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  • 1. Koivula, Robert W.
    et al.
    Forgie, Ian M.
    Kurbasic, Azra
    Vinuela, Ana
    Heggie, Alison
    Giordano, Giuseppe N.
    Hansen, Tue H.
    Hudson, Michelle
    Koopman, Anitra D. M.
    Rutters, Femke
    Siloaho, Maritta
    Allin, Kristine H.
    Brage, Soren
    Brorsson, Caroline A.
    Dawed, Adem Y.
    De Masi, Federico
    Groves, Christopher J.
    Kokkola, Tarja
    Mahajan, Anubha
    Perry, Mandy H.
    Rauh, Simone P.
    Ridderstrale, Martin
    Teare, Harriet J. A.
    Thomas, E. Louise
    Tura, Andrea
    Vestergaard, Henrik
    White, Tom
    Adamski, Jerzy
    Bell, Jimmy D.
    Beulens, Joline W.
    Brunak, Soren
    Dermitzakis, Emmanouil T.
    Froguel, Philippe
    Frost, Gary
    Gupta, Ramneek
    Hansen, Torben
    Hattersley, Andrew
    Jablonka, Bernd
    Kaye, Jane
    Laakso, Markku
    McDonald, Timothy J.
    Pedersen, Oluf
    Schwenk, Jochen M.
    Pavo, Imre
    Mari, Andrea
    McCarthy, Mark I.
    Ruetten, Hartmut
    Walker, Mark
    Pearson, Ewan
    Franks, Paul W.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine. Department of Clinical Sciences, Lund University Diabetes Centre, Genetic and Molecular Epidemiology Unit, CRC, Skåne University Hospital Malmö, Malmö, Sweden; Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, UK; Department of Nutrition, Harvard School of Public Health, Boston, MA, USA.
    Discovery of biomarkers for glycaemic deterioration before and after the onset of type 2 diabetes: descriptive characteristics of the epidemiological studies within the IMI DIRECT Consortium2019In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 62, no 9, p. 1601-1615Article in journal (Refereed)
    Abstract [en]

    Aims/hypothesis: Here, we describe the characteristics of the Innovative Medicines Initiative (IMI) Diabetes Research on Patient Stratification (DIRECT) epidemiological cohorts at baseline and follow-up examinations (18, 36 and 48 months of follow-up).

    Methods: From a sampling frame of 24,682 adults of European ancestry enrolled in population-based cohorts across Europe, participants at varying risk of glycaemic deterioration were identified using a risk prediction algorithm (based on age, BMI, waist circumference, use of antihypertensive medication, smoking status and parental history of type 2 diabetes) and enrolled into a prospective cohort study (n = 2127) (cohort 1, prediabetes risk). We also recruited people from clinical registries with type 2 diabetes diagnosed 6-24 months previously (n = 789) into a second cohort study (cohort 2, diabetes). Follow-up examinations took place at similar to 18 months (both cohorts) and at similar to 48 months (cohort 1) or similar to 36 months (cohort 2) after baseline examinations. The cohorts were studied in parallel using matched protocols across seven clinical centres in northern Europe.

    Results: Using ADA 2011 glycaemic categories, 33% (n = 693) of cohort 1 (prediabetes risk) had normal glucose regulation and 67% (n = 1419) had impaired glucose regulation. Seventy-six per cent of participants in cohort 1 was male. Cohort 1 participants had the following characteristics (mean +/- SD) at baseline: age 62 (6.2) years; BMI 27.9 (4.0) kg/m(2); fasting glucose 5.7 (0.6) mmol/l; 2 h glucose 5.9 (1.6) mmol/l. At the final follow-up examination the participants' clinical characteristics were as follows: fasting glucose 6.0 (0.6) mmol/l; 2 h OGTT glucose 6.5 (2.0) mmol/l. In cohort 2 (diabetes), 66% (n = 517) were treated by lifestyle modification and 34% (n = 272) were treated with metformin plus lifestyle modification at enrolment. Fifty-eight per cent of participants in cohort 2 was male. Cohort 2 participants had the following characteristics at baseline: age 62 (8.1) years; BMI 30.5 (5.0) kg/m(2); fasting glucose 7.2 (1.4) mmol/l; 2 h glucose 8.6 (2.8) mmol/l. At the final follow-up examination, the participants' clinical characteristics were as follows: fasting glucose 7.9 (2.0) mmol/l; 2 h mixed-meal tolerance test glucose 9.9 (3.4) mmol/l.

    Conclusions/interpretation: The IMI DIRECT cohorts are intensely characterised, with a wide-variety of metabolically relevant measures assessed prospectively. We anticipate that the cohorts, made available through managed access, will provide a powerful resource for biomarker discovery, multivariate aetiological analyses and reclassification of patients for the prevention and treatment of type 2 diabetes.

  • 2. Middeldorp, Christel M.
    et al.
    Mahajan, Anubha
    Horikoshi, Momoko
    Robertson, Neil R.
    Beaumont, Robin N.
    Bradfield, Jonathan P.
    Bustamante, Mariona
    Cousminer, Diana L.
    Day, Felix R.
    De Silva, N. Maneka
    Guxens, Monica
    Mook-Kanamori, Dennis O.
    St Pourcain, Beate
    Warrington, Nicole M.
    Adair, Linda S.
    Ahlqvist, Emma
    Ahluwalia, Tarunveer S.
    Almgren, Peter
    Ang, Wei
    Atalay, Mustafa
    Auvinen, Juha
    Bartels, Meike
    Beckmann, Jacques S.
    Bilbao, Jose Ramon
    Bond, Tom
    Borja, Judith B.
    Cavadino, Alana
    Charoen, Pimphen
    Chen, Zhanghua
    Coin, Lachlan
    Cooper, Cyrus
    Curtin, John A.
    Custovic, Adnan
    Das, Shikta
    Davies, Gareth E.
    Dedoussis, George V.
    Duijts, Liesbeth
    Eastwood, Peter R.
    Eliasen, Anders U.
    Elliott, Paul
    Eriksson, Johan G.
    Estivill, Xavier
    Fadista, Joao
    Fedko, Iryna O.
    Frayling, Timothy M.
    Gaillard, Romy
    Gauderman, W. James
    Geller, Frank
    Gilliland, Frank
    Gilsanz, Vincente
    Granell, Raquel
    Grarup, Niels
    Groop, Leif
    Hadley, Dexter
    Hakonarson, Hakon
    Hansen, Torben
    Hartman, Catharina A.
    Hattersley, Andrew T.
    Hayes, M. Geoffrey
    Hebebrand, Johannes
    Heinrich, Joachim
    Helgeland, Oyvind
    Henders, Anjali K.
    Henderson, John
    Henriksen, Tine B.
    Hirschhorn, Joel N.
    Hivert, Marie-France
    Hocher, Berthold
    Holloway, John W.
    Holt, Patrick
    Hottenga, Jouke-Jan
    Hypponen, Elina
    Iniguez, Carmen
    Johansson, Stefan
    Jugessur, Astanand
    Kahonen, Mika
    Kalkwarf, Heidi J.
    Kaprio, Jaakko
    Karhunen, Ville
    Kemp, John P.
    Kerkhof, Marjan
    Koppelman, Gerard H.
    Korner, Antje
    Kotecha, Sailesh
    Kreiner-Moller, Eskil
    Kulohoma, Benard
    Kumar, Ashish
    Kutalik, Zoltan
    Lahti, Jari
    Lappe, Joan M.
    Larsson, Henrik
    Lehtimaki, Terho
    Lewin, Alexandra M.
    Li, Jin
    Lichtenstein, Paul
    Lindgren, Cecilia M.
    Lindi, Virpi
    Linneberg, Allan
    Liu, Xueping
    Liu, Jun
    Lowe, William L., Jr.
    Lundstrom, Sebastian
    Lyytikainen, Leo-Pekka
    Ma, Ronald C. W.
    Mace, Aurelien
    Magi, Reedik
    Magnus, Per
    Mamun, Abdullah A.
    Mannikko, Minna
    Martin, Nicholas G.
    Mbarek, Hamdi
    McCarthy, Nina S.
    Medland, Sarah E.
    Melbye, Mads
    Melen, Erik
    Mohlke, Karen L.
    Monnereau, Claire
    Morgen, Camilla S.
    Morris, Andrew P.
    Murray, Jeffrey C.
    Myhre, Ronny
    Najman, Jackob M.
    Nivard, Michel G.
    Nohr, Ellen A.
    Nolte, Ilja M.
    Ntalla, Ioanna
    O'Reilly, Paul
    Oberfield, Sharon E.
    Oken, Emily
    Oldehinkel, Albertine J.
    Pahkala, Katja
    Palviainen, Teemu
    Panoutsopoulou, Kalliope
    Pedersen, Oluf
    Pennell, Craig E.
    Pershagen, Goran
    Pitkanen, Niina
    Plomin, Robert
    Power, Christine
    Prasad, Rashmi B.
    Prokopenko, Inga
    Pulkkinen, Lea
    Raikkonen, Katri
    Raitakari, Olli T.
    Reynolds, Rebecca M.
    Richmond, Rebecca C.
    Rivadeneira, Fernando
    Rodriguez, Alina
    Mid Sweden University, Faculty of Human Sciences, Department of Psychology and Social Work. Univ Exeter, Med Sch, Inst Biomed & Clin Sci, Royal Devon & Exeter Hosp, Exeter EX2 5DW, Devon, England; Imperial Coll London, Sch Publ Hlth, Dept Epidemiol & Biostat, MRC PHE Ctr Environm & Hlth, London W2 1PG, England.
    Rose, Richard J.
    Salem, Rany
    Santa-Marina, Loreto
    Saw, Seang-Mei
    Schnurr, Theresia M.
    Scott, James G.
    Selzam, Saskia
    Shepherd, John A.
    Simpson, Angela
    Skotte, Line
    Sleiman, Patrick M. A.
    Snieder, Harold
    Sorensen, Thorkild I. A.
    Standl, Marie
    Steegers, Eric A. P.
    Strachan, David P.
    Straker, Leon
    Strandberg, Timo
    Taylor, Michelle
    Teo, Yik-Ying
    Thiering, Elisabeth
    Torrent, Maties
    Tyrrell, Jessica
    Uitterlinden, Andre G.
    van Beijsterveldt, Toos
    van der Most, Peter J.
    van Duijn, Cornelia M.
    Viikari, Jorma
    Vilor-Tejedor, Natalia
    Vogelezang, Suzanne
    Vonk, Judith M.
    Vrijkotte, Tanja G. M.
    Vuoksimaa, Eero
    Wang, Carol A.
    Watkins, William J.
    Wichmann, H-Erich
    Willemsen, Gonneke
    Williams, Gail M.
    Wilson, James F.
    Wray, Naomi R.
    Xu, Shujing
    Xu, Cheng-Jian
    Yaghootkar, Hanieh
    Yi, Lu
    Zafarmand, Mohammad Hadi
    Zeggini, Eleftheria
    Zemel, Babette S.
    Hinney, Anke
    Lakka, Timo A.
    Whitehouse, Andrew J. O.
    Sunyer, Jordi
    Widen, Elisabeth E.
    Feenstra, Bjarke
    Sebert, Sylvain
    Jacobsson, Bo
    Njolstad, Pal R.
    Stoltenberg, Camilla
    Smith, George Davey
    Lawlor, Debbie A.
    Paternoster, Lavinia
    Timpson, Nicholas J.
    Ong, Ken K.
    Bisgaard, Hans
    Bonnelykke, Klaus
    Jaddoe, Vincent W. V.
    Tiemeier, Henning
    Jarvelin, Marjo-Riitta
    Evans, David M.
    Perry, John R. B.
    Grant, Struan F. A.
    Boomsma, Dorret I.
    Freathy, Rachel M.
    McCarthy, Mark I.
    Felix, Janine F.
    Tiemeier, Hen-Ning
    The Early Growth Genetics (EGG) and EArly Genetics and Lifecourse Epidemiology (EAGLE) consortia: design, results and future prospects2019In: European Journal of Epidemiology, ISSN 0393-2990, E-ISSN 1573-7284, Vol. 34, no 3, p. 279-300Article in journal (Refereed)
    Abstract [en]

    The impact of many unfavorable childhood traits or diseases, such as low birth weight and mental disorders, is not limited to childhood and adolescence, as they are also associated with poor outcomes in adulthood, such as cardiovascular disease. Insight into the genetic etiology of childhood and adolescent traits and disorders may therefore provide new perspectives, not only on how to improve wellbeing during childhood, but also how to prevent later adverse outcomes. To achieve the sample sizes required for genetic research, the Early Growth Genetics (EGG) and EArly Genetics and Lifecourse Epidemiology (EAGLE) consortia were established. The majority of the participating cohorts are longitudinal population-based samples, but other cohorts with data on early childhood phenotypes are also involved. Cohorts often have a broad focus and collect(ed) data on various somatic and psychiatric traits as well as environmental factors. Genetic variants have been successfully identified for multiple traits, for example, birth weight, atopic dermatitis, childhood BMI, allergic sensitization, and pubertal growth. Furthermore, the results have shown that genetic factors also partly underlie the association with adult traits. As sample sizes are still increasing, it is expected that future analyses will identify additional variants. This, in combination with the development of innovative statistical methods, will provide detailed insight on the mechanisms underlying the transition from childhood to adult disorders. Both consortia welcome new collaborations. Policies and contact details are available from the corresponding authors of this manuscript and/or the consortium websites.

  • 3.
    Schmidt, Amand F.
    et al.
    UCL, Inst Cardiovasc Sci, 222 Euston Rd, London NW1 2DA, England;Univ Utrecht, Univ Med Ctr Utrecht, Div Heart & Lungs, Dept Cardiol, Utrecht, Netherlands;UCLs BHF Res Accelerator Ctr, London, England.
    Holmes, Michael V.
    Univ Oxford, Nuffield Dept Populat Hlth, Clin Trial Serv Unit, Med Res Council Populat Hlth Res Unit, Oxford, England;Univ Oxford, Nuffield Dept Populat Hlth, Epidemiol Studies Unit CTSU, Oxford, England.
    Preiss, David
    Univ Oxford, Nuffield Dept Populat Hlth, Clin Trial Serv Unit, Med Res Council Populat Hlth Res Unit, Oxford, England;Univ Oxford, Nuffield Dept Populat Hlth, Epidemiol Studies Unit CTSU, Oxford, England.
    Swerdlow, Daniel I.
    UCL, Inst Cardiovasc Sci, 222 Euston Rd, London NW1 2DA, England;Imperial Coll London, Dept Med, London, England.
    Denaxas, Spiros
    UCLs BHF Res Accelerator Ctr, London, England;UCL, Hlth Data Res UK, 222 Euston Rd, London NW1 2DA, England;UCL, Inst Hlth Informat, 222 Euston Rd, London NW1 2DA, England;British Lib, Alan Turing Inst, 96 Euston Rd, London NW1 2DB, England.
    Fatemifar, Ghazaleh
    UCLs BHF Res Accelerator Ctr, London, England;UCL, Hlth Data Res UK, 222 Euston Rd, London NW1 2DA, England;UCL, Inst Hlth Informat, 222 Euston Rd, London NW1 2DA, England.
    Faraway, Rupert
    UCL, Inst Cardiovasc Sci, 222 Euston Rd, London NW1 2DA, England.
    Finan, Chris
    UCL, Inst Cardiovasc Sci, 222 Euston Rd, London NW1 2DA, England;UCLs BHF Res Accelerator Ctr, London, England.
    Valentine, Dennis
    UCLs BHF Res Accelerator Ctr, London, England;UCL, Farr Inst Hlth Informat, London, England.
    Fairhurst-Hunter, Zammy
    Univ Oxford, Nuffield Dept Populat Hlth, Clin Trial Serv Unit, Richard Doll Bldg,Old Rd Campus,Roosevelt Dr, Oxford OX3 7LF, England;Univ Oxford, Nuffield Dept Populat Hlth, Epidemiol Studies Unit CTSU, Richard Doll Bldg,Old Rd Campus,Roosevelt Dr, Oxford OX3 7LF, England.
    Hartwig, Fernando Pires
    Univ Fed Pelotas, Postgrad Program Epidemiol, Pelotas, RS, Brazil.
    Horta, Bernardo Lessa
    Univ Fed Pelotas, Postgrad Program Epidemiol, Pelotas, RS, Brazil.
    Hypponen, Elina
    Univ South Australia, Sansom Inst Hlth Res, Ctr Populat Hlth Res, Adelaide, SA, Australia;UCL GOS Inst Child Hlth, Populat Policy & Practice, London, England;South Australian Hlth & Med Res Inst, Adelaide, SA, Australia.
    Power, Christine
    UCL GOS Inst Child Hlth, Populat Policy & Practice, London, England.
    Moldovan, Max
    South Australian Hlth & Med Res Inst, Adelaide, SA, Australia.
    van Iperen, Erik
    Netherlands Heart Inst, Durrer Ctr Cardiovasc Res, Utrecht, Netherlands;Acad Med Ctr Amsterdam, Dept Clin Epidemiol Biostat & Bioinformat, Amsterdam, Netherlands.
    Hovingh, Kees
    Acad Med Ctr Amsterdam, Dept Vasc Med, Amsterdam, Netherlands.
    Demuth, Ilja
    Charite Univ Med Berlin, Berlin, Germany;Free Univ Berlin, Berlin, Germany;Humboldt Univ, Berlin, Germany;Berlin Inst Hlth, Lipid Clin, Interdisciplinary Metab Ctr, Berlin, Germany;Charite Univ Med Berlin, BCRT Berlin Inst Hlth, Ctr Regenerat Therapies, Berlin, Germany.
    Norman, Kristina
    Univ Potsdam, Inst Nutr Sci, D-14558 Nuthetal, Germany;Charite Univ Med Berlin, Geriatr Res Grp, D-13347 Berlin, Germany;German Inst Human Nutr Potsdam Rehbrucke, Dept Nutr & Gerontol, D-14558 Nuthetal, Germany.
    Steinhagen-Thiessen, Elisabeth
    Charite Univ Med Berlin, Berlin, Germany;Free Univ Berlin, Berlin, Germany;Humboldt Univ, Berlin, Germany;Berlin Inst Hlth, Lipid Clin, Interdisciplinary Metab Ctr, Berlin, Germany.
    Demuth, Juri
    ECA Econ GmbH, Berlin, Germany.
    Bertram, Lars
    Univ Lubeck, Lubeck Interdisciplinary Platform Genome Analyt L, Inst Neurogenet & Cardiogenet, Lubeck, Germany;Univ Oslo, Dept Psychol, Ctr Lifespan Changes Brain & Cognit LCBC, Oslo, Norway.
    Lill, Christina M.
    Univ Lubeck, Inst Neurogenet & Cardiogenet, Lubeck Interdisciplinary Platform Genome Analyt L, Genet & Mol Epidemiol Grp, Lubeck, Germany;Inst Human Genet, Lubeck, Germany;Imperial Coll, Sch Publ Hlth, Ageing Epidemiol Res Unit, London, England.
    Coassin, Stefan
    Med Univ Innsbruck, Dept Genet & Pharmacol, Inst Genet Epidemiol, A-6020 Innsbruck, Austria.
    Willeit, Johann
    Med Univ Innsbruck, Dept Neurol, Innsbruck, Austria.
    Kiechl, Stefan
    Med Univ Innsbruck, Dept Neurol, Innsbruck, Austria.
    Willeit, Karin
    Med Univ Innsbruck, Dept Neurol, Innsbruck, Austria;Univ Bern, Univ Hosp Bern, Inselspital, Dept Neurol, Bern, Switzerland.
    Mason, Dan
    Bradford Royal Infirm, Bradford Inst Hlth Res, Bradford, W Yorkshire, England.
    Wright, John
    Bradford Royal Infirm, Bradford Inst Hlth Res, Bradford, W Yorkshire, England.
    Morris, Richard
    UCL, Dept Primary Care & Populat Hlth, London, England.
    Wanamethee, Goya
    UCL, Dept Primary Care & Populat Hlth, London, England.
    Whincup, Peter
    St Georges Univ London, Populat Hlth Res Inst, London, England.
    Ben-Shlomo, Yoav
    Univ Bristol, Populat Hlth Sci, Bristol, Avon, England.
    McLachlan, Stela
    Univ Edinburgh, Usher Inst, Ctr Populat Hlth Sci, Edinburgh, Midlothian, Scotland.
    Price, Jackie F.
    Univ Edinburgh, Usher Inst, Ctr Populat Hlth Sci, Edinburgh, Midlothian, Scotland.
    Kivimaki, Mika
    UCL, UCL Inst Epidemiol & Hlth Care, Dept Epidemiol & Publ Hlth, London, England.
    Welch, Catherine
    UCL, UCL Inst Epidemiol & Hlth Care, Dept Epidemiol & Publ Hlth, London, England.
    Sanchez-Galvez, Adelaida
    UCL, UCL Inst Epidemiol & Hlth Care, Dept Epidemiol & Publ Hlth, London, England.
    Marques-Vidal, Pedro
    Lausanne Univ Hosp, Dept Med, Internal Med, Lausanne, Switzerland.
    Nicolaides, Andrew
    Imperial Coll, Dept Vasc Surg, London, England;Univ Nicosia, Nicosia Med Sch, Dept Surg, Nicosia, Cyprus.
    Panayiotou, Andrie G.
    Cyprus Univ Technol, Cyprus Int Inst Environm & Publ Hlth, Limassol, Cyprus.
    Onland-Moret, N. Charlotte
    Univ Utrecht, Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, Utrecht, Netherlands.
    van der Schouw, Yvonne T.
    Univ Utrecht, Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, Utrecht, Netherlands.
    Matullo, Giuseppe
    IIGM, Turin, Italy;Univ Turin, Dept Med Sci, Turin, Italy.
    Fiorito, Giovanni
    IIGM, Turin, Italy;Univ Turin, Dept Med Sci, Turin, Italy.
    Guarrera, Simonetta
    IIGM, Turin, Italy;Univ Turin, Dept Med Sci, Turin, Italy.
    Sacerdote, Carlotta
    Citta Salute & Sci Univ Hosp, Unit Canc Epidemiol, Turin, Italy;Ctr Canc Prevent CPO, Turin, Italy.
    Wareham, Nicholas J.
    Univ Cambridge, Addenbrookes Hosp, Sch Clin Med, MRC Epidemiol Unit,Inst Metab Sci, Cambridge Biomed Campus, Cambridge, England.
    Langenberg, Claudia
    Univ Cambridge, Addenbrookes Hosp, Sch Clin Med, MRC Epidemiol Unit,Inst Metab Sci, Cambridge Biomed Campus, Cambridge, England.
    Scott, Robert A.
    Univ Cambridge, Addenbrookes Hosp, Sch Clin Med, MRC Epidemiol Unit,Inst Metab Sci, Cambridge Biomed Campus, Cambridge, England.
    Luan, Jian'an
    Univ Cambridge, Addenbrookes Hosp, Sch Clin Med, MRC Epidemiol Unit,Inst Metab Sci, Cambridge Biomed Campus, Cambridge, England.
    Bobak, Martin
    UCL, UCL Inst Epidemiol & Hlth Care, Dept Epidemiol & Publ Hlth, London, England.
    Malyutina, Sofia
    Novosibirsk State Med Univ, Novosibirsk, Russia;Russian Acad Med Sci, Siberian Branch, Inst Internal & Prevent Med, Novosibirsk, Russia.
    Pajak, Andrzej
    Jagiellonian Univ, Coll Med, Fac Hlth Sci, Dept Epidemiol & Populat Studies, Krakow, Poland.
    Kubinova, Ruzena
    Natl Inst Publ Hlth, Prague, Czech Republic.
    Tamosiunas, Abdonas
    Lithuanian Univ Hlth Sci, Kaunas, Lithuania.
    Pikhart, Hynek
    UCL, UCL Inst Epidemiol & Hlth Care, Dept Epidemiol & Publ Hlth, London, England.
    Grarup, Niels
    Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Copenhagen, Denmark.
    Pedersen, Oluf
    Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Copenhagen, Denmark.
    Hansen, Torben
    Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Copenhagen, Denmark.
    Linneberg, Allan
    Univ Copenhagen, Fac Hlth & Med Sci, Dept Clin Med, Copenhagen, Denmark;Bispebjerg & Frederiksberg Hosp, Ctr Clin Res & Prevent, Copenhagen, Capital Region, Denmark.
    Jess, Tine
    Bispebjerg & Frederiksberg Hosp, Ctr Clin Res & Prevent, Copenhagen, Capital Region, Denmark.
    Cooper, Jackie
    UCL, Dept Med, Ctr Cardiovasc Genet, London, England.
    Humphries, Steve E.
    UCL, Dept Med, Ctr Cardiovasc Genet, London, England.
    Brilliant, Murray
    Marshfield Clin Res Inst, Ctr Human Genet, Marshfield, WI USA.
    Kitchner, Terrie
    Marshfield Clin Res Inst, Ctr Human Genet, Marshfield, WI USA.
    Hakonarson, Hakon
    Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA.
    Carrell, David S.
    Kaiser Permanente Washington Hlth Res Inst, Seattle, WA USA.
    McCarty, Catherine A.
    Univ Minnesota, Minneapolis, MN USA.
    Lester, Kirchner H.
    Geisinger, Danville, PA USA.
    Larson, Eric B.
    Kaiser Permanente Washington Hlth Res Inst, Seattle, WA USA.
    Crosslin, David R.
    Univ Washington Seattle, Dept Biomed Informat & Med Educ, Seattle, WA USA.
    de Andrade, Mariza
    Mayo Clin, Rochester, MN USA.
    Roden, Dan M.
    Vanderbilt Univ, Sch Med, Dept Med, Dept Pharmacol,Dept Biomed Informat, Nashville, TN 37212 USA.
    Denny, Joshua C.
    Vanderbilt Univ, 221 Kirkland Hall, Nashville, TN 37235 USA.
    Carty, Cara
    WHI, Seattle, WA USA.
    Hancock, Stephen
    Univ Newcastle, Newcastle, NSW, Australia.
    Attia, John
    Univ Newcastle, Newcastle, NSW, Australia;Hunter Med Res Inst, Publ Hlth Program, Newcastle, NSW, Australia.
    Holliday, Elizabeth
    Univ Newcastle, Newcastle, NSW, Australia;Hunter Med Res Inst, Publ Hlth Program, Newcastle, NSW, Australia.
    Scott, Rodney
    Univ Newcastle, Newcastle, NSW, Australia.
    Schofield, Peter
    Hunter New England Local Hlth Dist, Newcastle, NSW, Australia.
    O'Donnell, Martin
    Populat Hlth Res Inst, Hamilton, ON, Canada.
    Yusuf, Salim
    Populat Hlth Res Inst, Hamilton, ON, Canada.
    Chong, Michael
    Populat Hlth Res Inst, Hamilton, ON, Canada.
    Pare, Guillaume
    Populat Hlth Res Inst, Hamilton, ON, Canada.
    van der Harst, Pim
    Netherlands Heart Inst, Durrer Ctr Cardiovasc Res, Utrecht, Netherlands;Acad Med Ctr Amsterdam, Dept Clin Epidemiol Biostat & Bioinformat, Amsterdam, Netherlands;Univ Groningen, Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands;Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, Groningen, Netherlands.
    Said, M. Abdullah
    Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, Groningen, Netherlands.
    Eppinga, Ruben N.
    Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, Groningen, Netherlands.
    Verweij, Niek
    Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, Groningen, Netherlands.
    Snieder, Harold
    Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, Groningen, Netherlands.
    Christen, Tim
    Leiden Univ, Med Ctr, Dept Clin Epidemiol, Leiden, Netherlands.
    Mook-Kanamori, D. O.
    Leiden Univ, Med Ctr, Dept Clin Epidemiol, Leiden, Netherlands.
    Gustafsson, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Lind, Lars
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Stanford Univ, Dept Med, Sch Med, Div Cardiovasc Med, Stanford, CA 94305 USA;.
    Ingelsson, Erik
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Stanford Univ, Dept Med, Sch Med, Div Cardiovasc Med, Stanford, CA 94305 USA.
    Pazoki, Raha
    Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands;Imperial Coll London, Dept Epidemiol & Biostat, London, England.
    Franco, Oscar
    Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands.
    Hofman, Albert
    Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands.
    Uitterlinden, Andre
    Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands.
    Dehghan, Abbas
    Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands.
    Teumer, Alexander
    Univ Med Greifswald, Inst Community Med, Greifswald, Germany;DZHK German Ctr Cardiovasc Res, Partner Site Greifswald, Greifswald, Germany.
    Baumeister, Sebastian
    Univ Med Greifswald, Inst Community Med, Greifswald, Germany;Ludwig Maximilians Univ Munchen, Chair Epidemiol, UNIKA T Augsburg, Augsburg, Germany.
    Doerr, Marcus
    DZHK German Ctr Cardiovasc Res, Partner Site Greifswald, Greifswald, Germany;Univ Med Greifswald, Dept Internal Med B, Greifswald, Germany.
    Lerch, Markus M.
    Univ Med Greifswald, Dept Internal Med A, Greifswald, Germany.
    Voelker, Uwe
    DZHK German Ctr Cardiovasc Res, Partner Site Greifswald, Greifswald, Germany;Univ Med Greifswald, Interfac Inst Genet & Funct Genom, Greifswald, Germany.
    Voelzke, Henry
    Univ Med Greifswald, Inst Community Med, Greifswald, Germany;DZHK German Ctr Cardiovasc Res, Partner Site Greifswald, Greifswald, Germany.
    Ward, Joey
    Univ Glasgow, Inst Hlth & Wellbeing, Glasgow G12 8RZ, Lanark, Scotland.
    Pell, Jill P.
    Univ Glasgow, Inst Hlth & Wellbeing, Glasgow G12 8RZ, Lanark, Scotland.
    Meade, Tom
    London Sch Hyg & Trop Med, Dept Noncommunicable Dis Epidemiol, London, England.
    Christophersen, Ingrid E.
    Vestre Viken Hosp Trust, Baerum Hosp, Dept Med Res, Gjettum, Norway.
    Maitland-van der Zee, Anke H.
    Univ Utrecht, Fac Sci, Utrecht Inst Pharmaceut Sci, Div Pharmacoepidemiol & Clin Pharmacol, Utrecht, Netherlands;Univ Amsterdam, Acad Med Ctr, Dept Resp Med, Amsterdam, Netherlands.
    Baranova, Ekaterina V.
    Univ Glasgow, Robertson Ctr Biostat, Glasgow, Lanark, Scotland.
    Young, Robin
    Univ Glasgow, Robertson Ctr Biostat, Glasgow, Lanark, Scotland.
    Ford, Ian
    Univ Glasgow, Robertson Ctr Biostat, Glasgow, Lanark, Scotland.
    Campbell, Archie
    Univ Edinburgh, Inst Genet & Mol Med, Edinburgh, Midlothian, Scotland.
    Padmanabhan, Sandosh
    Univ Glasgow, Inst Cardiovasc & Med Sci, Glasgow G12 8TA, Lanark, Scotland.
    Bots, Michiel L.
    Cyprus Univ Technol, Cyprus Int Inst Environm & Publ Hlth, Limassol, Cyprus.
    Grobbee, Diederick E.
    Cyprus Univ Technol, Cyprus Int Inst Environm & Publ Hlth, Limassol, Cyprus.
    Froguel, Philippe
    Univ Lille, Inst Pasteur Lille, CNRS, UMR 8199,EGID, F-59000 Lille, France;Imperial Coll London, Dept Genom Common Dis, London W12 0NN, England.
    Thuillier, Dorothee
    Univ Lille, Inst Pasteur Lille, CNRS, UMR 8199,EGID, F-59000 Lille, France.
    Roussel, Ronan
    INSERM, Ctr Rech Cordeliers, U1138, Paris, France;Univ Paris Diderot, Sorbonne Paris Cite, UFR Med, Paris, France;Hop Bicha, AP HP, Dept Diabetol Endocrinol & Nutr, Paris, France.
    Bonnefond, Amelie
    Univ Lille, Inst Pasteur Lille, CNRS, UMR 8199,EGID, F-59000 Lille, France.
    Cariou, Bertrand
    Univ Nantes, CHU Nantes, CNRS, Inst Thorax,INSERM, Nantes, France.
    Smart, Melissa
    Univ Essex, Inst Social & Econ Res, Colchester, Essex, England.
    Bao, Yanchun
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.
    Kumari, Meena
    Boston Univ, Sch Med, Boston, MA 02118 USA.
    Mahajan, Anubha
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.
    Hopewell, Jemma C.
    Univ Oxford, Nuffield Dept Populat Hlth, Clin Trial Serv Unit, Richard Doll Bldg,Old Rd Campus,Roosevelt Dr, Oxford OX3 7LF, England;Univ Oxford, Nuffield Dept Populat Hlth, Epidemiol Studies Unit CTSU, Richard Doll Bldg,Old Rd Campus,Roosevelt Dr, Oxford OX3 7LF, England.
    Seshadri, Sudha
    Boston Univ, Sch Med, Boston, MA 02118 USA.
    Dale, Caroline
    UCL, Farr Inst Hlth Informat, London, England.
    Costa, Rui Providencia E.
    UCL, Farr Inst Hlth Informat, London, England.
    Ridker, Paul M.
    Harvard Med Sch, Ctr Cardiovasc Dis Prevent, Brigham & Womens Hosp, Boston, MA 02115 USA.
    Chasman, Daniel I.
    Harvard Med Sch, Ctr Cardiovasc Dis Prevent, Brigham & Womens Hosp, Boston, MA 02115 USA.
    Reiner, Alex P.
    UWash, Seattle, WA USA.
    Ritchie, Marylyn D.
    Penn State, State Coll, PA USA.
    Lange, Leslie A.
    Univ Colorado Denver, Denver, CO USA.
    Cornish, Alex J.
    Inst Canc Res, Div Genet & Epidemiol, London, England.
    Dobbins, Sara E.
    Inst Canc Res, Div Genet & Epidemiol, London, England.
    Hemminki, Kari
    German Canc Res Ctr, Div Mol Genet Epidemiol, Neuenheimer Feld 580, D-69120 Heidelberg, Germany;Deutsch Krebsforschungszentrum, Heidelberg, Germany.
    Kinnersley, Ben
    Inst Canc Res, Div Genet & Epidemiol, London, England.
    Sanson, Marc
    Inst Cerveau Moelle Epiniere ICM, Paris, France;UPMC Univ Paris 06, Sorbonne Univ, UMR S 1127, F-75013 Paris, France.
    Labreche, Karim
    Inst Cerveau Moelle Epiniere ICM, Paris, France;UPMC Univ Paris 06, Sorbonne Univ, UMR S 1127, F-75013 Paris, France.
    Simon, Matthias
    Bethel Clin, Dept Neurosurg, Kantensiek 11, D-33617 Bielefeld, Germany.
    Bondy, Melissa
    Baylor Coll Med, Dan L Duncan Canc Ctr, Dept Pediat, Div Hematol Oncol, Houston, TX 77030 USA.
    Law, Philip
    Inst Canc Res, Div Genet & Epidemiol, London, England.
    Speedy, Helen
    Inst Canc Res, Div Genet & Epidemiol, London, England.
    Allan, James
    Newcastle Univ, Northern Inst Canc Res, Newcastle Upon Tyne, Tyne & Wear, England.
    Li, Ni
    Inst Canc Res, Div Genet & Epidemiol, London, England.
    Went, Molly
    Inst Canc Res, Div Genet & Epidemiol, London, England.
    Weinhold, Niels
    Univ Arkansas Med Sci, Myeloma Inst Res & Therapy, Little Rock, AR 72205 USA.
    Morgan, Gareth
    Univ Arkansas Med Sci, Myeloma Inst Res & Therapy, Little Rock, AR 72205 USA.
    Sonneveld, Pieter
    Erasmus MC Canc Inst, Dept Hematol, NL-3075 EA Rotterdam, Netherlands.
    Nilsson, Bjorn
    Dept Lab Med, Hematol & Transfus Med, BMC B13, SE-22184 Lund, Sweden.
    Goldschmidt, Hartmut
    Univ Clin Heidelberg, Internal Med 5, Heidelberg, Germany;Natl Ctr Tumor Dis NCT, Heidelberg, Germany.
    Sud, Amit
    Inst Canc Res, Div Genet & Epidemiol, London, England.
    Engert, Andreas
    Univ Hosp Cologne, Dept Internal Med, Cologne, Germany.
    Hansson, Markus
    Skane Univ Hosp, Hematol Clin, Skane, Sweden;Lund Univ, Wallenberg Ctr Mol Med, Lund, Sweden.
    Hemingway, Harry
    UCLs BHF Res Accelerator Ctr, London, England;UCL, Hlth Data Res UK, 222 Euston Rd, London NW1 2DA, England;UCL, Inst Hlth Informat, 222 Euston Rd, London NW1 2DA, England;UCL, Univ Coll London Hosp, Biomed Res Ctr, Natl Inst Hlth Res, 222 Euston Rd, London NW1 2DA, England.
    Asselbergs, Folkert W.
    UCL, Inst Cardiovasc Sci, 222 Euston Rd, London NW1 2DA, England;Univ Utrecht, Univ Med Ctr Utrecht, Div Heart & Lungs, Dept Cardiol, Utrecht, Netherlands;UCLs BHF Res Accelerator Ctr, London, England;UCL, Hlth Data Res UK, London, England;UCL, Inst Hlth Informat, London, England.
    Patel, Riyaz S.
    UCL, Inst Cardiovasc Sci, 222 Euston Rd, London NW1 2DA, England;UCLs BHF Res Accelerator Ctr, London, England;St Bartholomews Hosp, Barts Heart Ctr, London, England.
    Keating, Brendan J.
    Univ Penn, Philadelphia, PA 19104 USA.
    Sattar, Naveed
    Univ Glasgow, Inst Cardiovasc & Med Sci, Glasgow G12 8TA, Lanark, Scotland.
    Houlston, Richard
    Inst Canc Res, Div Genet & Epidemiol, London, England.
    Casas, Juan P.
    Vet Affairs Boston Healthcare Syst, Massachusetts Vet Epidemiol & Res Informat Ctr MA, Boston, MA USA.
    Hingorani, Aroon D.
    UCL, Inst Cardiovasc Sci, 222 Euston Rd, London NW1 2DA, England;UCLs BHF Res Accelerator Ctr, London, England.
    Phenome-wide association analysis of LDL-cholesterol lowering genetic variants in PCSK92019In: BMC Cardiovascular Disorders, ISSN 1471-2261, E-ISSN 1471-2261, Vol. 19, no 1, article id 240Article in journal (Refereed)
    Abstract [en]

    Background: We characterised the phenotypic consequence of genetic variation at the PCSK9 locus and compared findings with recent trials of pharmacological inhibitors of PCSK9. Methods: Published and individual participant level data (300,000+ participants) were combined to construct a weighted PCSK9 gene-centric score (GS). Seventeen randomized placebo controlled PCSK9 inhibitor trials were included, providing data on 79,578 participants. Results were scaled to a one mmol/L lower LDL-C concentration. Results: The PCSK9 GS (comprising 4 SNPs) associations with plasma lipid and apolipoprotein levels were consistent in direction with treatment effects. The GS odds ratio (OR) for myocardial infarction (MI) was 0.53 (95% CI 0.42; 0.68), compared to a PCSK9 inhibitor effect of 0.90 (95% CI 0.86; 0.93). For ischemic stroke ORs were 0.84 (95% CI 0.57; 1.22) for the GS, compared to 0.85 (95% CI 0.78; 0.93) in the drug trials. ORs with type 2 diabetes mellitus (T2DM) were 1.29 (95% CI 1.11; 1.50) for the GS, as compared to 1.00 (95% CI 0.96; 1.04) for incident T2DM in PCSK9 inhibitor trials. No genetic associations were observed for cancer, heart failure, atrial fibrillation, chronic obstructive pulmonary disease, or Alzheimer's disease - outcomes for which large-scale trial data were unavailable. Conclusions: Genetic variation at the PCSK9 locus recapitulates the effects of therapeutic inhibition of PCSK9 on major blood lipid fractions and MI. While indicating an increased risk of T2DM, no other possible safety concerns were shown; although precision was moderate.

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