdam, Netherlands..
    de Groot, Lisette C. P. G. M.
    Wageningen Univ, Dept Human Nutr, POB 176700, NL-700 AA Wageningen, Netherlands..
    Enneman, Anke
    Erasmus MC, Dept Epidemiol, Postbus 2040, NL-3000 CA Rotterdam, Netherlands..
    Cupples, L. Adrienne
    Boston Univ, Dept Biostat, Sch Publ Hlth, Crosstown Ctr, 801 Massachusetts Ave,3rd Floor, Boston, MA 02118 USA.;Framingham Heart Dis Epidemiol Study, 73 Mt Wayte Ave, Framingham, MA 01702 USA..
    Booth, Sarah L.
    Tufts Univ, Vitamin K Lab, Jean Mayer USDA Human Nutr Res Ctr Aging, 711 Washington St, Boston, MA 02111 USA..
    Vasan, Ramachandran S.
    Framingham Heart Dis Epidemiol Study, 73 Mt Wayte Ave, Framingham, MA 01702 USA..
    Liu, Ching-Ti
    Boston Univ, Dept Biostat, Sch Publ Hlth, Crosstown Ctr, 801 Massachusetts Ave,3rd Floor, Boston, MA 02118 USA..
    Zhou, Yanhua
    Boston Univ, Dept Biostat, Sch Publ Hlth, Crosstown Ctr, 801 Massachusetts Ave,3rd Floor, Boston, MA 02118 USA..
    Ripatti, Samuli
    Univ Helsinki, Stat & Translat Genet, Biomedicum, Tukholmankatu 8, Helsinki 2U, Finland..
    Ohlsson, Claes
    Univ Gothenburg, Dept Internal Med & Clin Nutr, Vita Straket 11, S-41345 Gothenburg, Sweden..
    Vandenput, Liesbeth
    Univ Gothenburg, Dept Internal Med & Clin Nutr, Vita Straket 11, S-41345 Gothenburg, Sweden..
    Lorentzon, Mattias
    Univ Gothenburg, Dept Geriatr Med, S-43180 Molndal, Sweden.;Sahlgrens Univ Hosp, S-43180 Molndal, Sweden..
    Eriksson, Johan G.
    Univ Helsinki, Dept Gen Practice & Primary Hlth Care, POB 20,Tukholmankatu 8 B, FIN-00014 Helsinki, Finland.;Univ Helsinki, Helsinki Univ Hosp, POB 20,Tukholmankatu 8 B, FIN-00014 Helsinki, Finland.;Univ Helsinki, Folkhalsan Res Ctr, POB 2000014, Helsinki, Finland..
    Shea, M. Kyla
    Tufts Univ, Vitamin K Lab, Jean Mayer USDA Human Nutr Res Ctr Aging, 711 Washington St, Boston, MA 02111 USA..
    Houston, Denise K.
    Wake Forest Sch Med, Sticht Ctr Healthy Aging & Alzheimers Prevent, Med Ctr Blvd, Winston Salem, NC 27157 USA..
    Kritchevsky, Stephen B.
    Wake Forest Sch Med, Sticht Ctr Healthy Aging & Alzheimers Prevent, Med Ctr Blvd, Winston Salem, NC 27157 USA..
    Liu, Yongmei
    Wake Forest Sch Med, Div Publ Hlth Sci, Dept Epidemiol & Prevent, Med Ctr Blvd, Winston Salem, NC 27157 USA..
    Lohman, Kurt K.
    Wake Forest Sch Med, Div Publ Hlth Sci, Dept Biostat Sci, Med Ctr Blvd, Winston Salem, NC 27157 USA..
    Ferrucci, Luigi
    NIA, Longitudinal Studies Sect, Intramural Res Program, NIH, Baltimore, MD 21225 USA..
    Peacock, Munro
    Indiana Univ, Dept Med, Endocrinol, 1120W Michigan St, Indianapolis, IN 46202 USA..
    Gieger, Christian
    German Res Ctr Environm Hlth, Mol Epidemiol, AME, Ingolstadter Landstr 1, D-85764 Neuherberg, Germany..
    Beekman, Marian
    Leiden Univ, Mol Epidemiol, Med Ctr, Einthovenweg 20, NL-2333 ZC Leiden, Netherlands..
    Slagboom, Eline
    Leiden Univ, Mol Epidemiol, Med Ctr, Einthovenweg 20, NL-2333 ZC Leiden, Netherlands..
    Deelen, Joris
    Leiden Univ, Mol Epidemiol, Med Ctr, Einthovenweg 20, NL-2333 ZC Leiden, Netherlands.;Max Planck Inst Biol Ageing, Joseph Stelzmann Str 9b, D-50931 Cologne, Germany..
    van Heemst, Diana
    Leiden Univ, Gerontol & Geriatr, Med Ctr, Albinusdreef 2, NL-2333 ZA Leiden, Netherlands..
    Kleber, Marcus E.
    Heidelberg Univ, Med Fac Mannheim, Dept Med Nephrol Hypertensiol Rheumatol Endocrino, Theodor Kutzer Ufer1, D-68167 Mannheim, Germany..
    Maerz, Winfried
    Heidelberg Univ, Med Fac Mannheim, Dept Med Nephrol Hypertensiol Rheumatol Endocrino, Theodor Kutzer Ufer1, D-68167 Mannheim, Germany.;Med Univ Graz, Clin Inst Med & Chem Lab Diagnost, Auenbruggerpl 15, A-8036 Graz, Austria.;SYNLAB Holding Deutschland GmbH, Gubener Str 39, D-86156 Augsburg, Germany..
    de Boer, Ian H.
    Univ Washington, Div Nephrol, 325 Ninth Ave, Washington, DC 98104 USA.;Univ Washington, Kidney Res Inst, 325 Ninth Ave, Washington, DC 98104 USA..
    Wood, Alexis C.
    ARS, USDA, Childrens Nutr Res Ctr, 1100 Bates Ave, Houston, TX 77071 USA..
    Rotter, Jerome I.
    Harbor UCLA Med Ctr, Inst Translat Genom & Populat Sci, Los Angeles Biomed Res Inst, Torrance, CA 90502 USA.;Harbor UCLA Med Ctr, Dept Pediat, Torrance, CA 90502 USA..
    Rich, Stephen S.
    Univ Virginia, Dept Publ Hlth Sci, Charlottesville, VA 22908 USA.;Univ Virginia, Ctr Publ Hlth Genom, Charlottesville, VA 22908 USA..
    Robinson-Cohen, Cassianne
    Vanderbilt Univ, Div Nephrol, Dept Med, Med Ctr, 1161 21st Ave S, Nashville, TN 37232 USA..
    den Heijer, Martin
    Erasmus MC, Dept Internal Med, Postbus 2040, NL-3000 CA Rotterdam, Netherlands..
    Jarvelin, Marjo-Riitta
    Imperial Coll London, Epidemiol & Biostat Sch Publ Hlth, 156 Norfolk Pl,St Marys Campus, London W2 1PG, England.;Univ Oulu, Fac Med, Ctr Life Course Hlth Res, Oulu 90014, Finland.;Univ Oulu, Bioctr Oulu, POB 5000,Aapistie 5A, FI-90014 Oulu, Finland.;Oulu Univ Hosp, Unit Primary Care, Kajaanintie 50 POB 20,90029 OYS, FI-90220 Oulu, Finland..
    Cavadino, Alana
    UCL, Populat Policy & Practice, Inst Child Hlth, Great Ormond St, London WC1E 6BT, England.;Queen Mary Univ London, Ctr Environm & Prevent Med, Wolfson Inst Prevent Med, Barts & London Sch Med & Dent, Charterhouse Sq, London EC1M 6BQ, England..
    Joshi, Peter K.
    Univ Edinburgh, Usher Inst Populat Hlth Sci & Informat, Ctr Global Hlth Res, Teviot Pl, Edinburgh EH8 9AG, Midlothian, Scotland..
    Wilson, James F.
    Univ Edinburgh, Usher Inst Populat Hlth Sci & Informat, Ctr Global Hlth Res, Teviot Pl, Edinburgh EH8 9AG, Midlothian, Scotland.;Univ Edinburgh, MRC Inst Genet Mol Med, Western Gen Hosp, MRC Human Genet Unit, Edinburgh EH4 2XU, Midlothian, Scotland..
    Hayward, Caroline
    Univ Edinburgh, MRC Inst Genet Mol Med, Western Gen Hosp, MRC Human Genet Unit, Edinburgh EH4 2XU, Midlothian, Scotland..
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Michaëlsson, Karl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Trompet, Stella
    Leiden Univ, Gerontol & Geriatr, Med Ctr, Albinusdreef 2, NL-2333 ZA Leiden, Netherlands.;Leiden Univ, Dept Cardiol, Med Ctr, Albinusdreef 2, NL-2333 ZA Leiden, Netherlands..
    Zillikens, M. Carola
    Erasmus MC, Dept Internal Med, Postbus 2040, NL-3000 CA Rotterdam, Netherlands..
    Uitterlinden, Andre G.
    Erasmus MC, Dept Epidemiol, Postbus 2040, NL-3000 CA Rotterdam, Netherlands.;Erasmus MC, Dept Internal Med, Postbus 2040, NL-3000 CA Rotterdam, Netherlands..
    Rivadeneira, Fernando
    Erasmus MC, Dept Epidemiol, Postbus 2040, NL-3000 CA Rotterdam, Netherlands.;Erasmus MC, Dept Internal Med, Postbus 2040, NL-3000 CA Rotterdam, Netherlands..
    Broer, Linda
    Erasmus MC, Dept Internal Med, Postbus 2040, NL-3000 CA Rotterdam, Netherlands..
    Zgaga, Lina
    Univ Dublin, Trinity Coll Dublin, Dept Publ Hlth & Primary Care, Inst Populat Hlth, D02 PN40, Dublin 24, Ireland..
    Campbell, Harry
    Univ Edinburgh, Usher Inst Populat Hlth Sci & Informat, Ctr Global Hlth Res, Teviot Pl, Edinburgh EH8 9AG, Midlothian, Scotland.;Univ Edinburgh, Western Gen Hosp, Inst Genet & Mol Med, Edinburgh EH4 2XU, Midlothian, Scotland..
    Theodoratou, Evropi
    Univ Edinburgh, Usher Inst Populat Hlth Sci & Informat, Ctr Global Hlth Res, Teviot Pl, Edinburgh EH8 9AG, Midlothian, Scotland.;Univ Edinburgh, Western Gen Hosp, Inst Genet & Mol Med, Edinburgh EH4 2XU, Midlothian, Scotland..
    Farrington, Susan M.
    Univ Edinburgh, Western Gen Hosp, Inst Genet & Mol Med, Edinburgh EH4 2XU, Midlothian, Scotland..
    Timofeeva, Maria
    Univ Edinburgh, Western Gen Hosp, Inst Genet & Mol Med, Edinburgh EH4 2XU, Midlothian, Scotland..
    Dunlop, Malcolm G.
    Univ Edinburgh, Western Gen Hosp, Inst Genet & Mol Med, Edinburgh EH4 2XU, Midlothian, Scotland..
    Valdes, Ana M.
    Kings Coll London, Dept Twin Res & Genet Epidemiol, St Thomas Campus,Westminster Bridge Rd, London SE1 7EH, England.;Univ Nottingham, Sch Med, City Hosp, Hucknall Rd, Nottingham NG5 1PB, England..
    Tikkanen, Emmi
    Univ Helsinki, FIMM Inst Mol Med Finland, POB 20, FI-00014 Helsinki, Finland..
    Lehtimaki, Terho
    Fimlab Labs, Dept Clin Chem, Tampere 33520, Finland.;Univ Tampere, Dept Clin Chem, Finnish Cardiovasc Res Ctr Tampere, Fac Med & Life Sci, Tampere 33014, Finland..
    Lyytikainen, Leo-Pekka
    Fimlab Labs, Dept Clin Chem, Tampere 33520, Finland.;Univ Tampere, Dept Clin Chem, Finnish Cardiovasc Res Ctr Tampere, Fac Med & Life Sci, Tampere 33014, Finland..
    Kahonen, Mika
    Tampere Univ Hosp, Dept Clin Physiol, Tampere 33521, Finland.;Univ Tampere, Dept Clin Physiol, Finnish Cardiovasc Res Ctr Tampere, Fac Med & Life Sci, Tampere 33014, Finland..
    Raitakari, Olli T.
    Turku Univ Hosp, Dept Clin Physiol & Nucl Med, Turku 20521, Finland.;Univ Turku, Res Ctr Appl & Prevent Cardiovasc Med, Turku 20014, Finland..
    Mikkila, Vera
    Acad Finland, Hakaniemenranta 6,POB 131, FI-00531 Helsinki, Finland..
    Ikram, M. Arfan
    Erasmus MC, Dept Epidemiol, Postbus 2040, NL-3000 CA Rotterdam, Netherlands..
    Sattar, Naveed
    BHF Glasgow Cardiovasc Res Ctr, Fac Med, Univ Ave, Glasgow G12 8QQ, Lanark, Scotland..
    Jukema, J. Wouter
    Leiden Univ, Dept Cardiol, Med Ctr, Albinusdreef 2, NL-2333 ZA Leiden, Netherlands.;Leiden Univ, Einthoven Lab Expt Vasc Med, Med Ctr, Albinusdreef 2, NL-2333 ZA Leiden, Netherlands..
    Wareham, Nicholas J.
    Univ Cambridge, MRC Epidemiol Unit, Sch Clin Med, Cambridge Biomed Campus, Cambridge CB2 0QQ, England..
    Langenberg, Claudia
    Univ Cambridge, MRC Epidemiol Unit, Sch Clin Med, Cambridge Biomed Campus, Cambridge CB2 0QQ, England..
    Forouhi, Nita G.
    Univ Cambridge, MRC Epidemiol Unit, Sch Clin Med, Cambridge Biomed Campus, Cambridge CB2 0QQ, England..
    Gundersen, Thomas E.
    Vitas AS, Gaustadaleen 21, N-0349 Oslo, Norway..
    Khaw, Kay-Tee
    Univ Cambridge, Strangeways Res Lab, Dept Publ Hlth & Primary Care, Worts Causeway, Cambridge CB1 8RN, England..
    Butterworth, Adam S.
    Univ Cambridge, Strangeways Res Lab, Dept Publ Hlth & Primary Care, Worts Causeway, Cambridge CB1 8RN, England..
    Danesh, John
    Univ Cambridge, Strangeways Res Lab, Dept Publ Hlth & Primary Care, Worts Causeway, Cambridge CB1 8RN, England.;Wellcome Trust Sanger Inst, Wellcome Genome Campus, Cambridge CB10 1SA, England..
    Spector, Timothy
    Kings Coll London, Dept Twin Res & Genet Epidemiol, St Thomas Campus,Westminster Bridge Rd, London SE1 7EH, England..
    Wang, Thomas J.
    Vanderbilt Heart & Vasc Inst, Div Cardiovasc Med, 2220 Pierce Ave 383 Preston Res Bldg, Nashville, TN 37232 USA..
    Hypponen, Elina
    UCL, Populat Policy & Practice, Inst Child Hlth, Great Ormond St, London WC1E 6BT, England.;Univ South Australia, Ctr Populat Hlth Res, Sansom Inst Hlth Res, Adelaide, SA 5001, Australia..
    Kraft, Peter
    Harvard TH Chan Sch Publ Hlth, Program Genet Epidemiol & Stat Genet, Dept Epidemiol, 677 Huntington Ave, Boston, MA USA..
    Kiel, Douglas P.
    Hebrew SeniorLife, Inst Aging Res, 1200 Ctr St, Boston, MA 02131 USA.;Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02115 USA.;Harvard Med Sch, Boston, MA 02115 USA.;Broad Inst Harvard & Massachusetts Inst Technol, Boston, MA 02142 USA..
    Genome-wide association study in 79,366 European-ancestry individuals informs the genetic architecture of 25-hydroxyvitamin D levels2018In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 9, article id 260Article in journal (Refereed)
    Abstract [en]

    Vitamin D is a steroid hormone precursor that is associated with a range of human traits and diseases. Previous GWAS of serum 25-hydroxyvitamin D concentrations have identified four genome-wide significant loci (GC, NADSYN1/DHCR7, CYP2R1, CYP24A1). In this study, we expand the previous SUNLIGHT Consortium GWAS discovery sample size from 16,125 to 79,366 (all European descent). This larger GWAS yields two additional loci harboring genome-wide significant variants (P = 4.7×10−9 at rs8018720 in SEC23A, and P = 1.9×10−14 at rs10745742 in AMDHD1). The overall estimate of heritability of 25-hydroxyvitamin D serum concentrations attributable to GWAS common SNPs is 7.5%, with statistically significant loci explaining 38% of this total. Further investigation identifies signal enrichment in immune and hematopoietic tissues, and clustering with autoimmune diseases in cell-type-specific analysis. Larger studies are required to identify additional common SNPs, and to explore the role of rare or structural variants and gene–gene interactions in the heritability of circulating 25-hydroxyvitamin D levels.

  • 121.
    Jobs, Elisabeth
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Adamsson, Viola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Jobs, Magnus
    Nerpin, Elisabet
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Ingelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Ärnlöv, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Risérus, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Influence of a prudent diet on circulating cathepsin S in humans2014In: Nutrition Journal, ISSN 1475-2891, E-ISSN 1475-2891, Vol. 13, p. 84-Article in journal (Refereed)
    Abstract [en]

    Background: Increased circulating cathepsin S levels have been linked to increased risk of cardiometabolic diseases and cancer. However, whether cathepsin S is a modifiable risk factor is unclear. We aimed to investigate the effects of a prudent diet on plasma cathepsin S levels in healthy individuals. Findings: Explorative analyses of a randomized study were performed in 88 normal to slightly overweight and hyperlipidemic men and women (aged 25 to 65) that were randomly assigned to ad libitum prudent diet, i.e. healthy Nordic diet (ND) or a control group (habitual Western diet) for 6 weeks. Whereas all foods in the ND were provided, the control group was advised to consume their habitual diet throughout the study. The ND was in line with dietary recommendations, e. g. low in saturated fats, sugars and salt, but high in plant-based foods rich in fibre and unsaturated fats. The ND significantly decreased cathepsin S levels (from 20.1 (+/-4.0 SD) to 19.7 mu g/L (+/-4.3 SD)) compared with control group (from 18.2 (+/-2.9 SD) to 19.1 mu g/L (+/-3.8 SD)). This difference remained after adjusting for sex and change in insulin sensitivity (P = 0.03), and near significant after adjusting for baseline cathepsin S levels (P = 0.06), but not for change in weight or LDL-C. Changes in cathepsin S levels were directly correlated with change in LDL-C. Conclusions: Compared with a habitual control diet, a provided ad libitum healthy Nordic diet decreased cathepsin S levels in healthy individuals, possibly mediated by weight loss or lowered LDL-C. These differences between groups in cathepsin S were however not robust and therefore need further investigation.

  • 122. Joshi, Peter K
    et al.
    Esko, Tonu
    Mattsson, Hannele
    Eklund, Niina
    Gandin, Ilaria
    Nutile, Teresa
    Jackson, Anne U
    Schurmann, Claudia
    Smith, Albert V
    Zhang, Weihua
    Okada, Yukinori
    Stančáková, Alena
    Faul, Jessica D
    Zhao, Wei
    Bartz, Traci M
    Concas, Maria Pina
    Franceschini, Nora
    Enroth, Stefan
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Vitart, Veronique
    Trompet, Stella
    Guo, Xiuqing
    Chasman, Daniel I
    O'Connel, Jeffrey R
    Corre, Tanguy
    Nongmaithem, Suraj S
    Chen, Yuning
    Mangino, Massimo
    Ruggiero, Daniela
    Traglia, Michela
    Farmaki, Aliki-Eleni
    Kacprowski, Tim
    Bjonnes, Andrew
    van der Spek, Ashley
    Wu, Ying
    Giri, Anil K
    Yanek, Lisa R
    Wang, Lihua
    Hofer, Edith
    Rietveld, Cornelius A
    McLeod, Olga
    Cornelis, Marilyn C
    Pattaro, Cristian
    Verweij, Niek
    Baumbach, Clemens
    Abdellaoui, Abdel
    Warren, Helen R
    Vuckovic, Dragana
    Mei, Hao
    Bouchard, Claude
    Perry, John R B
    Cappellani, Stefania
    Mirza, Saira S
    Benton, Miles C
    Broeckel, Ulrich
    Medland, Sarah E
    Lind, Penelope A
    Malerba, Giovanni
    Drong, Alexander
    Yengo, Loic
    Bielak, Lawrence F
    Zhi, Degui
    van der Most, Peter J
    Shriner, Daniel
    Mägi, Reedik
    Hemani, Gibran
    Karaderi, Tugce
    Wang, Zhaoming
    Liu, Tian
    Demuth, Ilja
    Zhao, Jing Hua
    Meng, Weihua
    Lataniotis, Lazaros
    van der Laan, Sander W
    Bradfield, Jonathan P
    Wood, Andrew R
    Bonnefond, Amelie
    Ahluwalia, Tarunveer S
    Hall, Leanne M
    Salvi, Erika
    Yazar, Seyhan
    Carstensen, Lisbeth
    de Haan, Hugoline G
    Abney, Mark
    Afzal, Uzma
    Allison, Matthew A
    Amin, Najaf
    Asselbergs, Folkert W
    Bakker, Stephan J L
    Barr, R Graham
    Baumeister, Sebastian E
    Benjamin, Daniel J
    Bergmann, Sven
    Boerwinkle, Eric
    Bottinger, Erwin P
    Campbell, Archie
    Chakravarti, Aravinda
    Chan, Yingleong
    Chanock, Stephen J
    Chen, Constance
    Chen, Y-D Ida
    Collins, Francis S
    Connell, John
    Correa, Adolfo
    Cupples, L Adrienne
    Smith, George Davey
    Davies, Gail
    Dörr, Marcus
    Ehret, Georg
    Ellis, Stephen B
    Feenstra, Bjarke
    Feitosa, Mary F
    Ford, Ian
    Fox, Caroline S
    Frayling, Timothy M
    Friedrich, Nele
    Geller, Frank
    Scotland, Generation
    Gillham-Nasenya, Irina
    Gottesman, Omri
    Graff, Misa
    Grodstein, Francine
    Gu, Charles
    Haley, Chris
    Hammond, Christopher J
    Harris, Sarah E
    Harris, Tamara B
    Hastie, Nicholas D
    Heard-Costa, Nancy L
    Heikkilä, Kauko
    Hocking, Lynne J
    Homuth, Georg
    Hottenga, Jouke-Jan
    Huang, Jinyan
    Huffman, Jennifer E
    Hysi, Pirro G
    Ikram, M Arfan
    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.
    Joensuu, Anni
    Johansson, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Jousilahti, Pekka
    Jukema, J Wouter
    Kähönen, Mika
    Kamatani, Yoichiro
    Kanoni, Stavroula
    Kerr, Shona M
    Khan, Nazir M
    Koellinger, Philipp
    Koistinen, Heikki A
    Kooner, Manraj K
    Kubo, Michiaki
    Kuusisto, Johanna
    Lahti, Jari
    Launer, Lenore J
    Lea, Rodney A
    Lehne, Benjamin
    Lehtimäki, Terho
    Liewald, David C M
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Loh, Marie
    Lokki, Marja-Liisa
    London, Stephanie J
    Loomis, Stephanie J
    Loukola, Anu
    Lu, Yingchang
    Lumley, Thomas
    Lundqvist, Annamari
    Männistö, Satu
    Marques-Vidal, Pedro
    Masciullo, Corrado
    Matchan, Angela
    Mathias, Rasika A
    Matsuda, Koichi
    Meigs, James B
    Meisinger, Christa
    Meitinger, Thomas
    Menni, Cristina
    Mentch, Frank D
    Mihailov, Evelin
    Milani, Lili
    Montasser, May E
    Montgomery, Grant W
    Morrison, Alanna
    Myers, Richard H
    Nadukuru, Rajiv
    Navarro, Pau
    Nelis, Mari
    Nieminen, Markku S
    Nolte, Ilja M
    O'Connor, George T
    Ogunniyi, Adesola
    Padmanabhan, Sandosh
    Palmas, Walter R
    Pankow, James S
    Patarcic, Inga
    Pavani, Francesca
    Peyser, Patricia A
    Pietilainen, Kirsi
    Poulter, Neil
    Prokopenko, Inga
    Ralhan, Sarju
    Redmond, Paul
    Rich, Stephen S
    Rissanen, Harri
    Robino, Antonietta
    Rose, Lynda M
    Rose, Richard
    Sala, Cinzia
    Salako, Babatunde
    Salomaa, Veikko
    Sarin, Antti-Pekka
    Saxena, Richa
    Schmidt, Helena
    Scott, Laura J
    Scott, William R
    Sennblad, Bengt
    Seshadri, Sudha
    Sever, Peter
    Shrestha, Smeeta
    Smith, Blair H
    Smith, Jennifer A
    Soranzo, Nicole
    Sotoodehnia, Nona
    Southam, Lorraine
    Stanton, Alice V
    Stathopoulou, Maria G
    Strauch, Konstantin
    Strawbridge, Rona J
    Suderman, Matthew J
    Tandon, Nikhil
    Tang, Sian-Tsun
    Taylor, Kent D
    Tayo, Bamidele O
    Töglhofer, Anna Maria
    Tomaszewski, Maciej
    Tšernikova, Natalia
    Tuomilehto, Jaakko
    Uitterlinden, Andre G
    Vaidya, Dhananjay
    van Hylckama Vlieg, Astrid
    van Setten, Jessica
    Vasankari, Tuula
    Vedantam, Sailaja
    Vlachopoulou, Efthymia
    Vozzi, Diego
    Vuoksimaa, Eero
    Waldenberger, Melanie
    Ware, Erin B
    Wentworth-Shields, William
    Whitfield, John B
    Wild, Sarah
    Willemsen, Gonneke
    Yajnik, Chittaranjan S
    Yao, Jie
    Zaza, Gianluigi
    Zhu, Xiaofeng
    Salem, Rany M
    Melbye, Mads
    Bisgaard, Hans
    Samani, Nilesh J
    Cusi, Daniele
    Mackey, David A
    Cooper, Richard S
    Froguel, Philippe
    Pasterkamp, Gerard
    Grant, Struan F A
    Hakonarson, Hakon
    Ferrucci, Luigi
    Scott, Robert A
    Morris, Andrew D
    Palmer, Colin N A
    Dedoussis, George
    Deloukas, Panos
    Bertram, Lars
    Lindenberger, Ulman
    Berndt, Sonja I
    Lindgren, Cecilia M
    Timpson, Nicholas J
    Tönjes, Anke
    Munroe, Patricia B
    Sørensen, Thorkild I A
    Rotimi, Charles N
    Arnett, Donna K
    Oldehinkel, Albertine J
    Kardia, Sharon L R
    Balkau, Beverley
    Gambaro, Giovanni
    Morris, Andrew P
    Eriksson, Johan G
    Wright, Margie J
    Martin, Nicholas G
    Hunt, Steven C
    Starr, John M
    Deary, Ian J
    Griffiths, Lyn R
    Tiemeier, Henning
    Pirastu, Nicola
    Kaprio, Jaakko
    Wareham, Nicholas J
    Pérusse, Louis
    Wilson, James G
    Girotto, Giorgia
    Caulfield, Mark J
    Raitakari, Olli
    Boomsma, Dorret I
    Gieger, Christian
    van der Harst, Pim
    Hicks, Andrew A
    Kraft, Peter
    Sinisalo, Juha
    Knekt, Paul
    Johannesson, Magnus
    Magnusson, Patrik K E
    Hamsten, Anders
    Schmidt, Reinhold
    Borecki, Ingrid B
    Vartiainen, Erkki
    Becker, Diane M
    Bharadwaj, Dwaipayan
    Mohlke, Karen L
    Boehnke, Michael
    van Duijn, Cornelia M
    Sanghera, Dharambir K
    Teumer, Alexander
    Zeggini, Eleftheria
    Metspalu, Andres
    Gasparini, Paolo
    Ulivi, Sheila
    Ober, Carole
    Toniolo, Daniela
    Rudan, Igor
    Porteous, David J
    Ciullo, Marina
    Spector, Tim D
    Hayward, Caroline
    Dupuis, Josée
    Loos, Ruth J F
    Wright, Alan F
    Chandak, Giriraj R
    Vollenweider, Peter
    Shuldiner, Alan R
    Ridker, Paul M
    Rotter, Jerome I
    Sattar, Naveed
    Gyllensten, Ulf
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    North, Kari E
    Pirastu, Mario
    Psaty, Bruce M
    Weir, David R
    Laakso, Markku
    Gudnason, Vilmundur
    Takahashi, Atsushi
    Chambers, John C
    Kooner, Jaspal S
    Strachan, David P
    Campbell, Harry
    Hirschhorn, Joel N
    Perola, Markus
    Polašek, Ozren
    Wilson, James F
    Directional dominance on stature and cognition in diverse human populations2015In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 523, no 7561, p. 459-462Article in journal (Refereed)
    Abstract [en]

    Homozygosity has long been associated with rare, often devastating, Mendelian disorders, and Darwin was one of the first to recognize that inbreeding reduces evolutionary fitness. However, the effect of the more distant parental relatedness that is common in modern human populations is less well understood. Genomic data now allow us to investigate the effects of homozygosity on traits of public health importance by observing contiguous homozygous segments (runs of homozygosity), which are inferred to be homozygous along their complete length. Given the low levels of genome-wide homozygosity prevalent in most human populations, information is required on very large numbers of people to provide sufficient power. Here we use runs of homozygosity to study 16 health-related quantitative traits in 354,224 individuals from 102 cohorts, and find statistically significant associations between summed runs of homozygosity and four complex traits: height, forced expiratory lung volume in one second, general cognitive ability and educational attainment (P < 1 × 10(-300), 2.1 × 10(-6), 2.5 × 10(-10) and 1.8 × 10(-10), respectively). In each case, increased homozygosity was associated with decreased trait value, equivalent to the offspring of first cousins being 1.2 cm shorter and having 10 months' less education. Similar effect sizes were found across four continental groups and populations with different degrees of genome-wide homozygosity, providing evidence that homozygosity, rather than confounding, directly contributes to phenotypic variance. Contrary to earlier reports in substantially smaller samples, no evidence was seen of an influence of genome-wide homozygosity on blood pressure and low density lipoprotein cholesterol, or ten other cardio-metabolic traits. Since directional dominance is predicted for traits under directional evolutionary selection, this study provides evidence that increased stature and cognitive function have been positively selected in human evolution, whereas many important risk factors for late-onset complex diseases may not have been.

  • 123. Justice, Anne E.
    et al.
    Giedraitis, Vilmantas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    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.
    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 Cardiovascular Institute, Stanford University, Stanford, CA, USA.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Epidemiology.
    Wallentin, Lars
    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.
    Lindgren, Cecilia M.
    Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution2019In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 51, no 3, p. 452-469Article in journal (Refereed)
    Abstract [en]

    Body-fat distribution is a risk factor for adverse cardiovascular health consequences. We analyzed the association of body-fat distribution, assessed by waist-to-hip ratio adjusted for body mass index, with 228,985 predicted coding and splice site variants available on exome arrays in up to 344,369 individuals from five major ancestries (discovery) and 132,177 European-ancestry individuals (validation). We identified 15 common (minor allele frequency, MAF ≥5%) and nine low-frequency or rare (MAF <5%) coding novel variants. Pathway/gene set enrichment analyses identified lipid particle, adiponectin, abnormal white adipose tissue physiology and bone development and morphology as important contributors to fat distribution, while cross-trait associations highlight cardiometabolic traits. In functional follow-up analyses, specifically in Drosophila RNAi-knockdowns, we observed a significant increase in the total body triglyceride levels for two genes (DNAH10 and PLXND1). We implicate novel genes in fat distribution, stressing the importance of interrogating low-frequency and protein-coding variants.

  • 124.
    Justice, Anne E.
    et al.
    Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27599 USA..
    Winkler, Thomas W.
    Univ Regensburg, Inst Epidemiol & Prevent Med, Dept Genet Epidemiol, D-93053 Regensburg, Germany..
    Feitosa, Mary F.
    Washington Univ, Sch Med, Dept Genet, Div Stat Genom, St Louis, MO 63108 USA..
    Graff, Misa
    Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27599 USA..
    Fisher, Virginia A.
    Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA..
    Young, Kristin
    Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27599 USA..
    Barata, Llilda
    Washington Univ, Sch Med, Dept Genet, Div Stat Genom, St Louis, MO 63108 USA..
    Deng, Xuan
    Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA..
    Czajkowski, Jacek
    Washington Univ, Sch Med, Dept Genet, Div Stat Genom, St Louis, MO 63108 USA..
    Hadley, David
    St Georges Univ London, Populat Hlth Res Inst, London SW17 0RE, England.;TransMed Syst Inc, Cupertino, CA 95014 USA..
    Ngwa, Julius S.
    Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA.;Johns Hopkins Bloomberg Sch Publ Hlth, Dept Biostat, Baltimore, MD USA..
    Ahluwalia, Tarunveer S.
    Univ Copenhagen, Fac Hlth & Med Sci, Sect Metab Genet, Novo Nordisk Fdn Ctr Basic Metab Res, Copenhagen, Denmark.;Steno Diabet Ctr, Gentofte, Denmark..
    Chu, Audrey Y.
    NHLBI Framingham Heart Study, Framingham, MA 01702 USA.;Brigham & Womens Hosp, Div Prevent Med, 75 Francis St, Boston, MA 02115 USA.;Harvard Med Sch, Boston, MA USA..
    Heard-Costa, Nancy L.
    NHLBI Framingham Heart Study, Framingham, MA 01702 USA.;Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA..
    Lim, Elise
    Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA..
    Perez, Jeremiah
    Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA..
    Eicher, John D.
    Framingham Heart Dis Epidemiol Study, NIH, Natl Heart Lung & Blood Inst, Populat Sci Branch, Framingham, MA USA..
    Kutalik, Zoltan
    CHU Vaudois, Inst Social & Prevent Med IUMSP, Lausanne, Switzerland.;Univ Lausanne, Dept Computat Biol, Lausanne, Switzerland.;Swiss Inst Bioinformat, CH-1015 Lausanne, Switzerland..
    Xue, Luting
    Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA..
    Mahajan, Anubha
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England..
    Renstrom, Frida
    Umea Univ, Dept Biobank Res, Umea, Sweden.;Lund Univ, Dept Clin Sci, Genet & Mol Epidemiol Unit, SE-20502 Malmo, Sweden..
    Wu, Joseph
    Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA..
    Qi, Qibin
    Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10467 USA..
    Ahmad, Shafqat
    Brigham & Womens Hosp, Div Prevent Med, 75 Francis St, Boston, MA 02115 USA.;Harvard Med Sch, Boston, MA USA.;Lund Univ, Dept Clin Sci, Genet & Mol Epidemiol Unit, SE-20502 Malmo, Sweden.;Harvard T H Chan Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA..
    Alfred, Tamuno
    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 USA..
    Amin, Najaf
    Erasmus Univ, Med Ctr, Dept Epidemiol, Genet Epidemiol Unit, NL-3015 GE Rotterdam, Netherlands..
    Bielak, Lawrence F.
    Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA..
    Bonnefond, Amelie
    Univ Lille, CNRS, Inst Pasteur Lille, EGID,UMR 8199, Lille, France..
    Bragg, Jennifer
    Univ Michigan, Internal Med Nephrol, Ann Arbor, MI USA.;Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA.;Univ Michigan, Ctr Stat Genet, Ann Arbor, MI 48109 USA..
    Cadby, Gemma
    Univ Western Australia, Ctr Genet Origins Hlth & Dis, Crawley 6009, Australia..
    Chittani, Martina
    Univ Milan, Dept Hlth Sci, Via A Di Rudini 8, I-20142 Milan, Italy..
    Coggeshall, Scott
    Univ Washington, Dept Biostat, Seattle, WA 98195 USA..
    Corre, Tanguy
    CHU Vaudois, Inst Social & Prevent Med IUMSP, Lausanne, Switzerland.;Univ Lausanne, Dept Computat Biol, Lausanne, Switzerland.;Swiss Inst Bioinformat, CH-1015 Lausanne, Switzerland..
    Direk, Nese
    Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands.;Dokuz Eylul Univ, Dept Psychiat, Izmir, Turkey..
    Eriksson, Joel
    Univ Gothenburg, Sahlgrenska Acad, Dept Internal Med & Clin Nutr, Ctr Bone & Arthrit Res,Inst Med, Gothenburg, Sweden..
    Fischer, Krista
    Univ Tartu, Estonian Genome Ctr, EE-51010 Tartu, Estonia..
    Gorski, Mathias
    Univ Regensburg, Inst Epidemiol & Prevent Med, Dept Genet Epidemiol, D-93053 Regensburg, Germany.;Univ Hosp Regensburg, Dept Nephrol, Regensburg, Germany..
    Harder, Marie Neergaard
    Univ Copenhagen, Fac Hlth & Med Sci, Sect Metab Genet, Novo Nordisk Fdn Ctr Basic Metab Res, Copenhagen, Denmark..
    Horikoshi, Momoko
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England.;Univ Oxford, Churchill Hosp, Oxford Ctr Diabet Endocrinol & Metab, Oxford OX3 7LJ, England..
    Huang, Tao
    Harvard T H Chan Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA.;Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Epidemiol Domain, Singapore 117549, Singapore..
    Huffman, Jennifer E.
    Framingham Heart Dis Epidemiol Study, NIH, Natl Heart Lung & Blood Inst, Populat Sci Branch, Framingham, MA USA.;Univ Edinburgh, Inst Genet & Mol Med, MRC Human Genet Unit, Edinburgh, Midlothian, Scotland..
    Jackson, Anne U.
    Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA.;Univ Michigan, Ctr Stat Genet, Ann Arbor, MI 48109 USA..
    Justesen, Johanne Marie
    Univ Copenhagen, Fac Hlth & Med Sci, Sect Metab Genet, Novo Nordisk Fdn Ctr Basic Metab Res, Copenhagen, Denmark..
    Kanoni, Stavroula
    Queen Mary Univ London, Barts & London Sch Med & Dent, William Harvey Res Inst, London, England..
    Kinnunen, Leena
    Natl Inst Hlth & Welfare, Dept Hlth, FI-00271 Helsinki, Finland..
    Kleber, Marcus E.
    Heidelberg Univ, Med Fac Mannheim, Dept Med 5, Mannheim, Germany..
    Komulainen, Pirjo
    Kuopio Res Inst Exercise Med, Kuopio, Finland..
    Kumari, Meena
    Univ Essex, ISER, Colchester CO4 3SQ, Essex, England.;UCL, Dept Epidemiol & Publ Hlth, London WC1E 6BT, England..
    Lim, Unhee
    Univ Hawaii, Canc Ctr, Epidemiol Program, Honolulu, HI 96813 USA..
    Luan, Jian'an
    Univ Cambridge, Sch Clin Med, Inst Metab Sci, MRC Epidemiol Unit, Cambridge CB2 0QQ, England..
    Lyytikainen, Leo-Pekka
    Fimlab Labs, Dept Clin Chem, Tampere 33520, Finland.;Univ Tampere, Fac Med & Life Sci, Dept Clin Chem, Tampere 33014, Finland..
    Mangino, Massimo
    Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England.;Guys & St Thomas Fdn Trust, NIHR Biomed Res Ctr, London, England..
    Manichaikul, Ani
    Univ Virginia, Dept Publ Hlth Sci, Ctr Publ Hlth Genom, Charlottesville, VA 22903 USA.;Univ Virginia, Dept Publ Hlth Sci, Biostat Sect, Charlottesville, VA 22903 USA..
    Marten, Jonathan
    Univ Edinburgh, Inst Genet & Mol Med, MRC Human Genet Unit, Edinburgh, Midlothian, Scotland..
    Middelberg, Rita P. S.
    QIMR Berghofer Med Res Inst, Genet Epidemiol, Brisbane, Qld 4029, Australia..
    Mueller-Nurasyid, Martina
    German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Genet Epidemiol, D-85764 Neuherberg, Germany.;Ludwig Maximilians Univ Munchen, Univ Hosp Grosshadern, Dept Med 1, D-81377 Munich, Germany.;DZHK German Ctr Cardiovasc Res, Partner Site Munich Heart Alliance, Munich, Germany..
    Navarro, Pau
    Univ Edinburgh, Inst Genet & Mol Med, MRC Human Genet Unit, Edinburgh, Midlothian, Scotland..
    Perusse, Louis
    Univ Laval, Fac Med, Dept Kinesiol, Quebec City G1V 0A6, PQ, Canada.;Univ Laval, Inst Nutr & Funct Foods, Quebec City G1V 0A6, PQ, Canada..
    Pervjakova, Natalia
    Univ Tartu, Estonian Genome Ctr, EE-51010 Tartu, Estonia.;Univ Tartu, Inst Mol & Cell Biol, Dept Biotechnol, EE-51010 Tartu, Estonia..
    Sarti, Cinzia
    Dept Social & Hlth Care, Helsinki, Finland..
    Smith, Albert Vernon
    Iceland Heart Assoc, Kopavogur, Iceland.;Univ Iceland, Fac Med, Reykjavik, Iceland..
    Smith, Jennifer A.
    Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA..
    Stancakova, Alena
    Univ Eastern Finland, Inst Clin Med, Dept Med, Kuopio 70210, Finland..
    Strawbridge, Rona J.
    Karolinska Inst, Dept Med Solna, Cardiovasc Med Unit, Stockholm, Sweden.;Karolinska Univ Hosp Solna, Ctr Mol Med, Stockholm, Sweden..
    Stringham, Heather M.
    Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA.;Univ Michigan, Ctr Stat Genet, Ann Arbor, MI 48109 USA..
    Sung, Yun Ju
    Washington Univ, Sch Med, Div Biostat, St Louis, MO 63110 USA..
    Tanaka, Toshiko
    Natl Inst Aging, Translat Gerontol Branch, Baltimore, MD USA..
    Teumer, Alexander
    Univ Med Greifswald, Inst Community Med, Greifswald, Germany..
    Trompet, Stella
    Leiden Univ, Dept Cardiol, Med Ctr, Leiden, Netherlands.;Leiden Univ, Med Ctr, Dept Gerontol & Geriatr, Leiden, Netherlands..
    van der Laan, Sander W.
    UMC Utrecht, Div Heart & Lungs, Dept Cardiol, Lab Expt Cardiol, Utrecht, Netherlands..
    van der Most, Peter J.
    Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, Groningen, Netherlands..
    Van Vliet-Ostaptchouk, Jana V.
    Univ Groningen, Univ Med Ctr Groningen, Dept Endocrinol, Groningen, Netherlands..
    Vedantam, Sailaja L.
    Boston Childrens Hosp, Div Endocrinol, Boston, MA 02115 USA.;Boston Childrens Hosp, Div Genet, Boston, MA 02115 USA.;Boston Childrens Hosp, Ctr Basic & Translat Obes Res, Boston, MA 02115 USA.;Broad Inst Harvard, Cambridge, MA 02142 USA..
    Verweij, Niek
    Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, Groningen, Netherlands..
    Vink, Jacqueline M.
    Vrije Univ, Dept Biol Psychol, Amsterdam, Netherlands.;Radboud Univ Nijmegen, Behav Sci Inst, Nijmegen, Netherlands..
    Vitart, Veronique
    Univ Edinburgh, Inst Genet & Mol Med, MRC Human Genet Unit, Edinburgh, Midlothian, Scotland..
    Wu, Ying
    Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA..
    Yengo, Loic
    Univ Lille, CNRS, Inst Pasteur Lille, EGID,UMR 8199, Lille, France..
    Zhang, Weihua
    Imper Coll London, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England.;Ealing Hosp NHS Trust, Cardiol, Southall, Middx, England..
    Zhao, Jing Hua
    Univ Cambridge, Sch Clin Med, Inst Metab Sci, MRC Epidemiol Unit, Cambridge CB2 0QQ, England..
    Zimmermann, Martina E.
    Univ Regensburg, Inst Epidemiol & Prevent Med, Dept Genet Epidemiol, D-93053 Regensburg, Germany..
    Zubair, Niha
    Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA..
    Abecasis, Goncalo R.
    Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA.;Univ Michigan, Ctr Stat Genet, Ann Arbor, MI 48109 USA..
    Adair, Linda S.
    Univ N Carolina, Gillings Sch Global Publ Hlth, Dept Nutr, Chapel Hill, NC 27599 USA..
    Afaq, Saima
    Imper Coll London, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England.;Ealing Hosp NHS Trust, Cardiol, Southall, Middx, England..
    Afzal, Uzma
    Imper Coll London, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England.;Ealing Hosp NHS Trust, Cardiol, Southall, Middx, England..
    Bakker, Stephan J. L.
    Univ Med Ctr Groningen, Univ Groningen, Dept Med, Groningen, Netherlands..
    Bartz, Traci M.
    Univ Washington, Dept Biostat, Seattle, WA 98195 USA.;Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA 98101 USA..
    Beilby, John
    Busselton Populat Med Res Inst, Nedlands, WA 6009, Australia.;Sir Charles Gairdner Hosp, PathWest Lab Med WA, Nedlands, WA 6009, Australia.;Univ Western Australia, Sch Pathol, 35 Stirling Hwy, Crawley, WA 6009, Australia.;Univ Western Australia, Laboraty Med, 35 Stirling Hwy, Crawley, WA 6009, Australia..
    Bergman, Richard N.
    Cedars Sinai Med Ctr, Diabet & Obes Res Inst, Los Angeles, CA 90048 USA..
    Bergmann, Sven
    Univ Lausanne, Dept Computat Biol, Lausanne, Switzerland.;Swiss Inst Bioinformat, CH-1015 Lausanne, Switzerland..
    Biffar, Reiner
    Univ Med Greifswald, Clin Prosthet Dent Gerostomatol & Mat Sci, Greifswald, Germany..
    Blangero, John
    Univ Texas Rio Grande Valley, South Texas Diabet & Obes Inst, Brownsville, TX USA..
    Boerwinkle, Eric
    Univ Texas Hlth Sci Ctr, Human Genet Ctr, POB 20186, Houston, TX 77225 USA..
    Bonnycastle, Lori L.
    Natl Human Genome Res Inst, Med Genom & Metab Genet Branch, NIH, Bethesda, MD 20892 USA..
    Bottinger, Erwin
    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 USA..
    Braga, Daniele
    Univ Milan, Dept Hlth Sci, Via A Di Rudini 8, I-20142 Milan, Italy..
    Buckley, Brendan M.
    Univ Coll Cork, Dept Pharmacol & Therapeut, Cork, Ireland..
    Buyske, Steve
    Rutgers State Univ, Dept Genet, Piscataway, NJ 08854 USA.;Rutgers State Univ, Dept Stat & Biostat, Piscataway, NJ 08854 USA..
    Campbell, Harry
    Univ Edinburgh, Usher Inst Populat Hlth Sci & Informat, Edinburgh, Midlothian, Scotland..
    Chambers, John C.
    Imper Coll London, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England.;Ealing Hosp NHS Trust, Cardiol, Southall, Middx, England.;Imperial Coll Healthcare NHS Trust, London, England..
    Collins, Francis S.
    Natl Human Genome Res Inst, Med Genom & Metab Genet Branch, NIH, Bethesda, MD 20892 USA..
    Curran, Joanne E.
    Univ Texas Rio Grande Valley, South Texas Diabet & Obes Inst, Brownsville, TX USA..
    de Borst, Gert J.
    UMC Utrecht, Dept Vasc Surg, Div Surg Specialties, Utrecht, Netherlands..
    de Craen, Anton J. M.
    Leiden Univ, Med Ctr, Dept Gerontol & Geriatr, Leiden, Netherlands..
    de Geus, Eco J. C.
    Vrije Univ, Dept Biol Psychol, Amsterdam, Netherlands.;Vrije Univ, FMGO Inst, Amsterdam, Netherlands.;Vrije Univ, Med Ctr, Amsterdam, Netherlands..
    Dedoussis, George
    Harokopio Univ, Sch Hlth Sci & Educ, Dept Nutr & Dietet, Athens, Greece..
    Delgado, Graciela E.
    Heidelberg Univ, Med Fac Mannheim, Dept Med 5, Mannheim, Germany..
    den Ruijter, Hester M.
    UMC Utrecht, Div Heart & Lungs, Dept Cardiol, Lab Expt Cardiol, Utrecht, Netherlands..
    Eiriksdottir, Gudny
    Iceland Heart Assoc, Kopavogur, Iceland..
    Eriksson, Anna L.
    Univ Gothenburg, Sahlgrenska Acad, Dept Internal Med & Clin Nutr, Ctr Bone & Arthrit Res,Inst Med, Gothenburg, Sweden..
    Esko, Tonu
    Univ Tartu, Estonian Genome Ctr, EE-51010 Tartu, Estonia.;Boston Childrens Hosp, Div Endocrinol, Boston, MA 02115 USA.;Boston Childrens Hosp, Div Genet, Boston, MA 02115 USA.;Boston Childrens Hosp, Ctr Basic & Translat Obes Res, Boston, MA 02115 USA.;Broad Inst Harvard, Cambridge, MA 02142 USA..
    Faul, Jessica D.
    Univ Michigan, Inst Social Res, Survey Res Ctr, Ann Arbor, MI 48109 USA..
    Ford, Ian
    Univ Glasgow, Robertson Ctr Biostat, Glasgow, Lanark, Scotland..
    Forrester, Terrence
    Univ West Indies, Trop Med Res Inst, Trop Metab Res Unit, Mona JMAAW15, Jamaica, NY USA..
    Gertow, Karl
    Karolinska Inst, Dept Med Solna, Cardiovasc Med Unit, Stockholm, Sweden.;Karolinska Univ Hosp Solna, Ctr Mol Med, Stockholm, Sweden..
    Gigante, Bruna
    Karolinska Inst, Inst Environm Med, Unit Cardiovasc Epidemiol, Stockholm, Sweden..
    Glorioso, Nicola
    Univ Sassari, Hypertens & Related Dis Ctr, AOU, Sassari, Italy..
    Gong, Jian
    Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA..
    Grallert, Harald
    German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Res Unit Mol Epidemiol, D-85764 Neuherberg, Germany.;German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol 2, D-85764 Neuherberg, Germany.;German Ctr Diabet Res, D-85764 Neuherberg, Germany..
    Grammer, Tanja B.
    Heidelberg Univ, Med Fac Mannheim, Dept Med 5, Mannheim, Germany..
    Grarup, Niels
    Univ Copenhagen, Fac Hlth & Med Sci, Sect Metab Genet, Novo Nordisk Fdn Ctr Basic Metab Res, Copenhagen, Denmark..
    Haitjema, Saskia
    UMC Utrecht, Div Heart & Lungs, Dept Cardiol, Lab Expt Cardiol, Utrecht, Netherlands..
    Hallmans, Goran
    Umea Univ, Sect Nutr Res, Dept Publ Hlth & Clin Med, Umea, Sweden..
    Hamsten, Anders
    Karolinska Inst, Dept Med Solna, Cardiovasc Med Unit, Stockholm, Sweden.;Karolinska Univ Hosp Solna, Ctr Mol Med, Stockholm, Sweden..
    Hansen, Torben
    St Georges Univ London, Populat Hlth Res Inst, London SW17 0RE, England..
    Harris, Tamara B.
    Natl Inst Aging, NIH, Lab Epidemiol Demog & Biometry, Bethesda, MD USA..
    Hartman, Catharina A.
    Univ Groningen, Univ Med Ctr Groningen, Interdisciplinary Ctr Psychopathol & Emot Regulat, Groningen, Netherlands..
    Hassinen, Maija
    Kuopio Res Inst Exercise Med, Kuopio, Finland..
    Hastie, Nicholas D.
    Univ Edinburgh, Inst Genet & Mol Med, MRC Human Genet Unit, Edinburgh, Midlothian, Scotland..
    Heath, Andrew C.
    Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA..
    Hernandez, Dena
    Natl Inst Aging, Lab Neurogenet, Bethesda, MD USA..
    Hindorff, Lucia
    Natl Human Genome Res Inst, NIH, Div Genom Med, Bethesda, MD 20892 USA..
    Hocking, Lynne J.
    Univ Aberdeen, Inst Med Sci, Foresterhill, Aberdeen AB25 2ZD, Scotland.;Univ Edinburgh, Ctr Genom & Expt Med, Generat Scotland, Edinburgh, Midlothian, Scotland..
    Hollensted, Mette
    Univ Copenhagen, Fac Hlth & Med Sci, Sect Metab Genet, Novo Nordisk Fdn Ctr Basic Metab Res, Copenhagen, Denmark..
    Holmen, Oddgeir L.
    Univ Trondheim Hosp, St Olav Hosp, Trondheim, Norway..
    Homuth, Georg
    Univ Med Greifswald, Interfac Inst Genet & Funct Genom, Greifswald, Germany..
    Hottenga, Jouke Jan
    Vrije Univ, Dept Biol Psychol, Amsterdam, Netherlands..
    Huang, Jie
    Wellcome Trust Sanger Inst, Dept Human Genet, Cambridge, England..
    Hung, Joseph
    Univ Western Australia, Sch Med & Pharmacol, 25 Stirling Hwy, Crawley, WA 6009, Australia.;Sir Charles Gairdner Hosp, Dept Cardiovasc Med, Nedlands, WA 6009, Australia..
    Hutri-Kahonen, Nina
    Tampere Univ Hosp, Dept Pediat, Tampere 33521, Finland.;Univ Tampere, Fac Med & Life Sci, Dept Pediat, Tampere 33014, Finland..
    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.
    James, Alan L.
    Busselton Populat Med Res Inst, Nedlands, WA 6009, Australia.;Univ Western Australia, Sch Med & Pharmacol, 25 Stirling Hwy, Crawley, WA 6009, Australia.;Sir Charles Gairdner Hosp, Dept Pulm Physiol & Sleep Med, Nedlands, WA 6009, Australia..
    Jansson, John-Olov
    Univ Gothenburg, Sahlgrenska Acad, Inst Neurosci & Physiol, Dept Physiol, Gothenburg, Sweden..
    Jarvelin, Marjo-Riitta
    Imperial Coll London, Sch Publ Hlth, MRC PHE Ctr Environm & Hlth, Dept Epidemiol & Biostat, Norfolk Pl, London, England.;Univ Oulu, Fac Med, Ctr Life Course Epidemiol, POB 5000, FI-90014 Oulu, Finland.;Univ Oulu, Bioctr Oulu, Oulu, Finland.;Oulu Univ Hosp, Unit Primary Care, Kajaanintie 50,POB 20, FI-90220 Oulu, Finland..
    Jhun, Min A.
    Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA..
    Jorgensen, Marit E.
    Steno Diabet Ctr, Gentofte, Denmark..
    Juonala, Markus
    Univ Turku, Dept Med, Turku 20520, Finland.;Turku Univ Hosp, Div Med, Turku 20521, Finland..
    Kahonen, Mika
    Tampere Univ Hosp, Dept Clin Physiol, Tampere 33521, Finland.;Univ Tampere, Fac Med & Life Sci, Dept Clin Physiol, Tampere 33014, Finland..
    Karlsson, Magnus
    Lund Univ, Skane Univ Hosp, Dept Orthoped & Clin Sci, Clin & Mol Osteoporosis Res Unit, Malmo, Sweden..
    Koistinen, Heikki A.
    Natl Inst Hlth & Welfare, Dept Hlth, FI-00271 Helsinki, Finland.;Univ Helsinki, Endocrinol, Dept Med, FI-00029 Helsinki, Finland.;Univ Helsinki, Endocrinol, Abdominal Ctr, FI-00029 Helsinki, Finland.;Univ Helsinki, Cent Hosp, FI-00029 Helsinki, Finland.;Minerva Fdn, Biomed 2U, FI-00290 Helsinki, Finland..
    Kolcic, Ivana
    Univ Split, Fac Med, Dept Publ Hlth, Split, Croatia..
    Kolovou, Genovefa
    Onassis Cardiac Surg Ctr, Dept Cardiol, Athens, Greece..
    Kooperberg, Charles
    Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA..
    Kramer, Bernhard K.
    Heidelberg Univ, Med Fac Mannheim, Dept Med 5, Mannheim, Germany..
    Kuusisto, Johanna
    Univ Eastern Finland, Dept Med, Kuopio 70210, Finland.;Kuopio Univ Hosp, Kuopio 70210, Finland..
    Kvaloy, Kirsti
    Norwegian Univ Sci & Technol, Dept Publ Hlth & Nursing, HUNT Res Ctr, N-7600 Levanger, Norway..
    Lakka, Timo A.
    Kuopio Res Inst Exercise Med, Kuopio, Finland.;Univ Eastern Finland, Inst Biomed Physiol, Kuopio, Finland..
    Langenberg, Claudia
    Univ Cambridge, Sch Clin Med, Inst Metab Sci, MRC Epidemiol Unit, Cambridge CB2 0QQ, England..
    Launer, Lenore J.
    Natl Inst Aging, NIH, Lab Epidemiol Demog & Biometry, Bethesda, MD USA..
    Leander, Karin
    Karolinska Inst, Inst Environm Med, Unit Cardiovasc Epidemiol, Stockholm, Sweden..
    Lee, Nanette R.
    Univ San Carlos, Off Populat Studies Fdn Inc, Cebu 6000, Philippines.;Univ San Carlos, Dept Anthropol Sociol & Hist, Cebu 6000, Philippines..
    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 OX3 7BN, England.;Univ Oxford, Big Data Inst, Li Ka Shing Ctr Hlth Informat & Discovery, Oxford OX3 7BN, England. Res Ctr Prevent & Hlth, Copenhagen, Denmark..
    Linneberg, Allan
    Minerva Fdn, Biomed 2U, FI-00290 Helsinki, Finland.;Rigshosp, Dept Clin Expt Res, Glostrup, Denmark.;Univ Copenhagen, Fac Hlth & Med Sci, Dept Clin Med, Copenhagen, Denmark..
    Lobbens, Stephane
    Univ Lille, CNRS, Inst Pasteur Lille, EGID,UMR 8199, Lille, France..
    Loh, Marie
    Imper Coll London, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England.;ASTAR, Agcy Sci Technol & Res, Translat Lab Genet Med TLGM, 8A Biomed Grove,Immunos Level 5, Singapore 138648, Singapore..
    Lorentzon, Mattias
    Univ Gothenburg, Sahlgrenska Acad, Dept Internal Med & Clin Nutr, Ctr Bone & Arthrit Res,Inst Med, Gothenburg, Sweden..
    Luben, Robert
    Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England..
    Lubke, Gitta
    Univ Notre Dame, Dept Psychol, Notre Dame, IN 46556 USA..
    Ludolph-Donislawski, Anja
    German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Genet Epidemiol, D-85764 Neuherberg, Germany.;Ludwig Maximilians Univ Munchen, Chair Genet Epidemiol, Inst Med Informat Biometry & Epidemiol, D-81377 Munich, Germany..
    Lupoli, Sara
    Univ Milan, Dept Hlth Sci, Via A Di Rudini 8, I-20142 Milan, Italy..
    Madden, Pamela A. F.
    Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA..
    Mannikko, Reija
    Kuopio Res Inst Exercise Med, Kuopio, Finland..
    Marques-Vidal, Pedro
    Lausanne Univ Hosp CHUV, Dept Med Internal Med, Lausanne, Switzerland..
    Martin, Nicholas G.
    QIMR Berghofer Med Res Inst, Genet Epidemiol, Brisbane, Qld 4029, Australia..
    McKenzie, Colin A.
    Univ West Indies, Trop Med Res Inst, Trop Metab Res Unit, Mona JMAAW15, Jamaica, NY USA..
    McKnight, Barbara
    Univ Washington, Dept Biostat, Seattle, WA 98195 USA.;Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA 98101 USA.;Fred Hutchinson Canc Res Ctr, Program Biostat & Biomath, Seattle, WA 98109 USA..
    Mellstrom, Dan
    Univ Gothenburg, Sahlgrenska Acad, Dept Internal Med & Clin Nutr, Ctr Bone & Arthrit Res,Inst Med, Gothenburg, Sweden..
    Menni, Cristina
    Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England..
    Montgomery, Grant W.
    QIMR Berghofer Med Res Inst, Mol Epidemiol, Brisbane, Qld 4029, Australia..
    Musk, A. W. (Bill)
    Busselton Populat Med Res Inst, Nedlands, WA 6009, Australia.;Univ Western Australia, Sch Populat Hlth, 35 Stirling Hwy, Crawley, WA 6009, Australia.;Sir Charles Gairdner Hosp, Dept Resp Med, Nedlands, WA 6009, Australia..
    Narisu, Narisu
    Natl Human Genome Res Inst, Med Genom & Metab Genet Branch, NIH, Bethesda, MD 20892 USA..
    Nauck, Matthias
    Univ Med Greifswald, Inst Clin Chem, Greifswald, Germany.;Univ Med Greifswald, Lab Med, Greifswald, Germany..
    Nolte, Ilja M.
    Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, Groningen, Netherlands..
    Oldehinkel, Albertine J.
    Univ Groningen, Univ Med Ctr Groningen, Interdisciplinary Ctr Psychopathol & Emot Regulat, Groningen, Netherlands..
    Olden, Matthias
    Univ Regensburg, Inst Epidemiol & Prevent Med, Dept Genet Epidemiol, D-93053 Regensburg, Germany..
    Ong, Ken K.
    Univ Cambridge, Sch Clin Med, Inst Metab Sci, MRC Epidemiol Unit, Cambridge CB2 0QQ, England..
    Padmanabhan, Sandosh
    Univ Aberdeen, Inst Med Sci, Foresterhill, Aberdeen AB25 2ZD, Scotland.;Univ Glasgow, BHF Glasgow CardiovascRes Ctr, Inst Cardiovasc & Med Sci, Glasgow, Lanark, Scotland..
    Peyser, Patricia A.
    Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA..
    Pisinger, Charlotta
    Glostrup Cty Hosp, Res Ctr Prevent & Hlth, Glostrup, Denmark.;Univ Copenhagen, Fac Hlth Sci, Dept Publ Hlth, Copenhagen, Denmark..
    Porteous, David J.
    Univ Edinburgh, Ctr Genom & Expt Med, Generat Scotland, Edinburgh, Midlothian, Scotland.;Univ Edinburgh, Inst Genet & Mol Med, Ctr Genom & Expt Med, Edinburgh, Midlothian, Scotland..
    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..
    Rankinen, Tuomo
    Pennington Biomed Res Ctr, Human Genom Lab, 6400 Perkins Rd, Baton Rouge, LA 70808 USA..
    Rao, D. C.
    Washington Univ, Sch Med, Div Biostat, St Louis, MO 63110 USA.;Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA.;Washington Univ, Sch Med, Dept Med, St Louis, MO 63110 USA..
    Rasmussen-Torvik, Laura J.
    Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, Chicago, IL 60611 USA..
    Rawal, Rajesh
    German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Res Unit Mol Epidemiol, D-85764 Neuherberg, Germany.;German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol 2, D-85764 Neuherberg, Germany..
    Rice, Treva
    Washington Univ, Sch Med, Div Biostat, St Louis, MO 63110 USA.;Univ Eastern Finland, Dept Med, Kuopio 70210, Finland.;Kuopio Univ Hosp, Kuopio 70210, Finland..
    Ridker, Paul M.
    Brigham & Womens Hosp, Div Prevent Med, 75 Francis St, Boston, MA 02115 USA.;Harvard Med Sch, Boston, MA USA.;Brigham & Womens Hosp, Div Cardiol, Boston, MA 02115 USA..
    Rose, Lynda M.
    Brigham & Womens Hosp, Div Prevent Med, 75 Francis St, Boston, MA 02115 USA.;Harvard Med Sch, Boston, MA USA..
    Bien, Stephanie A.
    Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA..
    Rudan, Igor
    Univ Edinburgh, Usher Inst Populat Hlth Sci & Informat, Edinburgh, Midlothian, Scotland..
    Sanna, Serena
    Cittadella Univ Monserrato, CNR, IRGB, I-09042 Monserrato, Italy..
    Sarzynski, Mark A.
    Pennington Biomed Res Ctr, Human Genom Lab, 6400 Perkins Rd, Baton Rouge, LA 70808 USA..
    Sattar, Naveed
    BHF Glasgow Cardiovasc Res Ctr, Fac Med, Glasgow, Lanark, Scotland..
    Savonen, Kai
    Kuopio Res Inst Exercise Med, Kuopio, Finland..
    Schlessinger, David
    Natl Inst Aging, NIH, Lab Genet, Baltimore, MD USA..
    Scholtens, Salome
    Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, Groningen, Netherlands..
    Schurmann, 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 USA..
    Scott, Robert A.
    Univ Cambridge, Sch Clin Med, Inst Metab Sci, MRC Epidemiol Unit, Cambridge CB2 0QQ, England..
    Sennblad, Bengt
    Karolinska Inst, Dept Med Solna, Cardiovasc Med Unit, Stockholm, Sweden.;Karolinska Univ Hosp Solna, Ctr Mol Med, Stockholm, Sweden.;Karolinska Inst, Sci Life Lab, Stockholm, Sweden..
    Siemelink, Marten A.
    UMC Utrecht, Div Heart & Lungs, Dept Cardiol, Lab Expt Cardiol, Utrecht, Netherlands..
    Silbernagel, Gunther
    Med Univ Graz, Dept Internal Med, Div Angiol, Graz, Austria..
    Slagboom, P. Eline
    Leiden Univ, Dept Mol Epidemiol, Med Ctr, Leiden, Netherlands..
    Snieder, Harold
    Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, Groningen, Netherlands..
    Staessen, Jan A.
    Univ Leuven, Dept Cardiovasc Sci, Res Unit Hypertens & Cardiovasc Epidemiol, Campus Sint Rafael,Kapucijnenvoer 35, Leuven, Belgium.;Maastricht Univ, R&D VitaK Grp, Brains Unlimited Bldg,Oxfordlaan 55, Maastricht, Netherlands..
    Stott, David J.
    Univ Glasgow, Inst Cardiovasc & Med Sci, Fac Med, Glasgow, Lanark, Scotland..
    Swertz, Morris A.
    Univ Groningen, Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands..
    Swift, Amy J.
    Natl Human Genome Res Inst, Med Genom & Metab Genet Branch, NIH, Bethesda, MD 20892 USA..
    Taylor, Kent D.
    Univ Calif Los Angeles, Med Ctr, Los Angeles Biomed Res Inst Harbor, Ctr Translat Genom & Populat Sci, Torrance, CA USA.;Univ Calif Los Angeles, Dept Pediat, Los Angeles, CA USA..
    Tayo, Bamidele O.
    Loyola Univ Chicago, Stritch Sch Med, Dept Publ Hlth Sci, Maywood, IL 61053 USA..
    Thorand, Barbara
    German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol 2, D-85764 Neuherberg, Germany.;German Ctr Diabet Res, D-85764 Neuherberg, Germany..
    Thuillier, Dorothee
    Univ Lille, CNRS, Inst Pasteur Lille, EGID,UMR 8199, Lille, France..
    Tuomilehto, Jaakko
    Dasman Diabet Inst, Res Div, Kuwait, Kuwait.;Danube Univ Krems, Dept Neurosci & Prevent Med, Krems 3500, Austria. Natl Inst Hlth & Welf, Chron Dis Prevent Unit, Helsinki, Finland.;King Abdulaziz Univ, Saudi Diabet Res Grp, Jeddah, Saudi Arabia..
    Uitterlinden, Andre G.
    Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands.;Erasmus MC, Dept Internal Med, Rotterdam, Netherlands..
    Vandenput, Liesbeth
    Univ Gothenburg, Sahlgrenska Acad, Dept Internal Med & Clin Nutr, Ctr Bone & Arthrit Res,Inst Med, Gothenburg, Sweden..
    Vohl, Marie-Claude
    Univ Laval, Inst Nutr & Funct Foods, Quebec City G1V 0A6, PQ, Canada.;Univ Laval, Sch Nutr, Laval, PQ, Canada..
    Volzke, Henry
    Univ Med Greifswald, Inst Community Med, Greifswald, Germany..
    Vonk, Judith M.
    Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, Groningen, Netherlands..
    Waeber, Gerard
    Lausanne Univ Hosp CHUV, Dept Med Internal Med, Lausanne, Switzerland..
    Waldenberger, Melanie
    German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Res Unit Mol Epidemiol, D-85764 Neuherberg, Germany.;German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol 2, D-85764 Neuherberg, Germany..
    Westendorp, R. G. J.
    Univ Copenhagen, Dept Publ Hlth, DK-1014 Copenhagen, Denmark.;Univ Copenhagen, Ctr Healthy Aging, DK-1014 Copenhagen, Denmark..
    Wild, Sarah
    Univ Edinburgh, Usher Inst Populat Hlth Sci & Informat, Edinburgh, Midlothian, Scotland..
    Willemsen, Gonneke
    Vrije Univ, Dept Biol Psychol, Amsterdam, Netherlands..
    Wolffenbuttel, Bruce H. R.
    Univ Groningen, Univ Med Ctr Groningen, Dept Endocrinol, Groningen, Netherlands..
    Wong, Andrew
    UCL, MRC Unit Lifelong Hlth & Ageing, 33 Bedford Pl, London WC1B 5JU, England..
    Wright, Alan F.
    Univ Edinburgh, Inst Genet & Mol Med, MRC Human Genet Unit, Edinburgh, Midlothian, Scotland..
    Zhao, Wei
    Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA..
    Zillikens, M. Carola
    Erasmus MC, Dept Internal Med, Rotterdam, Netherlands..
    Baldassarre, Damiano
    Univ Milan, Dipartimento Sci Farmacolog & Biomol, Milan, Italy.;IRCCS, Ctr Cardiolog Monzino, Milan, Italy..
    Balkau, Beverley
    INSERM, U 1018, F-94807 Villejuif, France..
    Bandinelli, Stefania
    Azienda USL Toscana Ctr, Geriatr Unit, Florence, Italy..
    Boger, Carsten A.
    Univ Hosp Regensburg, Dept Nephrol, Regensburg, Germany..
    Boomsma, Dorret I.
    Vrije Univ, Dept Biol Psychol, Amsterdam, Netherlands..
    Bouchard, Claude
    Pennington Biomed Res Ctr, Human Genom Lab, 6400 Perkins Rd, Baton Rouge, LA 70808 USA..
    Bruinenberg, Marcel
    Lifelines Cohort Study, POB 30001, NL-9700 RB Groningen, Netherlands..
    Chasman, Daniel I.
    Brigham & Womens Hosp, Div Prevent Med, 75 Francis St, Boston, MA 02115 USA.;Harvard Med Sch, Boston, MA USA.;Brigham & Womens Hosp, Div Genet, 75 Francis St, Boston, MA 02115 USA..
    Chen, Yii-Der Ida
    Univ Calif Los Angeles, Los Angeles BioMed Res Inst, Inst Translat Genom & Populat Sci, Torrance, CA 90502 USA.;Univ Calif Los Angeles, Dept Pediat Harbor, Torrance, CA 90502 USA..
    Chines, Peter S.
    Natl Human Genome Res Inst, Med Genom & Metab Genet Branch, NIH, Bethesda, MD 20892 USA..
    Cooper, Richard S.
    Loyola Univ Chicago, Stritch Sch Med, Dept Publ Hlth Sci, Maywood, IL 61053 USA..
    Cucca, Francesco
    Cittadella Univ Monserrato, CNR, IRGB, I-09042 Monserrato, Italy.;Univ Sassari, Dipartimento Sci Biomed, Sassari, Italy..
    Cusi, Daniele
    Sanipedia Srl, Bresso, Milano, Italy.;Inst Biomed Technol Natl Ctr Res Segrate, Milan, Italy..
    de Faire, Ulf
    Karolinska Inst, Inst Environm Med, Unit Cardiovasc Epidemiol, Stockholm, Sweden..
    Ferrucci, Luigi
    Natl Inst Aging, Translat Gerontol Branch, Baltimore, MD USA..
    Franks, Paul W.
    Lund Univ, Dept Clin Sci, Genet & Mol Epidemiol Unit, SE-20502 Malmo, Sweden.;Harvard T H Chan Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA.;Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden..
    Froguel, Philippe
    Univ Lille, CNRS, Inst Pasteur Lille, EGID,UMR 8199, Lille, France.;Imperial Coll London, Dept Genom Common Dis, London, England..
    Gordon-Larsen, Penny
    Univ N Carolina, Gillings Sch Global Publ Hlth, Dept Nutr, Chapel Hill, NC 27599 USA.;Univ N Carolina, Carolina Populat Ctr, Chapel Hill, NC 27516 USA..
    Grabe, Hans-Jorgen
    Univ Med Greifswald, Dept Psychiat & Psychotherapy, Greifswald, Germany.;German Ctr Neurodegenerat Dis DZNE, Rostock & Greifswald Site, Greifswald, Germany..
    Gudnason, Vilmundur
    Iceland Heart Assoc, Kopavogur, Iceland.;Univ Iceland, Fac Med, Reykjavik, Iceland..
    Haiman, Christopher A.
    Univ Southern Calif, Norris Comprehens Canc Ctr, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90089 USA..
    Hayward, Caroline
    Univ Edinburgh, Inst Genet & Mol Med, MRC Human Genet Unit, Edinburgh, Midlothian, Scotland.;Univ Edinburgh, Ctr Genom & Expt Med, Generat Scotland, Edinburgh, Midlothian, Scotland..
    Hveem, Kristian
    Norwegian Univ Sci & Technol, Dept Publ Hlth & Nursing, HUNT Res Ctr, N-7600 Levanger, Norway..
    Johnson, Andrew D.
    Framingham Heart Dis Epidemiol Study, NIH, Natl Heart Lung & Blood Inst, Populat Sci Branch, Framingham, MA USA..
    Jukema, Wouter
    Leiden Univ, Dept Cardiol, Med Ctr, Leiden, Netherlands.;Durrer Ctr Cardiogenet Res, Amsterdam, Netherlands.;Interuniv Cardiol Inst Netherlands, Utrecht, Netherlands..
    Kardia, Sharon L. R.
    Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA..
    Kivimaki, Mika
    UCL, Dept Epidemiol & Publ Hlth, London WC1E 6BT, England..
    Kooner, Jaspal S.
    Ealing Hosp NHS Trust, Cardiol, Southall, Middx, England.;Imperial Coll Healthcare NHS Trust, London, England.;Imperial Coll London, Hammersmith Hosp, Fac Med, Natl Heart & Lung Inst, Hammersmith Campus, London, England..
    Kuh, Diana
    UCL, MRC Unit Lifelong Hlth & Ageing, 33 Bedford Pl, London WC1B 5JU, England..
    Laakso, Markku
    Univ Eastern Finland, Dept Med, Kuopio 70210, Finland.;Kuopio Univ Hosp, Kuopio 70210, Finland..
    Lehtimaki, Terho
    Fimlab Labs, Dept Clin Chem, Tampere 33520, Finland.;Univ Tampere, Fac Med & Life Sci, Dept Clin Chem, Tampere 33014, Finland..
    Le Marchand, Loic
    Univ Hawaii, Canc Ctr, Epidemiol Program, Honolulu, HI 96813 USA..
    Marz, Winfried
    Synlab Serv GmbH, Synlab Acad, Mannheim, Germany.;Med Univ Graz, Clin Inst Med, Graz, Austria.;Med Univ Graz, Chem Lab Diagnost, Graz, Austria..
    McCarthy, Mark I.
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England.;Univ Oxford, Churchill Hosp, Oxford Ctr Diabet Endocrinol & Metab, Oxford OX3 7LJ, England.;Churchill Hosp, Biomed Res Ctr, Oxford Natl Inst Hlth Res NIHR, Oxford, England..
    Metspalu, Andres
    Univ Tartu, Estonian Genome Ctr, EE-51010 Tartu, Estonia..
    Morris, Andrew P.
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England.;Univ Liverpool, Dept Biostat, Liverpool L69 3GL, Merseyside, England..
    Ohlsson, Claes
    Univ Gothenburg, Sahlgrenska Acad, Dept Internal Med & Clin Nutr, Ctr Bone & Arthrit Res,Inst Med, Gothenburg, Sweden..
    Palmer, Lyle J.
    Univ Adelaide, Sch Publ Hlth, Adelaide, SA 5005, Australia..
    Pasterkamp, Gerard
    UMC Utrecht, Div Heart & Lungs, Dept Cardiol, Lab Expt Cardiol, Utrecht, Netherlands.;UMC Utrecht, Div Labs & Pharm, Lab Clin Chem & Hematol, Utrecht, Netherlands..
    Pedersen, Oluf
    Univ Copenhagen, Fac Hlth & Med Sci, Sect Metab Genet, Novo Nordisk Fdn Ctr Basic Metab Res, Copenhagen, Denmark..
    Peters, Annette
    German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol 2, D-85764 Neuherberg, Germany.;German Ctr Diabet Res, D-85764 Neuherberg, Germany..
    Peters, Ulrike
    Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA..
    Polasek, Ozren
    Univ Edinburgh, Usher Inst Populat Hlth Sci & Informat, Edinburgh, Midlothian, Scotland.;Univ Split, Fac Med, Dept Publ Hlth, Split, Croatia..
    Psaty, Bruce M.
    Univ Washington, Dept Med, Seattle, WA 98195 USA.;Univ Washington, Dept Epidemiol, Seattle, WA 98101 USA.;Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA 98101 USA..
    Qi, Lu
    Harvard T H Chan Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA.;Tulane Univ, Sch Publ Hlth & Trop Med, Dept Epidemiol, New Orleans, LA 70118 USA..
    Rauramaa, Rainer
    Kuopio Res Inst Exercise Med, Kuopio, Finland..
    Smith, Blair H.
    Kuopio Univ Hosp, Dept Clin Physiol & Nucl Med, Kuopio, Finland. Univ Dundee, Ninewells Hosp, Div Populat Hlth Sci, Dundee DD2 4RB, Scotland. Univ Dundee, Med Sch, Dundee DD2 4RB, Scotland..
    Sorensen, Thorkild I. A.
    Univ Copenhagen, Fac Hlth & Med Sci, Sect Metab Genet, Novo Nordisk Fdn Ctr Basic Metab Res, Copenhagen, Denmark.;Bispebjerg & Frederiksberg Hosp, Dept Clin Epidemiol, Copenhagen, Denmark.;Univ Bristol, MRC Integrat Epidemiol Unit, Bristol, Avon, England..
    Strauch, Konstantin
    German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Genet Epidemiol, D-85764 Neuherberg, Germany.;Ludwig Maximilians Univ Munchen, Chair Genet Epidemiol, Inst Med Informat Biometry & Epidemiol, D-81377 Munich, Germany..
    Tiemeier, Henning
    Erasmus MC, Dept Psychiat, Rotterdam, Netherlands..
    Tremoli, Elena
    Univ Milan, Dipartimento Sci Farmacolog & Biomol, Milan, Italy.;IRCCS, Ctr Cardiolog Monzino, Milan, Italy..
    Van der Harst, Pim
    Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA.;Univ Groningen, Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands.;ICIN Netherlands Heart Inst, Durrer Ctr Cardiogenet Res, Utrecht, Netherlands..
    Vestergaard, Henrik
    Univ Copenhagen, Fac Hlth & Med Sci, Sect Metab Genet, Novo Nordisk Fdn Ctr Basic Metab Res, Copenhagen, Denmark.;Steno Diabet Ctr, Gentofte, Denmark..
    Vollenweider, Peter
    Lausanne Univ Hosp CHUV, Dept Med Internal Med, Lausanne, Switzerland..
    Wareham, Nicholas J.
    Univ Cambridge, Sch Clin Med, Inst Metab Sci, MRC Epidemiol Unit, Cambridge CB2 0QQ, England..
    Weir, David R.
    Univ Michigan, Inst Social Res, Survey Res Ctr, Ann Arbor, MI 48109 USA..
    Whitfield, John B.
    QIMR Berghofer Med Res Inst, Genet Epidemiol, Brisbane, Qld 4029, Australia..
    Wilson, James F.
    Univ Edinburgh, Inst Genet & Mol Med, MRC Human Genet Unit, Edinburgh, Midlothian, Scotland.;Univ Edinburgh, Usher Inst Populat Hlth Sci & Informat, Edinburgh, Midlothian, Scotland..
    Tyrrell, Jessica
    Univ Exeter, Med Sch, Genet Complex Traits, RILD Bldg, Exeter EX2 5DW, Devon, England.;Univ Exeter, European Ctr Environm & Human Hlth, Med Sch, Truro TR1 3HD, England..
    Frayling, Timothy M.
    Univ Exeter, Med Sch, Genet Complex Traits, Exeter EX1 2LU, Devon, England..
    Barroso, Ines
    Wellcome Trust Sanger Inst, Cambridge, England.;Addenbrookes Hosp, Inst Metab Sci, NIHR Cambridge Biomed Res Ctr, Box 289,Level 4, Cambridge CB2 OQQ, England.;Univ Cambridge, Addenbrookes Hosp, Metab Res Labs, Inst Metab Sci, Level 4,Box 289, Cambridge CB2 OQQ, England..
    Boehnke, Michael
    Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA.;Univ Michigan, Ctr Stat Genet, Ann Arbor, MI 48109 USA..
    Deloukas, Panagiotis
    Queen Mary Univ London, Barts & London Sch Med & Dent, William Harvey Res Inst, London, England.;Wellcome Trust Sanger Inst, Cambridge, England.;King Abdulaziz Univ, PACER HD, Jeddah, Saudi Arabia..
    Fox, Caroline S.
    NHLBI Framingham Heart Study, Framingham, MA 01702 USA..
    Hirschhorn, Joel N.
    Boston Childrens Hosp, Div Endocrinol, Boston, MA 02115 USA.;Boston Childrens Hosp, Div Genet, Boston, MA 02115 USA.;Boston Childrens Hosp, Ctr Basic & Translat Obes Res, Boston, MA 02115 USA.;Broad Inst Harvard, Cambridge, MA 02142 USA.;Harvard Med Sch, Dept Genet, Boston, MA 02115 USA..
    Hunter, David J.
    Harvard T H Chan Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA.;Broad Inst Harvard, Cambridge, MA 02142 USA.;Harvard T H Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA.;Brigham & Womens Hosp, Dept Med, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA.;Harvard Med Sch, Boston, MA 02115 USA..
    Spector, Tim D.
    Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England..
    Strachan, David P.
    St Georges Univ London, Populat Hlth Res Inst, London SW17 0RE, England.;St Georges Univ London, Div Populat Hlth Sci & Educ, London SW17 0RE, England..
    van Duijn, Cornelia M.
    Erasmus Univ, Med Ctr, Dept Epidemiol, Genet Epidemiol Unit, NL-3015 GE Rotterdam, Netherlands.;Netherlands Consortium Healthy Aging, Netherlands Genom Initiat, Leiden, Netherlands.;Ctr Med Syst Biol, Leiden, Netherlands..
    Heid, Iris M.
    Univ Regensburg, Inst Epidemiol & Prevent Med, Dept Genet Epidemiol, D-93053 Regensburg, Germany.;German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Genet Epidemiol, D-85764 Neuherberg, Germany..
    Mohlke, Karen L.
    Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA..
    Marchini, Jonathan
    Univ Oxford, Dept Stat, Oxford, England..
    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 USA.;Univ Cambridge, Sch Clin Med, Inst Metab Sci, MRC Epidemiol Unit, Cambridge CB2 0QQ, England.;Mt Sinai Sch Med, New York, NY 10029 USA.;Icahn Sch Med Mt Sinai, Mindich Child Hlth & Dev Inst, New York, NY 10029 USA..
    Kilpelainen, Tuomas O.
    Univ Copenhagen, Fac Hlth & Med Sci, Sect Metab Genet, Novo Nordisk Fdn Ctr Basic Metab Res, Copenhagen, Denmark.;Univ Cambridge, Sch Clin Med, Inst Metab Sci, MRC Epidemiol Unit, Cambridge CB2 0QQ, England.;Icahn Sch Med Mt Sinai, Dept Prevent Med, New York, NY 10029 USA..
    Liu, Ching-Ti
    Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA..
    Borecki, Ingrid B.
    Washington Univ, Sch Med, Dept Genet, Div Stat Genom, St Louis, MO 63108 USA..
    North, Kari E.
    Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27599 USA..
    Cupples, L. Adrienne
    Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA.;NHLBI Framingham Heart Study, Framingham, MA 01702 USA..
    Genome-wide meta-analysis of 241,258 adults accounting for smoking behaviour identifies novel loci for obesity traits2017In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 8, article id 14977Article in journal (Refereed)
    Abstract [en]

    Few genome-wide association studies (GWAS) account for environmental exposures, like smoking, potentially impacting the overall trait variance when investigating the genetic contribution to obesity-related traits. Here, we use GWAS data from 51,080 current smokers and 190,178 nonsmokers (87% European descent) to identify loci influencing BMI and central adiposity, measured as waist circumference and waist-to-hip ratio both adjusted for BMI. We identify 23 novel genetic loci, and 9 loci with convincing evidence of gene-smoking interaction (GxSMK) on obesity-related traits. We show consistent direction of effect for all identified loci and significance for 18 novel and for 5 interaction loci in an independent study sample. These loci highlight novel biological functions, including response to oxidative stress, addictive behaviour, and regulatory functions emphasizing the importance of accounting for environment in genetic analyses. Our results suggest that tobacco smoking may alter the genetic susceptibility to overall adiposity and body fat distribution.

  • 125.
    Kamble, Prasad G.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    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.
    Pereira, Maria J
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Lundkvist, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Cook, Naomi
    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.
    Franks, Paul W.
    Lund Univ, Diabet Ctr, Dept Clin Sci, Genet & Mol Epidemiol Unit, Malmo, Sweden.
    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.
    Eriksson, Jan W.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Ingelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Genotype-based recall to study metabolic effects of genetic variation: a pilot study of PPARG Pro12Ala carriers2017In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 122, no 4, p. 234-242Article in journal (Refereed)
    Abstract [en]

    AIM: To assess practical implications of genotype-based recall (GBR) studies, an increasingly popular approach for in-depth characterization of genotype-phenotype relationships.

    METHODS: We genotyped 2500 participants from the Swedish EpiHealth cohort and considered loss-of-function and missense variants in genes with relation to cardiometabolic traits as the basis for our GBR study. Therefore, we focused on carriers and non-carriers of the PPARG Pro12Ala (rs1801282) variant, as it is a relatively common variant with a minor allele frequency (MAF) of 0.14. It has also been shown to affect ligand binding and transcription, and carriage of the minor allele (Ala12) is associated with a reduced risk of type 2 diabetes. We re-invited 39 Pro12Pro, 34 Pro12Ala, and 30 Ala12Ala carriers and performed detailed anthropometric and serological assessments.

    RESULTS: The participation rates in the GBR study were 31%, 44%, and 40%, and accordingly we included 12, 15, and 13 individuals with Pro12Pro, Pro12Ala, and Ala12Ala variants, respectively. There were no differences in anthropometric or metabolic variables among the different genotype groups.

    CONCLUSIONS: Our report highlights that from a practical perspective, GBR can be used to study genotype-phenotype relationships. This approach can prove to be a valuable tool for follow-up findings from large-scale genetic discovery studies by undertaking detailed phenotyping procedures that might not be feasible in large studies. However, our study also illustrates the need for a larger pool of genotyped or sequenced individuals to allow for selection of rare variants with larger effects that can be examined in a GBR study of the present size.

  • 126.
    Kamble, Prasad G.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Pereira, Maria J
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    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.
    Lundkvist, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Castillejo-Lopez, Casimiro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular 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, Div Cardiovasc Med, Sch Med, Stanford, CA 94305 USA..
    Eriksson, Jan W
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    PPARG Pro12Ala variant in relation to adipose tissue metabolism and differentiation: a small genotype-based recall study2017In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 60, no S1, p. S173-S173, article id 375Article in journal (Other academic)
  • 127.
    Kamble, Prasad G.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Pereira, Maria J
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    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.
    Lundkvist, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    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.
    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.
    Eriksson, Jan W.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Role of peroxisome proliferator-activated receptor gamma Pro12Ala polymorphism in human adipose tissue: assessment of adipogenesis and adipocyte glucose and lipid turnover.2018In: Adipocyte, ISSN 2162-3945, E-ISSN 2162-397X, Vol. 7, no 4, p. 285-296Article in journal (Refereed)
    Abstract [en]

    Protective mechanisms of peroxisome proliferator-activated receptor gamma (PPARγ) Pro12Ala polymorphism in type 2 diabetes (T2D) are unclear. We obtained adipose tissue (AT) before and 3 h after oral glucose (OGTT) in carriers and non-carriers of the Ala allele (12 Pro/Pro, 15 Pro/Ala, and 13 Ala/Ala). Adipogenesis, adipocyte glucose uptake and lipolysis as well as PPARγ target genes expression were investigated and compared between the genotype groups. On fasting and post-OGTT, neither basal nor insulin-stimulated adipocyte glucose uptake differed between genotypes. Compared to fasting, a decreased hormone-sensitive lipase gene expression in Pro/Pro (p<0.05) also accompanied with a higher antilipolytic effect of insulin post-OGTT (p<0.01). The adipocyte size was similar across groups. Preadipocyte differentiation rates between Pro/Pro and Ala/Ala were unchanged. In conclusion, no major differences in AT differentiation, glucose uptake, lipolysis or expression of PPARγ target genes were observed between different PPARγ Pro12Ala genotypes. Albeit small, our study may suggest that other pathways in AT or effects exerted in other tissues might contribute to the Pro12Ala-mediated protection against T2D.

  • 128. Kassebaum, Nicholas J
    et al.
    Bertozzi-Villa, Amelia
    Coggeshall, Megan S
    Shackelford, Katya A
    Steiner, Caitlyn
    Heuton, Kyle R
    Gonzalez-Medina, Diego
    Barber, Ryan
    Huynh, Chantal
    Dicker, Daniel
    Templin, Tara
    Wolock, Timothy M
    Ozgoren, Ayse Abbasoglu
    Abd-Allah, Foad
    Abera, Semaw Ferede
    Achoki, Tom
    Adelekan, Ademola
    Ademi, Zanfina
    Adou, Arsène Kouablan
    Adsuar, José C
    Agardh, Emilie E
    Akena, Dickens
    Alasfoor, Deena
    Alemu, Zewdie Aderaw
    Alfonso-Cristancho, Rafael
    Alhabib, Samia
    Ali, Raghib
    Al Kahbouri, Mazin J
    Alla, François
    Allen, Peter J
    Almazroa, Mohammad A
    Alsharif, Ubai
    Alvarez, Elena
    Alvis-Guzmán, Nelson
    Amankwaa, Adansi A
    Amare, Azmeraw T
    Amini, Hassan
    Ammar, Walid
    Antonio, Carl A T
    Anwari, Palwasha
    Ärnlöv, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Arsenijevic, Valentina S Arsic
    Artaman, Ali
    Asad, Majed Masoud
    Asghar, Rana J
    Assadi, Reza
    Atkins, Lydia S
    Badawi, Alaa
    Balakrishnan, Kalpana
    Basu, Arindam
    Basu, Sanjay
    Beardsley, Justin
    Bedi, Neeraj
    Bekele, Tolesa
    Bell, Michelle L
    Bernabe, Eduardo
    Beyene, Tariku J
    Bhutta, Zulfiqar
    Bin Abdulhak, Aref
    Blore, Jed
    Basara, Berrak Bora
    Bose, Dipan
    Breitborde, Nicholas
    Cárdenas, Rosario
    Castañeda-Orjuela, Carlos A
    Castro, Ruben Estanislao
    Catalá-López, Ferrán
    Cavlin, Alanur
    Chang, Jung-Chen
    Che, Xuan
    Christophi, Costas A
    Chugh, Sumeet S
    Cirillo, Massimo
    Colquhoun, Samantha M
    Cooper, Leslie Trumbull
    Cooper, Cyrus
    da Costa Leite, Iuri
    Dandona, Lalit
    Dandona, Rakhi
    Davis, Adrian
    Dayama, Anand
    Degenhardt, Louisa
    De Leo, Diego
    Del Pozo-Cruz, Borja
    Deribe, Kebede
    Dessalegn, Muluken
    Deveber, Gabrielle A
    Dharmaratne, Samath D
    Dilmen, Uğur
    Ding, Eric L
    Dorrington, Rob E
    Driscoll, Tim R
    Ermakov, Sergei Petrovich
    Esteghamati, Alireza
    Faraon, Emerito Jose A
    Farzadfar, Farshad
    Felicio, Manuela Mendonca
    Fereshtehnejad, Seyed-Mohammad
    de Lima, Graça Maria Ferreira
    Forouzanfar, Mohammad H
    França, Elisabeth B
    Gaffikin, Lynne
    Gambashidze, Ketevan
    Gankpé, Fortuné Gbètoho
    Garcia, Ana C
    Geleijnse, Johanna M
    Gibney, Katherine B
    Giroud, Maurice
    Glaser, Elizabeth L
    Goginashvili, Ketevan
    Gona, Philimon
    González-Castell, Dinorah
    Goto, Atsushi
    Gouda, Hebe N
    Gugnani, Harish Chander
    Gupta, Rahul
    Gupta, Rajeev
    Hafezi-Nejad, Nima
    Hamadeh, Randah Ribhi
    Hammami, Mouhanad
    Hankey, Graeme J
    Harb, Hilda L
    Havmoeller, Rasmus
    Hay, Simon
    Pi, Ileana B Heredia
    Hoek, Hans W
    Hosgood, H Dean
    Hoy, Damian G
    Husseini, Abdullatif
    Idrisov, Bulat T
    Innos, Kaire
    Inoue, Manami
    Jacobsen, Kathryn H
    Jahangir, Eiman
    Jee, Sun Ha
    Jensen, Paul N
    Jha, Vivekanand
    Jiang, Guohong
    Juel, Knud
    Kabagambe, Edmond Kato
    Kan, Haidong
    Karam, Nadim E
    Karch, André
    Karema, Corine Kakizi
    Kaul, Anil
    Kawakami, Norito
    Kazanjan, Konstantin
    Kazi, Dhruv S
    Kemp, Andrew G
    Kengne, Andre Pascal
    Kereselidze, Maia
    Khader, Yousef Saleh
    Khalifa, Shams Eldin Ali Hassan
    Khan, Ejaz Ahmed
    Khang, Young-Ho
    Knibbs, Luke
    Kokubo, Yoshihiro
    Kosen, Soewarta
    Defo, Barthelemy Kuate
    Kulkarni, Chanda
    Kulkarni, Veena S
    Kumar, G Anil
    Kumar, Kaushalendra
    Kumar, Ravi B
    Kwan, Gene
    Lai, Taavi
    Lalloo, Ratilal
    Lam, Hilton
    Lansingh, Van C
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Lee, Jong-Tae
    Leigh, James
    Leinsalu, Mall
    Leung, Ricky
    Li, Xiaohong
    Li, Yichong
    Li, Yongmei
    Liang, Juan
    Liang, Xiaofeng
    Lim, Stephen S
    Lin, Hsien-Ho
    Lipshultz, Steven E
    Liu, Shiwei
    Liu, Yang
    Lloyd, Belinda K
    London, Stephanie J
    Lotufo, Paulo A
    Ma, Jixiang
    Ma, Stefan
    Machado, Vasco Manuel Pedro
    Mainoo, Nana Kwaku
    Majdan, Marek
    Mapoma, Christopher Chabila
    Marcenes, Wagner
    Marzan, Melvin Barrientos
    Mason-Jones, Amanda J
    Mehndiratta, Man Mohan
    Mejia-Rodriguez, Fabiola
    Memish, Ziad A
    Mendoza, Walter
    Miller, Ted R
    Mills, Edward J
    Mokdad, Ali H
    Mola, Glen Liddell
    Monasta, Lorenzo
    de la Cruz Monis, Jonathan
    Hernandez, Julio Cesar Montañez
    Moore, Ami R
    Mori, Rintaro
    Mueller, Ulrich O
    Mukaigawara, Mitsuru
    Naheed, Aliya
    Naidoo, Kovin S
    Nand, Devina
    Nangia, Vinay
    Nash, Denis
    Nejjari, Chakib
    Nelson, Robert G
    Neupane, Sudan Prasad
    Newton, Charles R
    Ng, Marie
    Nieuwenhuijsen, Mark J
    Nisar, Muhammad Imran
    Nolte, Sandra
    Norheim, Ole F
    Nyakarahuka, Luke
    Oh, In-Hwan
    Ohkubo, Takayoshi
    Olusanya, Bolajoko O
    Omer, Saad B
    Opio, John Nelson
    Orisakwe, Orish Ebere
    Pandian, Jeyaraj D
    Papachristou, Christina
    Park, Jae-Hyun
    Caicedo, Angel J Paternina
    Patten, Scott B
    Paul, Vinod K
    Pavlin, Boris Igor
    Pearce, Neil
    Pereira, David M
    Pesudovs, Konrad
    Petzold, Max
    Poenaru, Dan
    Polanczyk, Guilherme V
    Polinder, Suzanne
    Pope, Dan
    Pourmalek, Farshad
    Qato, Dima
    Quistberg, D Alex
    Rafay, Anwar
    Rahimi, Kazem
    Rahimi-Movaghar, Vafa
    Ur Rahman, Sajjad
    Raju, Murugesan
    Rana, Saleem M
    Refaat, Amany
    Ronfani, Luca
    Roy, Nobhojit
    Pimienta, Tania Georgina Sánchez
    Sahraian, Mohammad Ali
    Salomon, Joshua
    Sampson, Uchechukwu
    Santos, Itamar S
    Sawhney, Monika
    Sayinzoga, Felix
    Schneider, Ione J C
    Schumacher, Austin
    Schwebel, David C
    Seedat, Soraya
    Sepanlou, Sadaf G
    Servan-Mori, Edson E
    Shakh-Nazarova, Marina
    Sheikhbahaei, Sara
    Shibuya, Kenji
    Shin, Hwashin Hyun
    Shiue, Ivy
    Sigfusdottir, Inga Dora
    Silberberg, Donald H
    Silva, Andrea P
    Singh, Jasvinder A
    Skirbekk, Vegard
    Sliwa, Karen
    Soshnikov, Sergey S
    Sposato, Luciano A
    Sreeramareddy, Chandrashekhar T
    Stroumpoulis, Konstantinos
    Sturua, Lela
    Sykes, Bryan L
    Tabb, Karen M
    Talongwa, Roberto Tchio
    Tan, Feng
    Teixeira, Carolina Maria
    Tenkorang, Eric Yeboah
    Terkawi, Abdullah Sulieman
    Thorne-Lyman, Andrew L
    Tirschwell, David L
    Towbin, Jeffrey A
    Tran, Bach X
    Tsilimbaris, Miltiadis
    Uchendu, Uche S
    Ukwaja, Kingsley N
    Undurraga, Eduardo A
    Uzun, Selen Begüm
    Vallely, Andrew J
    van Gool, Coen H
    Vasankari, Tommi J
    Vavilala, Monica S
    Venketasubramanian, N
    Villalpando, Salvador
    Violante, Francesco S
    Vlassov, Vasiliy Victorovich
    Vos, Theo
    Waller, Stephen
    Wang, Haidong
    Wang, Linhong
    Wang, Sharon Xiaorong
    Wang, Yanping
    Weichenthal, Scott
    Weiderpass, Elisabete
    Weintraub, Robert G
    Westerman, Ronny
    Wilkinson, James D
    Woldeyohannes, Solomon Meseret
    Wong, John Q
    Wordofa, Muluemebet Abera
    Xu, Gelin
    Yang, Yang C
    Yano, Yuichiro
    Yentur, Gokalp Kadri
    Yip, Paul
    Yonemoto, Naohiro
    Yoon, Seok-Jun
    Younis, Mustafa Z
    Yu, Chuanhua
    Jin, Kim Yun
    El Sayed Zaki, Maysaa
    Zhao, Yong
    Zheng, Yingfeng
    Zhou, Maigeng
    Zhu, Jun
    Zou, Xiao Nong
    Lopez, Alan D
    Naghavi, Mohsen
    Murray, Christopher J L
    Lozano, Rafael
    Global, regional, and national levels and causes of maternal mortality during 1990-2013: a systematic analysis for the Global Burden of Disease Study 20132014In: The Lancet, ISSN 0140-6736, E-ISSN 1474-547X, Vol. 384, no 9947, p. 980-1004Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The fifth Millennium Development Goal (MDG 5) established the goal of a 75% reduction in the maternal mortality ratio (MMR; number of maternal deaths per 100 000 livebirths) between 1990 and 2015. We aimed to measure levels and track trends in maternal mortality, the key causes contributing to maternal death, and timing of maternal death with respect to delivery.

    METHODS: We used robust statistical methods including the Cause of Death Ensemble model (CODEm) to analyse a database of data for 7065 site-years and estimate the number of maternal deaths from all causes in 188 countries between 1990 and 2013. We estimated the number of pregnancy-related deaths caused by HIV on the basis of a systematic review of the relative risk of dying during pregnancy for HIV-positive women compared with HIV-negative women. We also estimated the fraction of these deaths aggravated by pregnancy on the basis of a systematic review. To estimate the numbers of maternal deaths due to nine different causes, we identified 61 sources from a systematic review and 943 site-years of vital registration data. We also did a systematic review of reports about the timing of maternal death, identifying 142 sources to use in our analysis. We developed estimates for each country for 1990-2013 using Bayesian meta-regression. We estimated 95% uncertainty intervals (UIs) for all values.

    FINDINGS: 292 982 (95% UI 261 017-327 792) maternal deaths occurred in 2013, compared with 376 034 (343 483-407 574) in 1990. The global annual rate of change in the MMR was -0·3% (-1·1 to 0·6) from 1990 to 2003, and -2·7% (-3·9 to -1·5) from 2003 to 2013, with evidence of continued acceleration. MMRs reduced consistently in south, east, and southeast Asia between 1990 and 2013, but maternal deaths increased in much of sub-Saharan Africa during the 1990s. 2070 (1290-2866) maternal deaths were related to HIV in 2013, 0·4% (0·2-0·6) of the global total. MMR was highest in the oldest age groups in both 1990 and 2013. In 2013, most deaths occurred intrapartum or postpartum. Causes varied by region and between 1990 and 2013. We recorded substantial variation in the MMR by country in 2013, from 956·8 (685·1-1262·8) in South Sudan to 2·4 (1·6-3·6) in Iceland.

    INTERPRETATION: Global rates of change suggest that only 16 countries will achieve the MDG 5 target by 2015. Accelerated reductions since the Millennium Declaration in 2000 coincide with increased development assistance for maternal, newborn, and child health. Setting of targets and associated interventions for after 2015 will need careful consideration of regions that are making slow progress, such as west and central Africa.

  • 129.
    Kennedy, Beatrice
    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. Örebro Univ, Sch Med Sci, Clin Epidemiol & Biostat, S-70281 Örebro, Sweden.
    Chen, Ruoqing
    Örebro Univ, Sch Med Sci, Clin Epidemiol & Biostat, S-70281 Örebro, Sweden;Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden.
    Fang, Fang
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden.
    Valdimarsdottir, Unnur
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden;Univ Iceland, Sch Hlth Sci, Fac Med, Ctr Publ Hlth Sci, Reykjavik, Iceland;Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA.
    Montgomery, Scott
    Orebro Univ, Sch Med Sci, Clin Epidemiol & Biostat, S-70281 Orebro, Sweden;UCL, Dept Epidemiol & Publ Hlth, London, England;Karolinska Inst, Karolinska Univ Hosp, Clin Epidemiol Unit, Stockholm, Sweden.
    Larsson, Henrik
    Orebro Univ, Sch Med Sci, Clin Epidemiol & Biostat, S-70281 Orebro, Sweden;Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden.
    Fall, Katja
    Orebro Univ, Sch Med Sci, Clin Epidemiol & Biostat, S-70281 Orebro, Sweden;Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden.
    Low stress resilience in late adolescence and risk of smoking, high alcohol consumption and drug use later in life2019In: Journal of Epidemiology and Community Health, ISSN 0143-005X, E-ISSN 1470-2738, Vol. 73, no 6, p. 496-501Article in journal (Refereed)
    Abstract [en]

    Background While compromised stress resilience constitutes a recognised risk factor for somatic and psychiatric disease development in general, the knowledge about how individual variation in vulnerability to stress may specifically influence the long-term risks of disadvantageous health behaviours is limited. Methods In this Swedish cohort study, we aimed to investigate the association between stress resilience in late adolescence and adult use of addictive substances. We included 9381 men with information on psychological stress resilience measured during military conscription examinations, who later responded to an extensive health survey (mean age 34.0 +/- 7.2 years) including detailed information on substance use. We modelled continuous outcomes using linear regression, binary outcomes with logistic regression and other categorical outcomes with multinomial logistic regression. Results We found that low stress resilience in adolescence conferred increased risks of all studied measures of addictive behaviour. After adjusting for childhood socioeconomic information, low stress resilience was associated with adult current regular smoking (relative risk ratio: 5.85, 95% CI 4.32 to 7.93), higher nicotine dependence scores (beta: 0.76, 95% CI 0.29 to 1.23), hazardous use of alcohol (>14 alcoholic drink-equivalents per week, OR: 1.72, 95% CI 1.37 to 2.16), DSM-IV criteria for alcohol dependence (OR: 1.74, 95% CI 1.35 to 2.25), and drug use (OR: 1.77, 95% CI 1.51 to 2.08). The results remained largely unchanged after further adjustments for adult educational attainment and occupation as well as for additional conscription covariates. Conclusion Low stress resilience in late adolescence appears to be associated with an increased risk of disadvantageous and addictive health behaviours in adulthood.

  • 130.
    Kennedy, Beatrice
    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. Örebro Univ, Clin Epidemiol & Biostat, Sch Med Sci, Örebro, Sweden.
    Chen, Ruoqing
    Örebro Univ, Clin Epidemiol & Biostat, Sch Med Sci, Örebro, Sweden; Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden.
    Valdimarsdottir, Nur
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden; Univ Iceland, Ctr Publ Hlth Sci, Fac Med, Sch Hlth Sci, Reykjavik, Iceland; Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA.
    Montgomery, Scott
    Örebro Univ, Clin Epidemiol & Biostat, Sch Med Sci, Örebro, Sweden; UCL, Dept Epidemiol & Publ Hlth, London, England; Karolinska Inst, Clin Epidemiol Unit, Karolinska Univ Hosp, Stockholm, Sweden.
    Fang, Fang
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden.
    Fall, Katja
    Örebro Univ, Clin Epidemiol & Biostat, Sch Med Sci, Örebro, Sweden; Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden.
    Childhood Bereavement and Lower Stress Resilience in Late Adolescence2018In: Journal of Adolescent Health, ISSN 1054-139X, E-ISSN 1879-1972, Vol. 63, no 1, p. 108-114Article in journal (Refereed)
    Abstract [en]

    Purpose: Although childhood traumatic experiences are recognized as important determinants for adolescent psychiatric health in general, our objective was to explore the specific influence of childhood bereavement on the stress resilience development trajectory.

    Methods: In this national register-based cohort study, we identified 407,639 men born in Sweden between 1973 and 1983, who underwent compulsory military enlistment examinations in late adolescence, including measures of psychological stress resilience. We defined exposure as loss of a first-degree family member in childhood, and estimated relative risk ratios (RRRs) for reduced (moderate or low), compared with high, stress resilience with 95% confidence intervals (CIs) using multinomial logistic regression.

    Results: Loss of a parent or sibling in childhood conferred a 49% increased risk of subsequent low stress resilience (RRR, 1.49, 95% CI, 1.41–1.57) and an 8% increased risk of moderate stress resilience (RRR, 1.08, 95% CI, 1.03–1.13) in late adolescence. There was also a graded increase in risk with increasing age at loss; teenagers were at higher risk for low resilience (RRR, 1.64, 95% CI, 1.52–1.77) than children aged 7–12 (RRR, 1.47, 95% CI, 1.34–1.61) and 6 years (RRR, 1.16 95% CI, 1.02–1.32). The excess risk was observed for all causes of death, including suicide and unexpected deaths as well as deaths due to other illnesses. The associations remained after exclusion of parents with a history of hospitalization for psychiatric diagnoses.

    Conclusions: The long-term consequences of childhood bereavement may include lower stress resilience in late adolescence.

  • 131. Kilpeläinen, Tuomas O
    et al.
    Carli, Jayne F Martin
    Skowronski, Alicja A
    Sun, Qi
    Kriebel, Jennifer
    Feitosa, Mary F
    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.
    Drong, Alexander W
    Hayes, James E
    Zhao, Jinghua
    Pers, Tune H
    Schick, Ursula
    Grarup, Niels
    Kutalik, Zoltán
    Trompet, Stella
    Mangino, Massimo
    Kristiansson, Kati
    Beekman, Marian
    Lyytikäinen, Leo-Pekka
    Eriksson, Joel
    Henneman, Peter
    Lahti, Jari
    Tanaka, Toshiko
    Luan, Jian'an
    Greco M, Fabiola Del
    Pasko, Dorota
    Renström, Frida
    Willems, Sara M
    Mahajan, Anubha
    Rose, Lynda M
    Guo, Xiuqing
    Liu, Yongmei
    Kleber, Marcus E
    Pérusse, Louis
    Gaunt, Tom
    Ahluwalia, Tarunveer S
    Ju Sung, Yun
    Ramos, Yolande F
    Amin, Najaf
    Amuzu, Antoinette
    Barroso, Inês
    Bellis, Claire
    Blangero, John
    Buckley, Brendan M
    Böhringer, Stefan
    I Chen, Yii-Der
    de Craen, Anton J N
    Crosslin, David R
    Dale, Caroline E
    Dastani, Zari
    Day, Felix R
    Deelen, Joris
    Delgado, Graciela E
    Demirkan, Ayse
    Finucane, Francis M
    Ford, Ian
    Garcia, Melissa E
    Gieger, Christian
    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.
    Hallmans, Göran
    Hankinson, Susan E
    Havulinna, Aki S
    Herder, Christian
    Hernandez, Dena
    Hicks, Andrew A
    Hunter, David J
    Illig, Thomas
    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.
    Ioan-Facsinay, Andreea
    Jansson, John-Olov
    Jenny, Nancy S
    Jørgensen, Marit E
    Jørgensen, Torben
    Karlsson, Magnus
    Koenig, Wolfgang
    Kraft, Peter
    Kwekkeboom, Joanneke
    Laatikainen, Tiina
    Ladwig, Karl-Heinz
    LeDuc, Charles A
    Lowe, Gordon
    Lu, Yingchang
    Marques-Vidal, Pedro
    Meisinger, Christa
    Menni, Cristina
    Morris, Andrew P
    Myers, Richard H
    Männistö, Satu
    Nalls, Mike A
    Paternoster, Lavinia
    Peters, Annette
    Pradhan, Aruna D
    Rankinen, Tuomo
    Rasmussen-Torvik, Laura J
    Rathmann, Wolfgang
    Rice, Treva K
    Brent Richards, J
    Ridker, Paul M
    Sattar, Naveed
    Savage, David B
    Söderberg, Stefan
    Timpson, Nicholas J
    Vandenput, Liesbeth
    van Heemst, Diana
    Uh, Hae-Won
    Vohl, Marie-Claude
    Walker, Mark
    Wichmann, Heinz-Erich
    Widén, Elisabeth
    Wood, Andrew R
    Yao, Jie
    Zeller, Tanja
    Zhang, Yiying
    Meulenbelt, Ingrid
    Kloppenburg, Margreet
    Astrup, Arne
    Sørensen, Thorkild I A
    Sarzynski, Mark A
    Rao, D C
    Jousilahti, Pekka
    Vartiainen, Erkki
    Hofman, Albert
    Rivadeneira, Fernando
    Uitterlinden, André G
    Kajantie, Eero
    Osmond, Clive
    Palotie, Aarno
    Eriksson, Johan G
    Heliövaara, Markku
    Knekt, Paul B
    Koskinen, Seppo
    Jula, Antti
    Perola, Markus
    Huupponen, Risto K
    Viikari, Jorma S
    Kähönen, Mika
    Lehtimäki, Terho
    Raitakari, Olli T
    Mellström, Dan
    Lorentzon, Mattias
    Casas, Juan P
    Bandinelli, Stefanie
    März, Winfried
    Isaacs, Aaron
    van Dijk, Ko W
    van Duijn, Cornelia M
    Harris, Tamara B
    Bouchard, Claude
    Allison, Matthew A
    Chasman, Daniel I
    Ohlsson, Claes
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Scott, Robert A
    Langenberg, Claudia
    Wareham, Nicholas J
    Ferrucci, Luigi
    Frayling, Timothy M
    Pramstaller, Peter P
    Borecki, Ingrid B
    Waterworth, Dawn M
    Bergmann, Sven
    Waeber, Gérard
    Vollenweider, Peter
    Vestergaard, Henrik
    Hansen, Torben
    Pedersen, Oluf
    Hu, Frank B
    Eline Slagboom, P
    Grallert, Harald
    Spector, Tim D
    Jukema, J W
    Klein, Robert J
    Schadt, Erik E
    Franks, Paul W
    Lindgren, Cecilia M
    Leibel, Rudolph L
    Loos, Ruth J F
    Genome-wide meta-analysis uncovers novel loci influencing circulating leptin levels2016In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 7, article id 10494Article in journal (Refereed)
    Abstract [en]

    Leptin is an adipocyte-secreted hormone, the circulating levels of which correlate closely with overall adiposity. Although rare mutations in the leptin (LEP) gene are well known to cause leptin deficiency and severe obesity, no common loci regulating circulating leptin levels have been uncovered. Therefore, we performed a genome-wide association study (GWAS) of circulating leptin levels from 32,161 individuals and followed up loci reaching P<10(-6) in 19,979 additional individuals. We identify five loci robustly associated (P<5 × 10(-8)) with leptin levels in/near LEP, SLC32A1, GCKR, CCNL1 and FTO. Although the association of the FTO obesity locus with leptin levels is abolished by adjustment for BMI, associations of the four other loci are independent of adiposity. The GCKR locus was found associated with multiple metabolic traits in previous GWAS and the CCNL1 locus with birth weight. Knockdown experiments in mouse adipose tissue explants show convincing evidence for adipogenin, a regulator of adipocyte differentiation, as the novel causal gene in the SLC32A1 locus influencing leptin levels. Our findings provide novel insights into the regulation of leptin production by adipose tissue and open new avenues for examining the influence of variation in leptin levels on adiposity and metabolic health.

  • 132. Knowles, Joshua W.
    et al.
    Hao, Ke
    Xie, Weija
    Weedon, Michael N.
    Zhang, Zhongyang
    Paaanen, Jussil
    Goodarzi, Mark O.
    Hansson, Ola
    Pankow, James S.
    Chenemsetty, Indumathi
    Carcamo-Orive, Ivan
    Assimes, Themisrocles
    Morris, Andrew
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Chen, Yii-Der I.
    Schadt, Eric E.
    Makinen, Ville-Petteri
    Yang, Xia
    Abbasi, Fahi
    Attie, Alan
    Keller, Mark
    Greenawalt, Danielle
    Rotter, Jerome I.
    Sinako, Alan
    Hsiung, Agnes
    Cordell, Heather J.
    Reaven, Gerald
    Groop, Leif
    Laakso, Markku
    Ingelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Frayling, Timothy M.
    Walker, Mark
    Quertermous, Thomas
    Genetic and Functional Analyses Identify NAT2 as a Human Insulin Sensitivity Gene2013In: Circulation, ISSN 0009-7322, E-ISSN 1524-4539, Vol. 128, no 22Article in journal (Other academic)
  • 133. Knowles, Joshua W.
    et al.
    Xie, Weijia
    Zhang, Zhongyang
    Chennemsetty, Indumathi
    Assimes, Themistocles L.
    Paananen, Jussi
    Hansson, Ola
    Pankow, James
    Goodarzi, Mark O.
    Carcamo-Orive, Ivan
    Morris, Andrew P.
    Chen, Yii-Der I.
    Maekinen, Ville-Petteri
    Ganna, Andrea
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Mahajan, Anubha
    Guo, Xiuqing
    Abbasi, Fahim
    Greenawalt, Danielle M.
    Lum, Pek
    Molony, Cliona
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Lindgren, Cecilia
    Raffel, Leslie J.
    Tsao, Philip S.
    Schadt, Eric E.
    Rotter, Jerome I.
    Sinaiko, Alan
    Reaven, Gerald
    Yang, Xia
    Hsiung, Chao A.
    Groop, Leif
    Cordell, Heather J.
    Laakso, Markku
    Hao, Ke
    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, Timothy M.
    Weedon, Michael N.
    Walker, Mark
    Quertermous, Thomas
    Identification and validation of N-acetyltransferase 2 as an insulin sensitivity gene2015In: Journal of Clinical Investigation, ISSN 0021-9738, E-ISSN 1558-8238, Vol. 125, no 4, p. 1739-1751Article in journal (Refereed)
    Abstract [en]

    Decreased insulin sensitivity, also referred to as insulin resistance (IR), is a fundamental abnormality in patients with type 2 diabetes and a risk factor for cardiovascular disease. While IR predisposition is heritable, the genetic basis remains largely unknown. The GENEticS of Insulin Sensitivity consortium conducted a genome-wide association study (GWAS) for direct measures of insulin sensitivity, such as euglycemic clamp or insulin suppression test, in 2,764 European individuals, with replication in an additional 2,860 individuals. The presence of a nonsynonymous variant of N-acetyltransferase 2 (NAT2) [rs1208 (803A>G, K268R)] was strongly associated with decreased insulin sensitivity that was independent of BMI. The rs1208 "A" allele was nominally associated with IR-related traits, including increased fasting glucose, hemoglobin A1C, total and LDL cholesterol, triglycerides, and coronary artery disease. NAT2 acetylates arylamine and hydrazine drugs and carcinogens, but predicted acetylator NAT2 phenotypes were not associated with insulin sensitivity. In a murine adipocyte cell line, silencing of NAT2 ortholog Nat1 decreased insulin-mediated glucose uptake, increased basal and isoproterenol-stimulated lipolysis, and decreased adipocyte differentiation, while Nat1 overexpression produced opposite effects. Nat1-deficient mice had elevations in fasting blood glucose, insulin, and triglycerides and decreased insulin sensitivity, as measured by glucose and insulin tolerance tests, with intermediate effects in Nat1 heterozygote mice. Our results support a role for NAT2 in insulin sensitivity.

  • 134.
    Kraja, Aldi T.
    et al.
    Washington Univ, Sch Med, Div Stat Genom, Dept Genet, St Louis, MO 63108 USA.;Washington Univ, Sch Med, Ctr Genome Sci & Syst Biol, St Louis, MO 63108 USA..
    Cook, James P.
    Univ Liverpool, Dept Biostatist, Liverpool, Merseyside, England..
    Warren, Helen R.
    William Harvey Res Inst, Dept Clin Pharmacol, London, England.;Queen Mary Univ London, London Sch Med & Dent, London, England.;Queen Mary Univ London, Natl Inst Hlth Res, Baits Cardiovasc Biomed Res Unit, London, England..
    Surendran, Praveen
    MRC BHF Cardiovasc Epidemiol Ctr, Dept Publ Hlth & Primary Care, Cambridge, England..
    Liu, Chunyu
    Framingham Heart Dis Epidemiol Study, Framingham, MA USA.;NHLBI, Populat Sci Branch, Div Intramural Res, Bldg 10, Bethesda, MD 20892 USA..
    Evangelou, Evangelos
    Imperial Coll London, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England.;Univ Ioannina, Med Sch, Dept Hyg & Epidemiol, Ioannina, Greece..
    Manning, Alisa K.
    Massachusetts Gen Hosp, Ctr Genom Med, Boston, MA 02114 USA.;Hebrew SeniorLife, Dept Med, Boston, MA USA..
    Grarup, Niels
    Univ Copenhagen, Novo Nordisk Fdn Ctr Basic Metab Res, Fac Hlth & Med Sci, Copenhagen, Denmark..
    Drenos, Fotios
    Univ Bristol, Sch Social & Community Med, Med Res Council Integrat Epidemiol Unit, Bristol, Avon, England.;UCL, Ctr Cardiovasc Genet, Inst Cardiovasc Sci, London, England..
    Sim, Xueling
    Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA.;Univ Michigan, Ctr Stat Genet, Ann Arbor, MI 48109 USA.;Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore, Singapore..
    Smith, Albert Vernon
    MRC BHF Cardiovasc Epidemiol Ctr, Dept Publ Hlth & Primary Care, Cambridge, England.;Iceland Heart Assoc, Kopavogur, Iceland.;Univ Iceland, Fac Med, Reykjavik, Iceland..
    Amin, Najaf
    Erasmus MC, Dept Epidemiol, Genet Epidemiol Unit, Rotterdam, Netherlands..
    Blakemore, Alexandra I. F.
    Imperial Coll London, Sect Invest Med, Dept Med, London, England.;Brunel Univ, Dept Life Sci, London, England..
    Bork-Jensen, Jette
    Univ Copenhagen, Novo Nordisk Fdn Ctr Basic Metab Res, Fac Hlth & Med Sci, Copenhagen, Denmark..
    Brandslund, Ivan
    Lillebaelt Hosp, Dept Clin Biochem, Vejle, Denmark.;Univ Southern Denmark, Inst Reg Hlth Res, Odense, Denmark..
    Farmaki, Aliki-Eleni
    Harokopio Univ, Sch Hlth Sci & Educ, Dept Nutr & Dietet, Athens, Greece..
    Fava, Cristiano
    Lund Univ, Dept Clin Sci, Malmo, Sweden.;Univ Verona, Dept Med, Verona, Italy..
    Ferreira, Teresa
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England..
    Herzig, Karl-Heinz
    Univ Oulu, Res Unit Biomed, Oulu, Finland.;Univ Oulu, Bioctr Oulu, Oulu, Finland.;Med Res Ctr, Oulu, Finland.;Oulu Univ Hosp, Oulu, Finland.;Poznan Univ Med Sci, Dept Gastroenterol & Metab, Poznan, Poland..
    Giri, Ayush
    Vanderbilt Univ, Med Ctr, Vanderbilt Epidemiol Ctr, Inst Med & Publ Hlth, Nashville, TN 37235 USA..
    Giulianini, Franco
    Brigham & Womens Hosp, Div Prevent Med, 75 Francis St, Boston, MA 02115 USA..
    Grove, Megan L.
    McGovern Med Sch, Human Genet Ctr, Sch Publ Hlth, Houston, TX USA.;Univ Texas Hlth Sci Ctr Houston, Houston, TX 77030 USA..
    Guo, Xiuqing
    Harbor UCLA Med Ctr, Inst Translat Genom & Populat Sci, Torrance, CA 90509 USA.;Harbor UCLA Med Ctr, Dept Pediat, Torrance, CA 90509 USA..
    Harris, Sarah E.
    Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh, Midlothian, Scotland.;Univ Edinburgh, Ctr Genom & Expt Med, Edinburgh, Midlothian, Scotland..
    Have, Christian T.
    Univ Copenhagen, Novo Nordisk Fdn Ctr Basic Metab Res, Fac Hlth & Med Sci, Copenhagen, Denmark..
    Havulinna, Aki S.
    Natl Inst Hlth & Welf, Dept Hlth, Helsinki, Finland.;Inst Mol Med Finland, Helsinki, Finland..
    Zhang, He
    Univ Michigan, Dept Internal Med, Div Cardiovasc Med, Ann Arbor, MI 48109 USA..
    Jorgensen, Marit E.
    Steno Diabet Ctr, Gentofte, Denmark..
    Karajamaki, AnneMari
    Vaasa Cent Hosp, Dept Primary Hlth Care, Vaasa, Finland.;Vaasa Hlth Care Ctr, Diabet Ctr, Vaasa, Finland..
    Kooperberg, Charles
    Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA USA..
    Linneberg, Allan
    Res Ctr Prevent & Hlth, Copenhagen, Denmark.;Rigshosp, Dept Clin Expt Res, Glostrup, Denmark..
    Little, Louis
    William Harvey Res Inst, Dept Clin Pharmacol, London, England.;Queen Mary Univ London, London Sch Med & Dent, London, England..
    Liu, Yongmei
    Wake Forest Baptist Med Ctr, Epidemiol & Prevent Ctr Genom & Personalized Med, Med Ctr Blvd, Winston Salem, NC USA.;Vanderbilt Univ, Sch Med, Div Epidemiol, Dept Med,Vanderbilt Ingram Canc Ctr,Vanderbilt Ep, Nashville, TN 37212 USA..
    Bonnycastle, Lori L.
    NHGRI, Med Genom & Metab Genet Branch, NIH, Bethesda, MD 20892 USA..
    Lu, Yingchang
    Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA..
    Magi, Reedik
    Univ Tartu, Estonian Genome Ctr, Tartu, Estonia..
    Mahajan, Anubha
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England..
    Malerba, Giovanni
    Univ Verona, Dept Neurosci Biomed & Movement, Sect Biol & Genet, Verona, Italy..
    Marioni, Riccardo E.
    Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh, Midlothian, Scotland.;Univ Edinburgh, Ctr Genom & Expt Med, Edinburgh, Midlothian, Scotland..
    Mei, Hao
    Univ Mississippi, Med Ctr, Dept Data Sci, Jackson, MS 39216 USA..
    Menni, Cristina
    Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England..
    Morrison, Alanna C.
    McGovern Med Sch, Human Genet Ctr, Sch Publ Hlth, Houston, TX USA.;Univ Texas Hlth Sci Ctr Houston, Houston, TX 77030 USA..
    Padmanabhan, Sandosh
    Univ Glasgow, British Heart Fdn, Inst Cardiovasc & Med Sci, Coll Med Vet & Life Sci,Glasgow Cardiovasc Res Ct, Glasgow, Lanark, Scotland..
    Palmas, Walter
    Columbia Univ, Dept Med, Med Ctr, New York, NY USA..
    Poveda, Alaitz
    Lund Univ, Dept Clin Sci, Genet & Mol Epidemiol Unit, Malmo, Sweden..
    Rauramaa, Rainer
    Univ Eastern Finland, Kuopio Res Inst Exercise Med, Kuopio, Finland.;Univ Eastern Finland, Dept Clin Physiol & Nucl Med, Kuopio, Finland..
    Rayner, Nigel William
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Radcliffe Dept Med, Oxford, England.;Kuopio Univ Hosp, Kuopio, Finland..
    Riaz, Muhammad
    Wellcome Trust Sanger Inst, Hinxton, England.;Univ Leicester, Dept Cardiovasc Sci, Leicester, Leics, England.;Glenfield Hosp, NIHR Leicester Biomed Res Ctr, Leicester, Leics, England..
    Rice, Ken
    Univ Washington, Dept Biostat, Seattle, WA 98195 USA..
    Richard, Melissa A.
    McGovern Med Sch, Human Genet Ctr, Sch Publ Hlth, Houston, TX USA.;McGovern Med Sch, Brown Fdn Inst Mol Med, Houston, TX 77030 USA..
    Smith, Jennifer A.
    Univ Michigan, Dept Epidemiol, Sch Publ Hlth, Ann Arbor, MI 48109 USA..
    Southam, Lorraine
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.;Kuopio Univ Hosp, Kuopio, Finland..
    Stancakova, Alena
    Univ Eastern Finland, Kuopio, Finland..
    Stirrups, Kathleen E.
    William Harvey Res Inst, Dept Clin Pharmacol, London, England.;Queen Mary Univ London, London Sch Med & Dent, London, England.;MRC BHF Cardiovasc Epidemiol Ctr, Dept Haematol, Cambridge, England..
    Tragante, Vinicius
    Univ Med Ctr Utrecht, Dept Cardiol, Utrecht, Netherlands..
    Tuomi, Tiinamaija
    Helsinki Univ Cent Hosp, Folkhalsan Res Ctr, Helsinki, Finland.;Helsinki Univ Cent Hosp, Dept Endocrinol, Helsinki, Finland.;Umea Univ, Dept Biobank Res, Umea, Sweden.;Univ Helsinki, Finnish Inst Mol Med, Helsinki, Finland..
    Tzoulald, Ioanna
    Imperial Coll London, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England.;Imperial Coll London, MRC PHE Ctr Environm & Hlth, London, England.;Univ Ioannina, Med Sch, Dept Hyg & Epidemiol, Ioannina, Greece..
    Varga, Tibor V.
    Univ Eastern Finland, Kuopio Res Inst Exercise Med, Kuopio, Finland..
    Weiss, Stefan
    Univ Med, Interfac Inst Genet & Funct Genom, Greifswald, Germany.;Ernst Moritz Arndt Univ Greifswald, Greifswald, Germany.;DZHK German Ctr Cardiovasc Res, Partner Site Greifswald, Berlin, Germany..
    Yiorkas, Andrianos M.
    Imperial Coll London, Sect Invest Med, Dept Med, London, England.;Brunel Univ, Dept Life Sci, London, England..
    Young, Robin
    MRC BHF Cardiovasc Epidemiol Ctr, Dept Publ Hlth & Primary Care, Cambridge, England..
    Zhang, Weihua
    Imperial Coll London, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England.;London North West Healthcare NHS Trust, Dept Cardiol, Ealing Hosp, London, England..
    Barnes, Michael R.
    Queen Mary Univ London, Natl Inst Hlth Res, Baits Cardiovasc Biomed Res Unit, London, England..
    Cabrera, Claudia P.
    William Harvey Res Inst, Dept Clin Pharmacol, London, England.;Queen Mary Univ London, London Sch Med & Dent, London, England.;Queen Mary Univ London, Natl Inst Hlth Res, Baits Cardiovasc Biomed Res Unit, London, England..
    Gao, He
    Imperial Coll London, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England.;Imperial Coll London, MRC PHE Ctr Environm & Hlth, London, England..
    Boehnke, Michael
    Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA.;Univ Michigan, Ctr Stat Genet, Ann Arbor, MI 48109 USA..
    Boerwinkle, Eric
    McGovern Med Sch, Human Genet Ctr, Sch Publ Hlth, Houston, TX USA.;Univ Texas Hlth Sci Ctr Houston, Houston, TX 77030 USA.;Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA..
    Chambers, John C.
    Imperial Coll London, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England.;London North West Healthcare NHS Trust, Dept Cardiol, Ealing Hosp, London, England.;Imperial Coll Healthcare NHS Trust, London, England..
    Connell, John M.
    Univ Dundee, Ninewells Hosp & Med Sch, Dundee, Scotland..
    Christensen, Cramer K.
    Lillebaelt Hosp, Med Dept, Vejle, Denmark..
    de Boer, Rudolf A.
    Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, Groningen, Netherlands..
    Deary, Ian J.
    Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh, Midlothian, Scotland.;Univ Edinburgh, Psychol, Edinburgh, Midlothian, Scotland..
    Dedoussis, George
    Harokopio Univ, Sch Hlth Sci & Educ, Dept Nutr & Dietet, Athens, Greece..
    Deloukas, Panos
    William Harvey Res Inst, Dept Clin Pharmacol, London, England.;Queen Mary Univ London, London Sch Med & Dent, London, England.;Queen Mary Univ London, Natl Inst Hlth Res, Baits Cardiovasc Biomed Res Unit, London, England..
    Dominiczak, Anna F.
    Univ Glasgow, British Heart Fdn, Inst Cardiovasc & Med Sci, Coll Med Vet & Life Sci,Glasgow Cardiovasc Res Ct, Glasgow, Lanark, Scotland..
    Dorr, Marcus
    Univ Med, Interfac Inst Genet & Funct Genom, Greifswald, Germany.;Ernst Moritz Arndt Univ Greifswald, Greifswald, Germany.;Univ Med Greifswald, Dept Internal Med B Cardiol Intens Care Med Infec, Greifswald, Germany..
    Joehanes, Roby
    Framingham Heart Dis Epidemiol Study, Framingham, MA USA.;NIH, Ctr Informat Technol, Math & Stat Comp Lab, Bldg 10, Bethesda, MD 20892 USA.;Hebrew SeniorLife, Inst Aging Res, Boston, MA USA..
    Edwards, Todd L.
    Vanderbilt Univ, Med Ctr, Vanderbilt Epidemiol Ctr, Inst Med & Publ Hlth, Nashville, TN 37235 USA..
    Esko, Tonu
    Univ Tartu, Estonian Genome Ctr, Tartu, Estonia..
    Fornage, Myriam
    McGovern Med Sch, Brown Fdn Inst Mol Med, Houston, TX 77030 USA..
    Franceschini, Nora
    Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA..
    Franks, Paul W.
    Lund Univ, Dept Clin Sci, Genet & Mol Epidemiol Unit, Malmo, Sweden.;Harvard TH Chan Sch Publ Hlth, Dept Nutr, Boston, MA USA.;Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden..
    Gambaro, Giovanni
    Univ Cattolica Sacro Cuore, Dept Nephrol & Dialysis, Rome, Italy..
    Groop, Leif
    Lund Univ Diabet Ctr, Dept Clin Sci Diabet & Endocrinol, Malmo, Sweden.;Univ Helsinki, Finnish Inst Mol Med, Helsinki, Finland..
    Hallmans, Goran
    Umea Univ, Dept Biobank Res, Umea, Sweden..
    Hansen, Torben
    Univ Copenhagen, Novo Nordisk Fdn Ctr Basic Metab Res, Fac Hlth & Med Sci, Copenhagen, Denmark..
    Hayward, Caroline
    Univ Edinburgh, Inst Genet & Mol Med, Med Res Council Human Genet Unit, Edinburgh, Midlothian, Scotland..
    Heikki, Oksa
    Tampere Univ Hosp, Tampere, Finland..
    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.
    Tuomilehto, Jaakko
    Natl Inst Hlth & Welf, Chron Dis Prevent Unit, Helsinki, Finland.;Dasman Diabet Inst, Kuwait, Kuwait.;King Abdulaziz Univ, Diabet Res Grp, Jeddah, Saudi Arabia.;Danube Univ Krems, Dept Neurosci & Prevent Med, Krems An Der Donau, Austria..
    Jarvelin, Marjo-Riitta
    Imperial Coll London, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England.;Imperial Coll London, MRC PHE Ctr Environm & Hlth, London, England.;Univ Oulu, Fac Med, Ctr Life Course Hlth Res, Oulu, Finland..
    Kardia, Sharon L. R.
    Univ Michigan, Dept Epidemiol, Sch Publ Hlth, Ann Arbor, MI 48109 USA..
    Karpe, Fredrik
    Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Radcliffe Dept Med, Oxford, England.;Oxford Univ Hosp Trust, Oxford NIHR Biomed Res Ctr, Oxford, England..
    Kooner, Jaspal S.
    London North West Healthcare NHS Trust, Dept Cardiol, Ealing Hosp, London, England.;Imperial Coll Healthcare NHS Trust, London, England.;Imperial Coll London, Natl Heart & Lung Inst, Hammersmith Hosp Campus, London, England..
    Lakka, Timo A.
    Univ Eastern Finland, Kuopio Res Inst Exercise Med, Kuopio, Finland.;Univ Eastern Finland, Dept Clin Physiol & Nucl Med, Kuopio, Finland.;Univ Eastern Finland, Inst Biomed Physiol, Kuopio, Finland..
    Langenberg, Claudia
    Univ Cambridge, Inst Metab Sci, MRC Epidemiol Unit, Sch Clin Med, Cambridge Biomed Campus, Cambridge, England..
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Loos, Ruth J. F.
    Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA..
    Laakso, Markku
    Univ Eastern Finland, Dept Med, Kuopio, Finland..
    McCarthy, Mark I.
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Radcliffe Dept Med, Oxford, England.;Oxford Univ Hosp Trust, Oxford NIHR Biomed Res Ctr, Oxford, England..
    Melander, Olle
    Lund Univ, Dept Clin Sci, Malmo, Sweden..
    Mohlke, Karen L.
    Univ N Carolina, Dept Genet, Chapel Hill, NC USA..
    Moris, Andrwe P.
    Univ Liverpool, Dept Biostatist, Liverpool, Merseyside, England..
    Palmer, Colin N. A.
    Univ Dundee, Ninewells Hosp & Med Sch, Med Res Inst, Dundee, Scotland. Univ Split, Fac Med, Split, Croatia..
    Pedersen, Oluf
    Polasek, Ozren
    Poulter, Neil R.
    Imperial Coll London, Int Ctr Circulatory Hlth, London, England..
    Province, Michael A.
    Washington Univ, Sch Med, Div Stat Genom, Dept Genet, St Louis, MO 63108 USA.;Washington Univ, Sch Med, Ctr Genome Sci & Syst Biol, St Louis, MO 63108 USA..
    Psaty, Bruce M.
    Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA.;Univ Washington, Dept Epidemiol & Hlth Serv, Seattle, WA 98195 USA.;Kaiser Permanente Washington Hlth Res Inst, Seattle, WA USA. Wake Forest Sch Med, Dept Biostat Sci, Div Publ Hlth Sci, Winston Salem, NC USA..
    Ridker, Paul M.
    Hebrew SeniorLife, Dept Med, Boston, MA USA.;Harvard Med Sch, Boston, MA USA.;Brigham & Womens Hosp, Div Prevent Med, 75 Francis St, Boston, MA 02115 USA..
    Rotter, Jerome I.
    Harbor UCLA Med Ctr, Inst Translat Genom & Populat Sci, Torrance, CA 90509 USA.;Harbor UCLA Med Ctr, Dept Pediat, Torrance, CA 90509 USA..
    Rudan, Igor
    Univ Edinburgh, Usher Inst Populat Hlth Sci & Informat, Edinburgh, Midlothian, Scotland. Univ Edinburgh, Alzheimer Scotland Res Ctr, Edinburgh, Midlothian, Scotland..
    Salomaa, Veikko
    Natl Inst Hlth & Welf, Dept Hlth, Helsinki, Finland..
    Samani, Nilesh J.
    Wellcome Trust Sanger Inst, Hinxton, England.;Univ Leicester, Dept Cardiovasc Sci, Leicester, Leics, England.;Glenfield Hosp, NIHR Leicester Biomed Res Ctr, Leicester, Leics, England..
    Sever, Peter J.
    Imperial Coll London, Int Ctr Circulatory Hlth, London, England..
    Skaaby, Tea
    Res Ctr Prevent & Hlth, Copenhagen, Denmark..
    Stafford, Jeanette M.
    Starr, John M.
    van der Harst, Pim
    Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, Groningen, Netherlands.;Univ Groningen, Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands..
    van der Meer, Peter
    Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, Groningen, Netherlands..
    van Duijn, Cornelia M.
    Erasmus MC, Dept Epidemiol, Genet Epidemiol Unit, Rotterdam, Netherlands..
    Vergnaud, Anne-Claire
    Imperial Coll London, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England..
    Gudnason, Vilmundur
    Iceland Heart Assoc, Kopavogur, Iceland.;Univ Iceland, Fac Med, Reykjavik, Iceland..
    Wareham, Nicholas J.
    Univ Cambridge, Inst Metab Sci, MRC Epidemiol Unit, Sch Clin Med, Cambridge Biomed Campus, Cambridge, England..
    Wilson, James G.
    Univ Mississippi, Med Ctr, Dept Physiol & Biophys, Jackson, MS 39216 USA..
    Willer, Cristen J.
    Univ Michigan, Dept Internal Med, Div Cardiovasc Med, Ann Arbor, MI 48109 USA.;Univ Michigan, Dept Computat Med & Bioinformat, Ann Arbor, MI 48109 USA.;Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA..
    Witte, Daniel R.
    Aarhus Univ, Dept Publ Hlth, Aarhus, Denmark.;Danish Diabet Acad, Odense, Denmark..
    Zeggini, Eleftheria
    Kuopio Univ Hosp, Kuopio, Finland..
    Saleheen, Danish
    MRC BHF Cardiovasc Epidemiol Ctr, Dept Publ Hlth & Primary Care, Cambridge, England.;Univ Penn, Perelman Sch Med, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA.;Ctr Noncommunicable Dis, Karachi, Pakistan..
    Butterworth, Adam S.
    MRC BHF Cardiovasc Epidemiol Ctr, Dept Publ Hlth & Primary Care, Cambridge, England.;Univ Cambridge, Cambridge Ctr Excellence, British Heart Fdn, Dept Med, Cambridge, England..
    Danesh, John
    MRC BHF Cardiovasc Epidemiol Ctr, Dept Publ Hlth & Primary Care, Cambridge, England.;NIHR Blood & Transplant Res Unit Donor Hlth & Gen, Cambridge, England.;Univ Cambridge, Cambridge Ctr Excellence, British Heart Fdn, Dept Med, Cambridge, England.;Kuopio Univ Hosp, Kuopio, Finland..
    Asselbergs, Folkert W.
    UCL, Fac Populat Hlth Sci, London, England.;Univ Med Ctr Utrecht, Dept Cardiol, Utrecht, Netherlands..
    Wain, Louise V.
    Univ Leicester, Dept Hlth Sci, Leicester, Leics, England..
    Ehret, Georg B.
    Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Ctr Complex Dis Genom, Baltimore, MD USA.;Geneva Univ Hosp, Dept Med, Geneva, Switzerland..
    Chasman, Daniel I.
    Hebrew SeniorLife, Dept Med, Boston, MA USA.;Harvard Med Sch, Boston, MA USA.;Brigham & Womens Hosp, Div Prevent Med, 75 Francis St, Boston, MA 02115 USA..
    Caulfield, Mark J.
    William Harvey Res Inst, Dept Clin Pharmacol, London, England.;Queen Mary Univ London, London Sch Med & Dent, London, England.;Queen Mary Univ London, Natl Inst Hlth Res, Baits Cardiovasc Biomed Res Unit, London, England..
    Elliott, Paul
    Imperial Coll London, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England.;Imperial Coll London, MRC PHE Ctr Environm & Hlth, London, England.;Imperial Coll London, Natl Inst Hlth Res Imperial Coll Healthcare NHS T, Biomed Res Unit, London, England..
    Lindgren, Cecilia M.
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Oxford, Big Data Inst, Li Ka Shing Ctr Hlth Informat & Discovery, Oxford, England.;Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA USA..
    Levy, Daniel
    Framingham Heart Dis Epidemiol Study, Framingham, MA USA.;NHLBI, Populat Sci Branch, Div Intramural Res, Bldg 10, Bethesda, MD 20892 USA..
    Newton-Cheh, Christopher
    Massachusetts Gen Hosp, Ctr Genom Med, Boston, MA 02114 USA.;Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA.;Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA USA..
    Munroe, Patricia B.
    William Harvey Res Inst, Dept Clin Pharmacol, London, England.;Queen Mary Univ London, London Sch Med & Dent, London, England..
    Howson, Joanna M. M.
    Queen Mary Univ London, Natl Inst Hlth Res, Baits Cardiovasc Biomed Res Unit, London, England.;MRC BHF Cardiovasc Epidemiol Ctr, Dept Publ Hlth & Primary Care, Cambridge, England..
    New Blood Pressure-Associated Loci Identified in Meta-Analyses of 475000 Individuals2017In: Circulation: Cardiovascular Genetics, ISSN 1942-325X, E-ISSN 1942-3268, Vol. 10, no 5, article id e001778Article in journal (Refereed)
    Abstract [en]

    Background - Genome-wide association studies have recently identified >400 loci that harbor DNA sequence variants that influence blood pressure (BP). Our earlier studies identified and validated 56 single nucleotide variants (SNVs) associated with BP from meta-analyses of exome chip genotype data. An additional 100 variants yielded suggestive evidence of association.

    Methods and Results - Here, we augment the sample with 140886 European individuals from the UK Biobank, in whom 77 of the 100 suggestive SNVs were available for association analysis with systolic BP or diastolic BP or pulse pressure. We performed 2 meta-analyses, one in individuals of European, South Asian, African, and Hispanic descent (pan-ancestry, approximate to 475000), and the other in the subset of individuals of European descent (approximate to 423000). Twenty-one SNVs were genome-wide significant (P<5x10(-8) ) for BP, of which 4 are new BP loci: rs9678851 (missense, SLC4A1AP), rs7437940 (AFAP1), rs13303 (missense, STAB1), and rs1055144 (7p15.2). In addition, we identified a potentially independent novel BP-associated SNV, rs3416322 (missense, SYNPO2L) at a known locus, uncorrelated with the previously reported SNVs. Two SNVs are associated with expression levels of nearby genes, and SNVs at 3 loci are associated with other traits. One SNV with a minor allele frequency <0.01, (rs3025380 at DBH) was genome-wide significant.

    Conclusions - We report 4 novel loci associated with BP regulation, and 1 independent variant at an established BP locus. This analysis highlights several candidate genes with variation that alter protein function or gene expression for potential follow-up.

  • 135.
    Kramer, Irene Fleur
    et al.
    Maastricht Univ, Med Ctr, Dept Human Movement Sci, Maastricht, Netherlands.;Maastricht Univ, Med Ctr, Dept Surg, Div Trauma Surg, Maastricht, Netherlands..
    Snijders, Tim
    Maastricht Univ, Med Ctr, Dept Human Movement Sci, Maastricht, Netherlands..
    Smeets, Joey S. J.
    Maastricht Univ, Med Ctr, Dept Human Movement Sci, Maastricht, Netherlands..
    Leenders, Marika
    Maastricht Univ, Med Ctr, Dept Human Movement Sci, Maastricht, Netherlands..
    van Kranenburg, Janneau
    Maastricht Univ, Med Ctr, Dept Human Movement Sci, Maastricht, Netherlands..
    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. Maastricht Univ, Med Ctr, Dept Human Biol, Maastricht, Netherlands.
    Verdijk, Lex B.
    Maastricht Univ, Med Ctr, Dept Human Movement Sci, Maastricht, Netherlands..
    Poeze, Martijn
    Maastricht Univ, Med Ctr, Dept Surg, Div Trauma Surg, Maastricht, Netherlands..
    van Loon, Luc J. C.
    Maastricht Univ, Med Ctr, Dept Human Movement Sci, Maastricht, Netherlands..
    Extensive Type II Muscle Fiber Atrophy in Elderly Female Hip Fracture Patients2017In: The journals of gerontology. Series A, Biological sciences and medical sciences, ISSN 1079-5006, E-ISSN 1758-535X, Vol. 72, no 10, p. 1369-1375Article in journal (Refereed)
    Abstract [en]

    Background: Sarcopenia, or the loss of muscle mass and strength, is known to increase the risk for falls and (hip) fractures in older people. The objective of this study was to assess the skeletal muscle fiber characteristics in elderly female hip fracture patients.

    Method: Percutaneous needle biopsies were collected from the vastus lateralis muscle in 15 healthy young women (20 +/- 0.4 years), 15 healthy elderly women (79 +/- 1.7 years), and 15 elderly women with a fall-related hip fracture (82 +/- 1.5 years). Immunohistochemical analyses were performed to assess Type I and Type II muscle fiber size, and myonuclear and satellite cell content.

    Results: Type II muscle fiber size was significantly different between all groups (p <.05), with smaller Type II muscle fibers in the hip fracture patients (2,609 +/- 185 mu m(2)) compared with healthy elderly group (3,723 +/- 322 mu m(2)) and the largest Type II muscle fibers in the healthy young group (4,755 +/- 335 mu m(2)). Furthermore, Type I muscle fiber size was significantly lower in the hip fracture patients (4,684 +/- 211 mu m(2)) compared with the healthy elderly group (5,842 +/- 316 mu m(2), p =.02). The number of myonuclei per Type II muscle fiber was significantly lower in the healthy elderly and hip fracture group compared with the healthy young group (p =.011 and p =.002, respectively). Muscle fiber satellite cell content did not differ between groups.

    Conclusion: Elderly female hip fracture patients show extensive Type II muscle fiber atrophy when compared with healthy young or agematched healthy elderly controls. Type II muscle fiber atrophy is an important hallmark of sarcopenia and may predispose to falls and (hip) fractures in the older population.

  • 136.
    Kumar, Jitender
    et al.
    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.
    Lind, Lars
    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.
    No Evidence of a Causal Relationship between Plasma Homocysteine and Type 2 Diabetes: A Mendelian Randomization Study2015In: Frontiers in Cardiovascular Medicine, ISSN 1539-4565, E-ISSN 2296-701X, Vol. 2, article id 11Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Several observational studies have shown an association between increased circulating homocysteine and risk of type 2 diabetes (T2D). We aimed to assess whether this relation is causal using genetic data from large populations of individuals of European descent.

    METHODS: We investigated the association between homocysteine concentrations and blood glucose, plasma insulin, T2D in the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) cohort (n = 1,016). A score of five previously published single nucleotide polymorphisms (SNPs) from genes involved in homocysteine metabolism were utilized as genetic instrument for homocysteine concentrations. The effect estimate of this genetic score with T2D was determined using results from the DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) consortium (including 34,840 cases and 114,981 controls). Further, the effects of the genetic score with fasting glucose and insulin were determined using results from the Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC) (up to 38,238 non-diabetic participants).

    RESULTS: The genetic score provided a strong instrument for homocysteine concentrations (P = 2.7 × 10(-143), F = 650). In the PIVUS cohort, we found an association of homocysteine with fasting insulin [β = 0.056 (95% CI 0.021, 0.090), P = 0.001], but not with incident diabetes. We did not find any evidence of a causal effect of homocysteine on fasting glucose, fasting insulin, or T2D (P > 0.05 for all analyses) when using data from DIAGRAM or MAGIC studies.

    CONCLUSION: No evidence of a causal relationship of levels of plasma homocysteine with fasting glucose, fasting insulin, or T2D was observed.

  • 137.
    Kumar, Jitender
    et al.
    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.
    Salihovic, Samira
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    van Bavel, Bert
    MTM Research Centre, School of Science and Technology, Örebro University, Örebro, 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.
    Lind, P. Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Persistent organic pollutants and liver dysfunction biomarkers in a population-based human sample of men and women2014In: Environmental Research, ISSN 0013-9351, E-ISSN 1096-0953, Vol. 134, no SI, p. 251-256Article in journal (Refereed)
    Abstract [en]

    BACKGROUND AND OBJECTIVE: Persistent organic pollutants (POPs) are stable organic compounds generated through different industrial activities. Liver is involved in the metabolism of POPs, and hence exposure to POPs may interfere with liver function. Although a few studies have shown adverse effects of POPs on liver function, large-scale studies involving humans are lacking. We performed this large population-based cross-sectional study to assess the associations between different POPs and liver dysfunction biomarkers.

    METHODS: A total of 992 individuals (all aged 70 years, 50% males) were recruited as part of Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) cohort. The total toxic equivalency (TEQ) value was calculated for seven mono-ortho and two non-ortho substituted polychlorinated biphenyls (PCBs) and octachloro-p-dibenzodioxin (OCDD) to assess their toxicological effects. The association of TEQ values, summary measures of 16 PCBs (sum of PCBs) and three organochlorine pesticides (sum of OC pesticides) with liver dysfunction biomarkers (bilirubin; alkaline phosphatase, ALP; alanine aminotransferase, ALT; and gamma-glutamyltransferase, GGT) was analyzed utilizing linear regression analysis.

    RESULTS: The mono-ortho PCB TEQ values were found to be significantly positively associated with bilirubin (β=0.71, P=0.008), while sum of OC pesticide concentrations was negatively associated with ALP (β=-0.02, P=0.002) after adjusting for various potential confounders. When analyzed individually, a number of different POPs were associated with ALP, ALT and bilirubin. No such association with GGT was observed.

    CONCLUSION: Various POPs including PCBs, OCDD and pesticides were associated with the liver dysfunction biomarkers bilirubin, ALT and ALP, suggesting adverse effects on liver function from these environmental pollutants.

  • 138.
    Kumar, Jitender
    et al.
    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, Monica P.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Salihovic, Samira
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    van Bavel, Bert
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular 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.
    Influence of persistent organic pollutants on oxidative stress in population-based samples2014In: Chemosphere, ISSN 0045-6535, E-ISSN 1879-1298, Vol. 114, p. 303-309Article in journal (Refereed)
    Abstract [en]

    Persistent organic pollutants (POPs) are a large group of chemicals widely used and produced in various industrial applications. Many cell culture/animal studies have shown that POPs can induce oxidative stress. Since such data is lacking in humans, we conducted a large population-based study to analyze associations between POPs and oxidative stress markers. We measured following POPs; 16 polychlorinated biphenyls (PCBs), 5 organochlorine (OC) pesticides, octachlorinated dibenzo-p-dioxin, and polybrominated diphenyl ether 47, and oxidative stress markers; homocysteine, reduced [GSH] and oxidized glutathione [GSSG], glutathione ratio [GSSG/GSH], total glutathione, oxidized low-density lipoprotein [ox-LDL], ox-LDL antibodies, conjugated dienes, baseline conjugated dienes of LDL, and total anti-oxidative capacity in plasma samples collected from 992 70-year old individuals (50% women) from the population-based Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) cohort. Linear regression analyses were performed to study the associations between oxidative stress markers and summary measures of POPs including the total toxic equivalence (TEQ), sums of PCBs and BC pesticides (main exposures) while adjusting for potential confounders. In multivariable-adjusted analyses, sum of PCBs showed strong associations with ox-LDL (beta = 0.94; P = 2.9 * 10(-6)). Further, sum of PCBs showed association with glutathione-related markers (GSSG: beta = 0.01; P = 6.0 *10(-7); GSSG/GSH: beta = 0.002; P = 9.7 * 10(-10)), although in reverse direction. Other summary measures did not show any significant association with these markers. In our study of elderly individuals from the general population, we show that plasma levels of POPs are associated with markers of increased oxidative stress thereby suggesting that even low dose background exposure to POPs may be involved in oxidative stress.

  • 139.
    Kumar, Jitender
    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.
    Lind, Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    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, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Persistent Organic Pollutants and Inflammatory Markers in a Cross-Sectional Study of Elderly Swedish People: The PIVUS Cohort2014In: Journal of Environmental Health Perspectives, ISSN 0091-6765, E-ISSN 1552-9924, Vol. 122, no 9, p. 977-983Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Persistent organic pollutants (POPs) are compounds that are generated through various industrial activities and released in the surrounding environment. Different animal studies have shown effects of different POPs on various inflammatory markers. OBJECTIVE: Because very few studies have been conducted in humans, we assessed the associations between different POPs and inflammatory markers in a large population-based sample of elderly men and women (all 70 years of age) from Sweden. METHODS: This cross-sectional study investigated the concentrations of several polychlorinated biphenyls (PCBs), organochlorine pesticides, polychlorinated dibenzo-p-dioxin, and brominated diphenyl ether congeners and their association with a number of inflammatory markers [vascular cell adhesion molecule 1 (VCAM-1), intercellular adhesion molecule 1 (ICAM-1), E-selectin, C-reactive protein (CRP), total leucocyte count, tumor necrosis factor alpha (TNF-alpha), monocyte chemotactic protein 1 (MCP-1), and interleukin 6 (IL-6)] in 992 individuals. These individuals were recruited from the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) cohort. We used a total toxic equivalency (TEQ) value that measures toxicological effects with the relative potencies of various POPs. RESULTS: Following adjustment for potential confounders, the TEQ value (driven mainly by PCB-126) was significantly associated with levels of ICAM-1 (p < 10(-5)). A similar trend was also observed between sum of PCBs and VCAM-1 (p < 0.001). No significant associations were observed between levels of POPs and other inflammatory markers. CONCLUSIONS: TEQ values were associated with levels of ICAM-1, to a lesser degree also with VCAM-1, but not with CRP and several other inflammatory markers. These findings suggest an activation of vascular adhesion molecules by POPs, and particularly by PCB-126.

  • 140.
    Kumar, Jitender
    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.
    Lind, P. Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Salihovic, Samira
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    van Bavel, Bert
    Ekdahl, Kristina Nilsson
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Nilsson, Bo
    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.
    Influence of persistent organic pollutants on the complement system in a population-based human sample2014In: Environment International, ISSN 0160-4120, E-ISSN 1873-6750, Vol. 71, p. 94-100Article in journal (Refereed)
    Abstract [en]

    Background: Persistent organic pollutants (POPS) are toxic compounds generated through various industrial activities and have adverse effects on human health. Studies performed in cell cultures and animals have revealed that POPs can alter immune-system functioning. The complement system is part of innate immune system that helps to clear pathogens from the body. We performed a large-scale population-based study to find out associations between summary measures of different POPs and different complement system markers. Methods: In this cross-sectional study, 16 polychlorinated biphenyls (PCBs), 3 organochlorine (OC) pesticides, octachloro-p-dibenzodioxin, and 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) were analyzed for their association with levels of protein complement 3 (C3), 3a (C3a), 4 (C4) and C3a/C3 ratio. A total of 992 individuals (all aged 70 years, 50% females) were recruited from the Prospective Investigation of the Vasculature in Uppsala Seniors cohort. Regression analysis adjusting for a variety of confounders was performed to study the associations of different POP exposures (total toxic equivalency value or TEQ and sum of 16 PCBs) with protein complements. Results: The TEQ values were found to be positively associated with C3a (beta = 0.07, 95% CI = 0.017-0.131, p = 0.01) and C3a/C3 ratio (beta = 0.07, 95% Cl = 0.015-0.126, p = 0.01) taking possible confounders into account. The association observed was mainly driven by PCB-126. Conclusion: In this study involving 992 elderly individuals from the general population, we showed that POPs, mainly PCB-126, were associated with levels of complement system markers indicating that the association of these toxic compounds with downstream disease could be mediated by activation of immune system.

  • 141.
    La Merrill, M A
    et al.
    Department of Environmental Toxicology, University of California, Davis, CA, USA.
    Lind, P. Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    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. MTM Research Centre, School of Science and Technology, Örebro University, Örebro, Sweden, and Norwegian Institute for Water Research, NIVA, Oslo, Norway.
    van Bavel, B
    MTM Research Centre, School of Science and Technology, Örebro University, Örebro, Sweden, and Norwegian Institute for Water Research, NIVA, Oslo, Norway.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    The association between p,p'-DDE levels and left ventricular mass is mainly mediated by obesity2018In: Environmental Research, ISSN 0013-9351, E-ISSN 1096-0953, Vol. 160, p. 541-546, article id S0013-9351(17)31176-3Article in journal (Refereed)
    Abstract [en]

    BACKGROUND AND OBJECTIVES: The pesticide metabolite p,p'-DDE has been associated with left ventricular (LV) mass and known risk factors for LV hypertrophy in humans and in experimental models. We hypothesized that the associations of p,p'-DDE with LV hypertrophy risk factors, namely elevated glucose, adiposity and hypertension, mediate the association of p,p'-DDE with LV mass.

    METHODS: p,p'-DDE was measured in plasma from 70-year-old subjects (n = 988) of the Prospective Study of the Vasculature in Uppsala Seniors (PIVUS). When these subjects were 70-, 75- and 80- years old, LV characteristics were measured by echocardiography, while fasting glucose, body mass index (BMI) and blood pressure were assessed with standard clinical techniques.

    RESULTS: We found that p,p'-DDE levels were associated with increased fasting glucose, BMI, hypertension and LV mass in separate models adjusted for sex. Structural equation modeling revealed that the association between p,p'-DDE and LV mass was almost entirely mediated by BMI (70%), and also by hypertension (19%).

    CONCLUSION: The obesogenic effect of p,p'-DDE is a major determinant responsible for the association of p,p'-DDE with LV mass.

  • 142. Lagou, V.
    et al.
    Maegi, R.
    Surakka, I.
    Sarin, A. -P
    Horikoshi, M.
    Thorleifsson, G.
    Hagg, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Beekman, M.
    Ladenvall, C.
    Hottenga, J. -J
    Ried, J. S.
    McCarthy, M. I.
    Morris, A.
    Ripatti, S.
    Prokopenko, I.
    Pleiotropic effects on lipid levels and obesity identified in multi-trait meta-analysis of genome-wide association studies (GWAS) of type 2 diabetes related traits2013In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 56, p. S60-S60Article in journal (Other academic)
  • 143.
    Landegren, Nils
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity. Uppsala University, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Karolinska Univ Hosp, Dept Med Solna, Stockholm, Sweden.
    Rosen, Lindsey B.
    NIAID, Lab Clin Immunol & Microbiol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA.
    Freyhult, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab. Natl Bioinformat Infrastruct, Dept Med Sci, Uppsala, Sweden.
    Eriksson, Daniel
    Karolinska Inst, Karolinska Univ Hosp, Dept Med Solna, Stockholm, Sweden;Karolinska Univ Hosp, Dept Endocrinol Metab & Diabet, Stockholm, Sweden.
    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.
    Smith, Gustav
    Lund Univ, Skane Univ Hosp, Dept Cardiol, Clin Sci, Lund, Sweden;MIT, Broad Inst Harvard, Program Med & Populat Genet, Cambridge, MA 02139 USA;Lund Univ, Ctr Diabet, Wallenberg Ctr Mol Med, Lund, Sweden.
    Ferre, Elise M. N.
    NIAID, Lab Clin Immunol & Microbiol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA.
    Brodin, Petter
    Lund Univ, Skane Univ Hosp, Dept Cardiol, Clin Sci, Lund, Sweden;Karolinska Inst, Dept Womens & Childrens Hlth, Sci Life Lab, Stockholm, Sweden;Karolinska Univ Hosp, Dept Newborn Med, Stockholm, Sweden.
    Sharon, Donald
    Stanford Univ, Dept Genet, Sch Med, Stanford, CA 94305 USA.
    Snyder, Michael
    Lund Univ, Ctr Diabet, Wallenberg Ctr Mol Med, Lund, Sweden;Stanford Univ, Dept Genet, Sch Med, Stanford, CA 94305 USA.
    Lionakis, Michail
    NIAID, Lab Clin Immunol & Microbiol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA.
    Anderson, Mark
    Univ Calif San Francisco, Ctr Diabet, San Francisco, CA 94143 USA.
    Kampe, Olle
    Karolinska Inst, Karolinska Univ Hosp, Dept Med Solna, Stockholm, Sweden;Karolinska Univ Hosp, Dept Endocrinol Metab & Diabet, Stockholm, Sweden;Univ Bergen, KG Jebsen Ctr Autoimmune Dis, Bergen, Norway.
    Comment on 'AIRE-deficient patients harbor unique high-affinity disease-ameliorating autoantibodies'2019In: eLIFE, E-ISSN 2050-084X, Vol. 8, article id e43578Article in journal (Other academic)
    Abstract [en]

    The AIRE gene plays a key role in the development of central immune tolerance by promoting thymic presentation of tissue-specific molecules. Patients with AIRE-deficiency develop multiple autoimmune manifestations and display autoantibodies against the affected tissues. In 2016 it was reported that: i) the spectrum of autoantibodies in patients with AIRE-deficiency is much broader than previously appreciated; ii) neutralizing autoantibodies to type I interferons (IFNs) could provide protection against type 1 diabetes in these patients (Meyer et al., 2016). We attempted to replicate these new findings using a similar experimental approach in an independent patient cohort, and found no evidence for either conclusion.

  • 144.
    Lee, Sangin
    et al.
    Univ Texas Southwestern Med Ctr Dallas, Quantitat Biomed Res Ctr, Dallas, TX 75390 USA.
    Pawitan, Yudi
    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.
    Lee, Youngjo
    Seoul Natl Univ, Dept Stat, San56-1 Shin Lim Dong, Seoul 151747, South Korea.
    Sparse estimation of gene-gene interactions in prediction models2017In: Statistical Methods in Medical Research, ISSN 0962-2802, E-ISSN 1477-0334, Vol. 26, no 5, p. 2319-2332Article in journal (Refereed)
    Abstract [en]

    Current assessment of gene-gene interactions is typically based on separate parallel analysis, where each interaction term is tested separately, while less attention has been paid on simultaneous estimation of interaction terms in a prediction model. As the number of interaction terms grows fast, sparse estimation is desirable from statistical and interpretability reasons. There is a large literature on sparse estimation, but there is a natural hierarchy between the interaction and its corresponding main effects that requires special considerations. We describe random-effect models that impose sparse estimation of interactions under both strong and weak-hierarchy constraints. We develop an estimation procedure based on the hierarchical-likelihood argument and show that the modelling approach is equivalent to a penalty-based method, with the advantage of the models being more transparent and flexible. We compare the procedure with some standard methods in a simulation study and illustrate its application in an analysis of gene-gene interaction model to predict body-mass index.

  • 145. Ligthart, Symen
    et al.
    Vaez, Ahmad
    Võsa, Urmo
    Stathopoulou, Maria G
    de Vries, Paul S
    Prins, Bram P
    Van der Most, Peter J
    Tanaka, Toshiko
    Naderi, Elnaz
    Rose, Lynda M
    Wu, Ying
    Karlsson, Robert
    Barbalic, Maja
    Lin, Honghuang
    Pool, René
    Zhu, Gu
    Macé, Aurélien
    Sidore, Carlo
    Trompet, Stella
    Mangino, Massimo
    Sabater-Lleal, Maria
    Kemp, John P
    Abbasi, Ali
    Kacprowski, Tim
    Verweij, Niek
    Smith, Albert V
    Huang, Tao
    Marzi, Carola
    Feitosa, Mary F
    Lohman, Kurt K
    Kleber, Marcus E
    Milaneschi, Yuri
    Mueller, Christian
    Huq, Mahmudul
    Vlachopoulou, Efthymia
    Lyytikäinen, Leo-Pekka
    Oldmeadow, Christopher
    Deelen, Joris
    Perola, Markus
    Zhao, Jing Hua
    Feenstra, Bjarke
    Amini, Marzyeh
    Lahti, Jari
    Schraut, Katharina E
    Fornage, Myriam
    Suktitipat, Bhoom
    Chen, Wei-Min
    Li, Xiaohui
    Nutile, Teresa
    Malerba, Giovanni
    Luan, Jian'an
    Bak, Tom
    Schork, Nicholas
    Del Greco M, Fabiola
    Thiering, Elisabeth
    Mahajan, Anubha
    Marioni, Riccardo E
    Mihailov, Evelin
    Eriksson, Joel
    Ozel, Ayse Bilge
    Zhang, Weihua
    Nethander, Maria
    Cheng, Yu-Ching
    Aslibekyan, Stella
    Ang, Wei
    Gandin, Ilaria
    Yengo, Loïc
    Portas, Laura
    Kooperberg, Charles
    Hofer, Edith
    Rajan, Kumar B
    Schurmann, Claudia
    den Hollander, Wouter
    Ahluwalia, Tarunveer S
    Zhao, Jing
    Draisma, Harmen H M
    Ford, Ian
    Timpson, Nicholas
    Teumer, Alexander
    Huang, Hongyan
    Wahl, Simone
    Liu, YongMei
    Huang, Jie
    Uh, Hae-Won
    Geller, Frank
    Joshi, Peter K
    Yanek, Lisa R
    Trabetti, Elisabetta
    Lehne, Benjamin
    Vozzi, Diego
    Verbanck, Marie
    Biino, Ginevra
    Saba, Yasaman
    Meulenbelt, Ingrid
    O'Connell, Jeff R
    Laakso, Markku
    Giulianini, Franco
    Magnusson, Patrik K E
    Ballantyne, Christie M
    Hottenga, Jouke Jan
    Montgomery, Grant W
    Rivadineira, Fernando
    Rueedi, Rico
    Steri, Maristella
    Herzig, Karl-Heinz
    Stott, David J
    Menni, Cristina
    Frånberg, Mattias
    St Pourcain, Beate
    Felix, Stephan B
    Pers, Tune H
    Bakker, Stephan J L
    Kraft, Peter
    Peters, Annette
    Vaidya, Dhananjay
    Delgado, Graciela
    Smit, Johannes H
    Großmann, Vera
    Sinisalo, Juha
    Seppälä, Ilkka
    Williams, Stephen R
    Holliday, Elizabeth G
    Moed, Matthijs
    Langenberg, Claudia
    Räikkönen, Katri
    Ding, Jingzhong
    Campbell, Harry
    Sale, Michele M
    Chen, Yii-Der I
    James, Alan L
    Ruggiero, Daniela
    Soranzo, Nicole
    Hartman, Catharina A
    Smith, Erin N
    Berenson, Gerald S
    Fuchsberger, Christian
    Hernandez, Dena
    Tiesler, Carla M T
    Giedraitis, Vilmantas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Liewald, David
    Fischer, Krista
    Mellström, Dan
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Wang, Yunmei
    Scott, William R
    Lorentzon, Matthias
    Beilby, John
    Ryan, Kathleen A
    Pennell, Craig E
    Vuckovic, Dragana
    Balkau, Beverly
    Concas, Maria Pina
    Schmidt, Reinhold
    Mendes de Leon, Carlos F
    Bottinger, Erwin P
    Kloppenburg, Margreet
    Paternoster, Lavinia
    Boehnke, Michael
    Musk, A W
    Willemsen, Gonneke
    Evans, David M
    Madden, Pamela A F
    Kähönen, Mika
    Kutalik, Zoltán
    Zoledziewska, Magdalena
    Karhunen, Ville
    Kritchevsky, Stephen B
    Sattar, Naveed
    Lachance, Genevieve
    Clarke, Robert
    Harris, Tamara B
    Raitakari, Olli T
    Attia, John R
    van Heemst, Diana
    Kajantie, Eero
    Sorice, Rossella
    Gambaro, Giovanni
    Scott, Robert A
    Hicks, Andrew A
    Ferrucci, Luigi
    Standl, Marie
    Lindgren, Cecilia M
    Starr, John M
    Karlsson, Magnus
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Epidemiology.
    Li, Jun Z
    Chambers, John C
    Mori, Trevor A
    de Geus, Eco J C N
    Heath, Andrew C
    Martin, Nicholas G
    Auvinen, Juha
    Buckley, Brendan M
    de Craen, Anton J M
    Waldenberger, Melanie
    Strauch, Konstantin
    Meitinger, Thomas
    Scott, Rodney J
    McEvoy, Mark
    Beekman, Marian
    Bombieri, Cristina
    Ridker, Paul M
    Mohlke, Karen L
    Pedersen, Nancy L
    Morrison, Alanna C
    Boomsma, Dorret I
    Whitfield, John B
    Strachan, David P
    Hofman, Albert
    Vollenweider, Peter
    Cucca, Francesco
    Jarvelin, Marjo-Riitta
    Jukema, J Wouter
    Spector, Tim D
    Hamsten, Anders
    Zeller, Tanja
    Uitterlinden, André G
    Nauck, Matthias
    Gudnason, Vilmundur
    Qi, Lu
    Grallert, Harald
    Borecki, Ingrid B
    Rotter, Jerome I
    März, Winfried
    Wild, Philipp S
    Lokki, Marja-Liisa
    Boyle, Michael
    Salomaa, Veikko
    Melbye, Mads
    Eriksson, Johan G
    Wilson, James F
    Penninx, Brenda W J H
    Becker, Diane M
    Worrall, Bradford B
    Gibson, Greg
    Krauss, Ronald M
    Ciullo, Marina
    Zaza, Gianluigi
    Wareham, Nicholas J
    Oldehinkel, Albertine J
    Palmer, Lyle J
    Murray, Sarah S
    Pramstaller, Peter P
    Bandinelli, Stefania
    Heinrich, Joachim
    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 USA; Stanford Univ, Stanford Cardiovasc Inst, Stanford, CA USA.
    Deary, Ian J
    Mägi, Reedik
    Vandenput, Liesbeth
    van der Harst, Pim
    Desch, Karl C
    Kooner, Jaspal S
    Ohlsson, Claes
    Hayward, Caroline
    Lehtimäki, Terho
    Shuldiner, Alan R
    Arnett, Donna K
    Beilin, Lawrence J
    Robino, Antonietta
    Froguel, Philippe
    Pirastu, Mario
    Jess, Tine
    Koenig, Wolfgang
    Loos, Ruth J F
    Evans, Denis A
    Schmidt, Helena
    Smith, George Davey
    Slagboom, P Eline
    Eiriksdottir, Gudny
    Morris, Andrew P
    Psaty, Bruce M
    Tracy, Russell P
    Nolte, Ilja M
    Boerwinkle, Eric
    Visvikis-Siest, Sophie
    Reiner, Alex P
    Gross, Myron
    Bis, Joshua C
    Franke, Lude
    Franco, Oscar H
    Benjamin, Emelia J
    Chasman, Daniel I
    Dupuis, Josée
    Snieder, Harold
    Dehghan, Abbas
    Alizadeh, Behrooz Z
    Genome Analyses of >200,000 Individuals Identify 58 Loci for Chronic Inflammation and Highlight Pathways that Link Inflammation and Complex Disorders2018In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 103, no 5, p. 691-706, article id S0002-9297(18)30320-3Article in journal (Refereed)
    Abstract [en]

    C-reactive protein (CRP) is a sensitive biomarker of chronic low-grade inflammation and is associated with multiple complex diseases. The genetic determinants of chronic inflammation remain largely unknown, and the causal role of CRP in several clinical outcomes is debated. We performed two genome-wide association studies (GWASs), on HapMap and 1000 Genomes imputed data, of circulating amounts of CRP by using data from 88 studies comprising 204,402 European individuals. Additionally, we performed in silico functional analyses and Mendelian randomization analyses with several clinical outcomes. The GWAS meta-analyses of CRP revealed 58 distinct genetic loci (p < 5 × 10-8). After adjustment for body mass index in the regression analysis, the associations at all except three loci remained. The lead variants at the distinct loci explained up to 7.0% of the variance in circulating amounts of CRP. We identified 66 gene sets that were organized in two substantially correlated clusters, one mainly composed of immune pathways and the other characterized by metabolic pathways in the liver. Mendelian randomization analyses revealed a causal protective effect of CRP on schizophrenia and a risk-increasing effect on bipolar disorder. Our findings provide further insights into the biology of inflammation and could lead to interventions for treating inflammation and its clinical consequences.

  • 146.
    Lind, Lars
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Epidemiology.
    Elmstahl, Solve
    Lund Univ, Malmo Univ Hosp, Dept Clin 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;Stanford Univ, Stanford Cardiovasc Inst, Stanford, CA 94305 USA.
    Cardiometabolic Proteins Associated with Metabolic Syndrome2019In: Metabolic Syndrome and Related Disorders, ISSN 1540-4196, E-ISSN 1557-8518Article in journal (Refereed)
    Abstract [en]

    Background: Although metabolic syndrome (MetS) was described in the late 80s, the molecular mechanisms underlying clustering of risk factors in certain individuals are not fully understood. The present study used targeted proteomics to establish cardiometabolic proteins related to all MetS components, thereby providing new hypotheses regarding pathways involved in the pathogenesis of MetS.

    Methods: In the EpiHealth study, 249 cardiometabolic proteins were measured by proximity extension assay (PEA) and related to the five MetS components [consensus-modified National Cholesterol Education Program (NCEP) criteria] in 2,444 participants aged 45-75 years (50% women).

    Results: Thirty-one proteins were associated with systolic blood pressure following adjustment for age and sex (P < 0.000040, taking multiple testing into account). The corresponding number of proteins significantly associated with fasting glucose, waist circumference, high-density lipoprotein cholesterol, and serum triglycerides were 58, 132, 127, and 148. Twenty-two proteins were significantly related to all 5 MetS components, and of those, 20 were with MetS as a binary outcome (n = 600, 24% of the sample) following adjustment for age, sex, fat mass, and lifestyle factors (alcohol intake, smoking, education, and exercise habits).

    Conclusion: Using targeted proteomics, we identified 20 proteins reflecting a range of pathways, such as immunomodulation at different levels; regulation of adipocyte differentiation; lipid, carbohydrate, and amino acid metabolism; or insulin-like growth factor signaling, to be strongly associated with MetS independently of fat mass and lifestyle factors. Whether some of these proteins are causally involved in the pathogenesis of clustering of multiple risk factors in the same individual remains to be investigated.

  • 147.
    Lind, Lars
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Ng, Esther
    Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
    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. Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, USA.
    Lindgren, Cecilia
    Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK; Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, USA.
    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.
    van Bavel, Bert
    MTM Research Centre, School of Science and Technology, Örebro University, Sweden.
    Mahajan, Anubha
    Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
    Lampa, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Morris, Andrew P
    Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK; Department of Biostatistics, University of Liverpool, Liverpool, UK.
    Lind, P. Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Genetic and methylation variation in the CYP2B6 gene is related to circulating p,p'-dde levels in a population-based sample2017In: Environment International, ISSN 0160-4120, E-ISSN 1873-6750, Vol. 98, p. 212-218Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: Since the metabolism of the organochlorine pesticide dichlorodiphenyltrichloroethane (DDT) is not fully known in humans, we evaluated if circulating levels of a major breakdown product of DDT, p,p'-DDE, were related to genome-wide genetic and methylation variation in a population-based sample.

    METHODS: In the population-based Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study (1016 subjects all aged 70), circulating levels of p,p'-DDE were analyzed by high-resolution chromatography coupled to high-resolution mass spectrometry (HRGC/HRMS). Genetic variants were genotyped and imputed (1000 Genomes reference, March 2012 release). Methylation sites were assayed using the Illumina HumanMethylation450 array in whole blood. A genome-wide association study (GWAS) approach was applied.

    RESULTS: Evidence for genome-wide significant association with p,p'-DDE levels was observed only for a locus at chromosome 19 corresponding to the CYP2B6 gene (lead SNP rs7260538). Subjects being homozygote for the G allele showed a median level of 472ng/g lipid, while the corresponding level for those being homozygote for the T allele was 192ng/g lipid (p=1.5×10(-31)). An analysis conditioned on the lead SNP disclosed a distinct signal in the same gene (rs7255374, position chr19:41520351; p=2.2×10(-8)). A whole-genome methylation analysis showed one significant relationship vs. p,p'-DDE levels (p=6.2×10(-9)) located 7kb downstream the CYP2B6 gene (cg27089200, position chr19:41531976). This CpG-site was also related to the lead SNP (p=3.8×10(-35)), but mediated only 4% of the effect of the lead SNP on p,p'-DDE levels.

    CONCLUSION: Circulating levels of p,p'-DDE were related to genetic variation in the CYP2B6 gene in the general elderly population. DNA methylation in this gene is not closely linked to the p,p'-DDE levels.

  • 148.
    Lind, Lars
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Penell, Johanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Luttropp, Karin
    Nordfors, Louise
    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.
    Salihovic, Samira
    van Bavel, Bert
    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. 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.
    Global DNA hypermethylation is associated with high serum levels of persistent organic pollutants in an elderly population2013In: Environment International, ISSN 0160-4120, E-ISSN 1873-6750, Vol. 59, p. 456-461Article in journal (Refereed)
    Abstract [en]

    Dioxin exposure has experimentally been associated with changes in DNA methylation, an epigenetic change that is associated with disease. The present study aims to investigate if serum levels of dioxin and other persistent environmental pollutants are related to global DNA methylation in a human sample. In the population-based Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study (all aged 70), global DNA methylation was measured by the Luminometric Methylation Assay in 524 subjects. Twenty-three different POPs, including 16 PCBs, five pesticides, one dioxin (OCDD) and one brominated flame retardant (BDE47) were analysed by HRGC/HRMS. Ten single nucleotide polymorphisms (SNPs) in the Aryl hydrocarbon (Ah)-receptor were analysed by mini-sequencing. High levels of toxic equivalency (TEQ) for PCBs and dioxin were associated with DNA hypermethylation (p=0.030). This was mainly attributed to coplanar non-ortho PCBs. While no significant associations were found between DNA methylation and SNPs in the Ah-receptor, an interaction was found between the SNP rs2237297 and TEQ so that TEQ was associated with hypermethylation (p=0.009) only in subjects with one G-allele (n=103). Also high levels of the PCB126 congener, the OCDD, and the pesticide metabolite p,p'-DDE were related to DNA hypermethylation (p=0.01, 0.03 and 0.003, respectively). In conclusion, in a sample of elderly subjects, high TEQ including PCBs and the dioxin OCDD and high serum levels of PCB126, OCDD, and p,p'-DDE were related to global DNA hypermethylation in a cross-sectional analysis.

  • 149.
    Lind, Lars
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Penell, Johanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    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.
    Morris, Andrew P
    Lindgren, Cecilia
    Salihovic, Samira
    van Bavel, Bert
    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 CYP1A1 gene is related to circulating PCB118 levels in a population-based sample2014In: Environmental Research, ISSN 0013-9351, E-ISSN 1096-0953, Vol. 133, p. 135-140Article in journal (Refereed)
    Abstract [en]

    Several of the polychlorinated biphenyls (PCBs), i.e. the dioxin-like PCBs, are known to induce the P450 enzymes CYP1A1, CYP1A2 and CYP1B1 by activating the aryl hydrocarbon receptor (Ah)-receptor. We evaluated if circulating levels of PCBs in a population sample were related to genetic variation in the genes encoding these CYPs. In the population-based Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study (1016 subjects all aged 70), 21 SNPs in the CYP1A1, CYP1A2 and CYP1B1 genes were genotyped. Sixteen PCB congeners were analysed by high-resolution chromatography coupled to high-resolution mass spectrometry (HRGC/ HRMS). Of the investigated relationships between SNPs in the CYP1A1, CYP1A2 and CYP1B1 and six PCBs (congeners 118, 126, 156, 169, 170 and 206) that captures >80% of the variation of all PCBs measured, only the relationship between CYP1A1 rs2470893 was significantly related to PCB118 levels following strict adjustment for multiple testing (p=0.00011). However, there were several additional SNPs in the CYP1A2 and CYP1B1 that showed nominally significant associations with PCB118 levels (p-values in the 0.003-0.05 range). Further, several SNPs in the CYP1B1 gene were related to both PCB156 and PCB206 with p-values in the 0.005-0.05 range. Very few associations with p<0.05 were seen for PCB126, PCB169 or PCB170. Genetic variation in the CYP1A1 was related to circulating PCB118 levels in the general elderly population. Genetic variation in CYP1A2 and CYP1B1 might also be associated with other PCBs.

  • 150.
    Lind, Lars
    et al.
    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. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lampa, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Lind, P. Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Mixture effects of 30 environmental contaminants on incident metabolic syndrome: A prospective study2017In: Environment International, ISSN 0160-4120, E-ISSN 1873-6750, Vol. 107, p. 8-15Article in journal (Refereed)
    Abstract [en]

    Background: Several cross-sectional studies have linked different environmental contaminants to the metabolic syndrome (MetS). However, mixture effects have not been investigated and no prospective studies exist regarding environmental contaminants and the MetS.

    Objectives: To study mixture effects of contaminants on the risk of incident MetS in a prospective fashion.

    Methods: Our sample consisted of 452 subjects from the Prospective Study of the Vasculature in Uppsala Seniors (PIVUS) study (50% women, all aged 70 years) free from the MetS at baseline, being followed for 10 years. At baseline, 30 different environmental contaminants were measured; 6 polychlorinated biphenyls (PCBs), 3 organochlorine (OC) pesticides, one dioxin, one polybrominated diphenyl ether (all in plasma), 8 perfluoroalkyl substances (in plasma) and 11 metals (in whole blood). The MetS was defined by the ATPIII/NCEP criteria. Gradient boosted Classification and Regression Trees (CARTs) was used to evaluate potential synergistic and additive mixture effects on incident MetS.

    Results: During 10-year follow-up, 92 incident cases of the MetS occurred. PCB126, PCB170, hexachlorobenzene (HCB) and PCB118 levels were all associated with incident MetS in an additive fashion (OR 1.73 for a change from 10th to 90th percentile (95% CI 1.24-3.04) for PCB126, OR 0.63 (0.42-0.78) for PCB170, OR 1.44 (1.09-2.20) for HCB and OR 1.46 (1.13-2.43) for PCB118). No synergistic effects were found.

    Conclusion: A mixture of environmental contaminants, with PCB126, PCB170, HCB and PCB118 being the most important, showed associations with future development of the MetS in an additive fashion in this prospective study. Thus, mixture effects of environmental contaminants could contribute to the development of cardiometabolic derangements.

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