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  • 251.
    Roos, Vendela
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Elmstahl, Solve
    Lund Univ, Malmo Univ Hosp, Dept Hlth Sci, Div Geriatr Med, Malmo, Sweden..
    Ingelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Stanford Univ, Sch Med, Dept Med, Div Cardiovasc Med, Stanford, CA 94305 USA.;.
    Sundström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Ärnlöv, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Dalarna Univ, Sch Hlth & Social Studies, Falun, Sweden..
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Alterations in Multiple Lifestyle Factors in Subjects with the Metabolic Syndrome Independently of Obesity2017In: Metabolic Syndrome and Related Disorders, ISSN 1540-4196, E-ISSN 1557-8518, Vol. 15, no 3, p. 118-123Article in journal (Refereed)
    Abstract [en]

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

  • 252.
    Roos, Vendela
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Elmstahl, Solve
    Lund Univ, Malmo Univ Hosp, Div Geriatr Med, Dept Hlth Sci, Malmo, Sweden..
    Ingelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Stanford Univ, Sch Med, Dept Med, Div Cardiovasc Med, Stanford, CA 94305 USA..
    Sundström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Ärnlöv, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Dalarna Univ, Sch Hlth & Social Studies, Falun, Sweden..
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Metabolic Syndrome Development During Aging with Special Reference to Obesity Without the Metabolic Syndrome2017In: Metabolic Syndrome and Related Disorders, ISSN 1540-4196, E-ISSN 1557-8518, Vol. 15, no 1, p. 36-43Article in journal (Refereed)
    Abstract [en]

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

  • 253.
    Roselli, Carolina
    et al.
    Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA USA.
    Chaffin, Mark D.
    Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA USA.
    Weng, Lu-Chen
    Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA USA;Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA.
    Aeschbacher, Stefanie
    Univ Hosp Basel, Basel, Switzerland;Cardiovasc Res Inst Basel, Basel, Switzerland.
    Ahlberg, Gustav
    Copenhagen Univ Hosp, Dept Cardiol, Heart Ctr, Lab Mol Cardiol,Rigshosp, Copenhagen, Denmark;Univ Copenhagen, Dept Biomed Sci, Danish Natl Res Fdn Ctr Cardiac Arrhythmia, Copenhagen, Denmark;Univ Copenhagen, Fac Hlth & Med Sci, Dept Clin Med, Copenhagen, Denmark.
    Albert, Christine M.
    Brigham & Womens Hosp, Div Prevent & Cardiovasc Med, 75 Francis St, Boston, MA 02115 USA;Harvard Med Sch, Boston, MA USA.
    Almgren, Peter
    Lund Univ, Dept Clin Sci, Malmo, Sweden.
    Alonso, Alvaro
    Emory Univ, Rollins Sch Publ Hlth, Dept Epidemiol, Atlanta, GA 30322 USA.
    Anderson, Christopher D.
    Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA USA;Massachusetts Gen Hosp, Ctr Genom Med, Boston, MA 02114 USA.
    Aragam, Krishna G.
    Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA USA;Massachusetts Gen Hosp, Ctr Genom Med, Boston, MA 02114 USA.
    Arking, Dan E.
    Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD USA.
    Barnard, John
    Cleveland Clin, Dept Cardiovasc Med, Cleveland, OH USA;Cleveland Clin, Dept Cellular & Mol Med, Cleveland, OH USA;Cleveland Clin, Dept Mol Cardiol, Cleveland, OH USA;Cleveland Clin, Dept Quantitat Hlth Sci, Cleveland, OH USA.
    Bartz, Traci M.
    Univ Washington, Dept Med, Cardiovasc Hlth Res Unit Dept, Seattle, WA 98195 USA;Univ Washington, Dept Biostat, Seattle, WA 98195 USA.
    Benjamin, Emelia J.
    NHLBI, Framingham, MA USA;Boston Univ, Framingham Heart Study, Framingham, MA USA;Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA;Boston Univ, Dept Epidemiol, Sch Publ Hlth, Boston, MA USA.
    Bihlmeyer, Nathan A.
    Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Predoctoral Training Program Human Genet, Baltimore, MD USA.
    Bis, Joshua C.
    Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA.
    Bloom, Heather L.
    Emory Univ, Div Cardiol, Atlanta, GA 30322 USA;Atlanta VA Med Ctr, Atlanta, GA USA.
    Boerwinkle, Eric
    Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA.
    Bottinger, Erwin B.
    Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA;Icahn Sch Med Mt Sinai, Dept Pharmacol & Syst Therapeut, New York, NY 10029 USA.
    Brody, Jennifer A.
    Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA.
    Calkins, Hugh
    Johns Hopkins Univ, Baltimore, MD USA.
    Campbell, Archie
    Univ Edinburgh, Inst Genet & Mol Med, Ctr Genom & Expt Med, Generat Scotland, Edinburgh, Midlothian, Scotland.
    Cappola, Thomas P.
    Univ Penn, Penn Cardiovasc Inst, Philadelphia, PA 19104 USA;Univ Penn, Dept Med, Perelman Sch Med, Philadelphia, PA 19104 USA.
    Carlquist, John
    Intermt Med Ctr, Intermt Heart Inst, Murray, UT USA;Univ Utah, Div Cardiovasc Med, Salt Lake City, UT USA.
    Chasman, Daniel I.
    Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA USA;Harvard Med Sch, Boston, MA USA;Harvard Med Sch, Boston, MA USA;Brigham & Womens Hosp, Div Prevent Med, 75 Francis St, Boston, MA 02115 USA;Brigham & Womens Hosp, Div Genet, 75 Francis St, Boston, MA 02115 USA.
    Chen, Lin Y.
    Univ Minnesota, Sch Med, Dept Med, Div Cardiovasc, Minneapolis, MN 55455 USA.
    Chen, Yii-Der Ida
    Harbor UCLA Med Ctr, Dept Pediat, LABioMed, Inst Translat Genom & Populat Sci, Torrance, CA 90509 USA.
    Choi, Eue-Keun
    Seoul Natl Univ Hosp, Seoul, South Korea.
    Choi, Seung Hoan
    Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA USA.
    Christophersen, Ingrid E.
    Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA USA;Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA;Vestre Viken Hosp Trust, Baerum Hosp, Dept Med Res, Drammen, Norway.
    Chung, Mina K.
    Cleveland Clin, Dept Cardiovasc Med, Cleveland, OH USA;Cleveland Clin, Dept Cellular & Mol Med, Cleveland, OH USA;Cleveland Clin, Dept Mol Cardiol, Cleveland, OH USA;Cleveland Clin, Dept Quantitat Hlth Sci, Cleveland, OH USA.
    Cole, John W.
    Baltimore Vet Affairs Med Ctr, Dept Neurol, Baltimore, MD USA;Univ Maryland, Sch Med, Dept Neurol, Baltimore, MD 21201 USA.
    Conen, David
    Univ Hosp Basel, Basel, Switzerland;Cardiovasc Res Inst Basel, Basel, Switzerland;McMaster Univ, Populat Hlth Res Inst, Hamilton, ON, Canada.
    Cook, James
    Univ Liverpool, Dept Biostat, Liverpool, Merseyside, England.
    Crijns, Harry J.
    Maastricht Univ, Med Ctr, Maastricht, Netherlands;Maastricht Univ, Cardiovasc Res Inst Maastricht, Dept Cardiol, Maastricht, Netherlands.
    Cutler, Michael J.
    Intermt Med Ctr, Intermt Heart Inst, Murray, UT USA.
    Damrauer, Scott M.
    Univ Penn, Dept Surg, Perelman Sch Med, Philadelphia, PA 19104 USA;Corporal Michael Crescenz VA Med Ctr, Dept Surg, Philadelphia, PA USA.
    Daniels, Brian R.
    Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA USA.
    Darbar, Dawood
    Univ Illinois, Chicago, IL USA.
    Delgado, Graciela
    Heidelberg Univ, Med Fac Mannheim, Dept Med 5, Heidelberg, Germany.
    Denny, Joshua C.
    Vanderbilt Univ, Med Ctr, Dept Med, Nashville, TN USA.
    Dichgans, Martin
    Univ Hosp, LMU Munich, Inst Stroke & Dementia Res ISD, Munich, Germany;Munich Cluster Syst Neurol SyNergy, Munich, Germany;German Ctr Neurodegenerat Dis DZNE, Munich, Germany.
    Doerr, Marcus
    Univ Med Greifswald, Dept Internal Med B, Greifswald, Germany;Partner Site Greifswald, DZHK German Ctr Cardiovasc Res, Greifswald, Germany.
    Dudink, Elton A.
    Maastricht Univ, Med Ctr, Maastricht, Netherlands;Maastricht Univ, Cardiovasc Res Inst Maastricht, Dept Cardiol, Maastricht, Netherlands.
    Dudley, Samuel C.
    Univ Minnesota, Div Cardiovasc, Minneapolis, MN 55455 USA;Univ Minnesota, Lillehei Heart Inst, Minneapolis, MN USA.
    Esa, Nada
    Univ Massachusetts, Med Sch Worcester, Worcester, MA 01605 USA.
    Esko, Tonu
    Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA USA;Univ Tartu, Estonian Genome Ctr, Tartu, Estonia.
    Eskola, Markku
    Tampere Univ Hosp, Dept Cardiol, Heart Ctr, Tampere, Finland;Univ Tampere, Fac Med & Life Sci, Tampere, Finland.
    Fatkin, Diane
    Victor Chang Cardiac Res Inst, Darlinghurst, NSW, Australia;St Vincent Hosp, Darlinghurst, NSW, Australia;Univ New South Wales, Fac Med, Kensington, NSW, Australia.
    Felix, Stephan B.
    Univ Med Greifswald, Dept Internal Med B, Greifswald, Germany;Partner Site Greifswald, DZHK German Ctr Cardiovasc Res, Greifswald, Germany.
    Ford, Ian
    Univ Glasgow, Robertson Ctr Biostat, Glasgow, Lanark, Scotland.
    Franco, Oscar H.
    Erasmus Univ, Med Ctr Rotterdam, Dept Epidemiol, Rotterdam, Netherlands.
    Geelhoed, Bastiaan
    Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, Groningen, Netherlands.
    Grewal, Raji P.
    St Francis Med Ctr, Dept Neurosci, Trenton, NJ USA;Seton Hall Univ, Sch Hlth & Med Sci, S Orange, NJ USA.
    Gudnason, Vilmundur
    Icelandic Heart Assoc, Kopavogur, Iceland;Univ Iceland, Fac Med, Reykavik, Iceland.
    Guo, Xiuqing
    Harbor UCLA Med Ctr, Dept Pediat, LABioMed, Inst Translat Genom & Populat Sci, Torrance, CA 90509 USA.
    Gupta, Namrata
    Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA USA.
    Gustafsson, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Gutmann, Rebecca
    Univ Iowa, Div Cardiovasc Med, Abboud Cardiovasc Res Ctr, Iowa City, IA USA.
    Hamsten, Anders
    Karolinska Inst, Dept Med Solna, Atherosclerosis Res Unit, Cardiovasc Genet & Genom Grp, Stockholm, Sweden.
    Harris, Tamara B.
    NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA.
    Hayward, Caroline
    Univ Edinburgh, Inst Genet & Mol Med, MRC Human Genet Unit, Edinburgh, Midlothian, Scotland.
    Heckbert, Susan R.
    Univ Washington, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA;Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA;Kaiser Permanente, Washington Hlth Res Inst, Seattle, WA USA.
    Hernesniemi, Jussi
    Tampere Univ Hosp, Dept Cardiol, Heart Ctr, Tampere, Finland;Univ Tampere, Fac Med & Life Sci, Tampere, Finland;Univ Tampere, Fac Med & Life Sci, Dept Clin Chem, Fimlab Labs, Tampere, Finland;Univ Tampere, Fac Med & Life Sci, Finnish Cardiovasc Res Ctr Tampere, Tampere, Finland.
    Hocking, Lynne J.
    Univ Aberdeen, Inst Med Sci, Aberdeen, Scotland.
    Hofman, Albert
    Erasmus Univ, Med Ctr Rotterdam, Dept Epidemiol, Rotterdam, Netherlands.
    Horimoto, Andrea R. V. R.
    Univ Sao Paulo, Heart Inst, Lab Genet & Mol Cardiol, Sao Paulo, Brazil.
    Huang, Jie
    Boston VA Res Inst Inc, Boston, MA USA.
    Huang, Paul L.
    Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA.
    Huffman, Jennifer
    Univ Edinburgh, Inst Genet & Mol Med, MRC Human Genet Unit, Edinburgh, Midlothian, Scotland.
    Ingelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab. UStanford Univ, Dept Med, Sch Med, Div Cardiovasc Med, Stanford, CA 94305 USA.
    Ipek, Esra Gucuk
    Johns Hopkins Univ, Baltimore, MD USA.
    Ito, Kaoru
    RIKEN, Ctr Integrat Med Sci, Lab Cardiovasc Dis, Yokohama, Kanagawa, Japan.
    Jimenez-Conde, Jordi
    Inst Hosp Mar Invest Med, Hosp Mar, Dept Neurol, Neurovasc Res Grp IMIM, Barcelona, Spain;Univ Autonoma Barcelona, Med Dept, Barcelona, Spain.
    Johnson, Renee
    Victor Chang Cardiac Res Inst, Darlinghurst, NSW, Australia.
    Jukema, J. Wouter
    Leiden Univ, Med Ctr, Dept Cardiol, Leiden, Netherlands;Durrer Ctr Cardiogenet Res, Amsterdam, Netherlands;Interuniv Cardiol Inst Netherlands, Utrecht, Netherlands.
    Kaeaeb, Stefan
    Ludwig Maximilians Univ Munchen, Univ Hosp Munich, Dept Med 1, Munich, Germany;DZHK German Ctr Cardiovasc Res, Partner Site Munich Heart Alliance, Munich, Germany.
    Kahonen, Mika
    Univ Tampere, Fac Med & Life Sci, Tampere Univ Hosp, Dept Clin Physiol, Tampere, Finland;Univ Tampere, Fac Med & Life Sci, Finnish Cardiovasc Res Center Tampere, Tampere, Finland.
    Kamatani, Yoichiro
    RIKEN, Ctr Integrat Med Sci, Lab Stat Anal, Yokohama, Kanagawa, Japan.
    Kane, John P.
    Univ Calif San Francisco, Cardiovasc Res Inst, San Francisco, CA 94143 USA.
    Kastrati, Adnan
    DZHK German Ctr Cardiovasc Res, Partner Site Munich Heart Alliance, Munich, Germany;Tech Univ Munich, Klin Herz & Kreislauferkrankungen, Deutsch Herzzentrum Munchen, Munich, Germany.
    Kathiresan, Sekar
    Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA USA;Massachusetts Gen Hosp, Ctr Genom Med, Boston, MA 02114 USA.
    Katschnig-Winter, Petra
    Med Univ Graz, Dept Neurol, Graz, Austria.
    Kavousi, Maryam
    Erasmus Univ, Med Ctr Rotterdam, Dept Epidemiol, Rotterdam, Netherlands.
    Kessler, Thorsten
    Tech Univ Munich, Klin Herz & Kreislauferkrankungen, Deutsch Herzzentrum Munchen, Munich, Germany.
    Kietselaer, Bas L.
    Maastricht Univ, Med Ctr, Maastricht, Netherlands;Maastricht Univ, Cardiovasc Res Inst Maastricht, Dept Cardiol, Maastricht, Netherlands.
    Kirchhof, Paulus
    Univ Birmingham, Inst Cardiovasc Sci, Birmingham, W Midlands, England;Sandwell & West Birmingham Hosp NHS Trust, Birmingham, W Midlands, England;Univ Hosp Birmingham NHS Fdn Trust, Birmingham, W Midlands, England;AFNET, Munster, Germany.
    Kleber, Marcus E.
    Heidelberg Univ, Med Fac Mannheim, Dept Med 5, Heidelberg, Germany.
    Knight, Stacey
    Intermt Med Ctr, Intermt Heart Inst, Murray, UT USA;Univ Utah, Dept Med, Salt Lake City, UT 84112 USA.
    Krieger, Jose E.
    Univ Sao Paulo, Heart Inst, Lab Genet & Mol Cardiol, Sao Paulo, Brazil.
    Kubo, Michiaki
    RIKEN, Ctr Integrat Med Sci, Yokohama, Kanagawa, Japan.
    Launer, Lenore J.
    NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA.
    Laurikka, Jari
    Univ Tampere, Fac Med & Life Sci, Finnish Cardiovasc Res Center Tampere, Tampere, Finland;Univ Tampere, Fac Med & Life Sci, Tampere Univ Hosp, Heart Ctr,Dept Cardiothoracic Surg, Tampere, Finland.
    Lehtimaki, Terho
    Univ Tampere, Fac Med & Life Sci, Dept Clin Chem, Fimlab Labs, Tampere, Finland;Univ Tampere, Fac Med & Life Sci, Finnish Cardiovasc Res Ctr Tampere, Tampere, Finland.
    Leineweber, Kirsten
    Bayer, Dept Dis Genom, Wuppertal, Germany.
    Lemaitre, Rozenn N.
    Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA.
    Li, Man
    Johns Hopkins Univ, Dept Epidemiol, Baltimore, MD USA;Univ Utah, Sch Med, Div Nephrol & Hypertens Internal Med, Salt Lake City, UT USA.
    Lim, Hong Euy
    Korea Univ, Guro Hosp, Seoul, South Korea.
    Lin, Henry J.
    Harbor UCLA Med Ctr, Dept Pediat, LABioMed, Inst Translat Genom & Populat Sci, Torrance, CA 90509 USA.
    Lin, Honghuang
    NHLBI, Framingham, MA USA;Boston Univ, Framingham Heart Study, Framingham, MA USA;Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Lindgren, Cecilia M.
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.
    Lokki, Marja-Liisa
    Univ Helsinki, Medicum, Transplantat Lab, Helsinki, Finland.
    London, Barry
    Univ Iowa, Div Cardiovasc Med, Abboud Cardiovasc Res Ctr, Iowa City, IA USA.
    Loos, Ruth J. F.
    Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA;Icahn Sch Med Mt Sinai, Genet Obes & Related Metab Traits Program, New York, NY 10029 USA;Icahn Sch Med Mt Sinai, Mindich Child Hlth & Dev Inst, New York, NY USA.
    Low, Siew-Kee
    RIKEN, Ctr Integrat Med Sci, Lab Stat Anal, Yokohama, Kanagawa, Japan.
    Lu, Yingchang
    Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA;Icahn Sch Med Mt Sinai, Genet Obes & Related Metab Traits Program, New York, NY 10029 USA.
    Lyytikainen, Leo-Pekka
    Univ Tampere, Fac Med & Life Sci, Dept Clin Chem, Fimlab Labs, Tampere, Finland;Univ Tampere, Fac Med & Life Sci, Finnish Cardiovasc Res Ctr Tampere, Tampere, Finland.
    Macfarlane, Peter W.
    Univ Glasgow, Coll Med Vet & Life Sci, Inst Hlth & Wellbeing, Glasgow, Lanark, Scotland.
    Magnusson, Patrik K.
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden.
    Mahajan, Anubha
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.
    Malik, Rainer
    Univ Hosp, LMU Munich, Inst Stroke & Dementia Res ISD, Munich, Germany.
    Mansur, Alfredo J.
    Univ Sao Paulo, Heart Inst, Sao Paulo, Brazil.
    Marcus, Gregory M.
    Univ Calif San Francisco, Div Cardiol, San Francisco, CA 94143 USA.
    Margolin, Lauren
    Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA USA.
    Margulies, Kenneth B.
    Univ Penn, Penn Cardiovasc Inst, Philadelphia, PA 19104 USA;Univ Penn, Dept Med, Perelman Sch Med, Philadelphia, PA 19104 USA.
    Maerz, Winfried
    Med Univ Graz, Clin Inst Med & Chem Lab Diagnost, Graz, Austria;Synlab Serv GmbH, Synlab Acad, Mannheim, Germany.
    McManus, David D.
    Univ Massachusetts, Med Sch Worcester, Worcester, MA 01605 USA.
    Melander, Olle
    Lund Univ, Dept Internal Med Clin Sci, Malmo, Sweden.
    Mohanty, Sanghamitra
    St Davids Med Ctr, Texas Cardiac Arrhythmia Inst, Austin, TX USA;Dell Med Sch, Austin, TX USA.
    Montgomery, Jay A.
    Vanderbilt Univ, Med Ctr, Dept Med, Nashville, TN USA.
    Morley, Michael P.
    Univ Penn, Penn Cardiovasc Inst, Philadelphia, PA 19104 USA;Univ Penn, Dept Med, Perelman Sch Med, Philadelphia, PA 19104 USA.
    Morris, Andrew P.
    Univ Liverpool, Dept Biostat, Liverpool, Merseyside, England.
    Mueller-Nurasyid, Martina
    Ludwig Maximilians Univ Munchen, Univ Hosp Munich, Dept Med 1, Munich, Germany;DZHK German Ctr Cardiovasc Res, Partner Site Munich Heart Alliance, Munich, Germany;Helmholtz Zentrum Munchen German Res Ctr Environm, Inst Genet Epidemiol, Neuherberg, Germany.
    Natale, Andrea
    St Davids Med Ctr, Texas Cardiac Arrhythmia Inst, Austin, TX USA;Dell Med Sch, Austin, TX USA.
    Nazarian, Saman
    Univ Penn, Philadelphia, PA USA.
    Neumann, Benjamin
    Ludwig Maximilians Univ Munchen, Univ Hosp Munich, Dept Med 1, Munich, Germany.
    Newton-Cheh, Christopher
    Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA USA;Massachusetts Gen Hosp, Ctr Genom Med, Boston, MA 02114 USA.
    Niemeijer, Maartje N.
    Erasmus Univ, Med Ctr Rotterdam, Dept Epidemiol, Rotterdam, Netherlands.
    Nikus, Kjell
    Tampere Univ Hosp, Dept Cardiol, Heart Ctr, Tampere, Finland;Univ Tampere, Fac Med & Life Sci, Tampere, Finland.
    Nilsson, Peter
    Lund Univ, Dept Clin Sci, Malmo, Sweden;Skane Univ Hosp, Malmo, Sweden.
    Noordam, Raymond
    Leiden Univ, Med Ctr, Dept Internal Med, Sect Gerontol & Geriatr, Leiden, Netherlands.
    Oellers, Heidi
    Atrial Fibrillat NETwork, Munster, Germany.
    Olesen, Morten S.
    Copenhagen Univ Hosp, Dept Cardiol, Heart Ctr, Lab Mol Cardiol,Rigshosp, Copenhagen, Denmark;Univ Copenhagen, Dept Biomed Sci, Danish Natl Res Fdn Ctr Cardiac Arrhythmia, Copenhagen, Denmark;Univ Copenhagen, Fac Hlth & Med Sci, Dept Clin Med, Copenhagen, Denmark.
    Orho-Melander, Marju
    Lund Univ, Dept Clin Sci, Malmo, Sweden.
    Padmanabhan, Sandosh
    Univ Glasgow, BHF Glasgow Cardiovasc Res Ctr, Inst Cardiovasc & Med Sci, Glasgow, Lanark, Scotland.
    Pak, Hui-Nam
    Yonsei Univ Hlth Syst, Seoul, South Korea.
    Pare, Guillaume
    McMaster Univ, Populat Hlth Res Inst, Hamilton, ON, Canada;McMaster Univ, Dept Pathol & Mol Med, Hamilton, ON, Canada.
    Pedersen, Nancy L.
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden.
    Pera, Joanna
    Jagiellonian Univ, Med Coll, Fac Med, Dept Neurol, Krakow, Poland.
    Pereira, Alexandre
    Univ Sao Paulo, Heart Inst, Lab Genet & Mol Biol, Sao Paulo, Brazil;Harvard Med Sch, Dept Genet, Boston, MA USA.
    Porteous, David
    Univ Edinburgh, Inst Genet & Mol Med, Ctr Genom & Expt Med, Generat Scotland, Edinburgh, Midlothian, Scotland.
    Psaty, Bruce M.
    Kaiser Permanente, Washington Hlth Res Inst, Seattle, WA USA;Univ Washington, Cardiovasc Hlth Res Unit, Dept Med, Seattle, WA 98195 USA;Univ Washington, Dept Epidemiol & Hlth Serv, Seattle, WA 98195 USA.
    Pulit, Sara L.
    Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA USA;Univ Utrecht, Univ Med Ctr Utrecht, Ctr Mol Med, Dept Genet, Utrecht, Netherlands;Univ Oxford, Big Data Inst, Li Ka Shing Ctr Hlth Informat & Discovery, Oxford, England.
    Pullinger, Clive R.
    Univ Calif San Francisco, Cardiovasc Res Inst, San Francisco, CA 94143 USA.
    Rader, Daniel J.
    Univ Penn, Perelman Sch Med, Dept Med, Div Cardiovasc Med, Philadelphia, PA USA.
    Refsgaard, Lena
    Copenhagen Univ Hosp, Dept Cardiol, Heart Ctr, Lab Mol Cardiol,Rigshosp, Copenhagen, Denmark;Univ Copenhagen, Dept Biomed Sci, Danish Natl Res Fdn Ctr Cardiac Arrhythmia, Copenhagen, Denmark;Univ Copenhagen, Fac Hlth & Med Sci, Dept Clin Med, Copenhagen, Denmark.
    Ribases, Marta
    Univ Autonoma Barcelona, Vall dHebron Res Inst VHIR, Grp Psychiat Mental Hlth & Addict, Psychiatr Genet Unit, Barcelona, Spain;Hosp Univ Vall dHebron, Dept Psychiat, Barcelona, Spain;Inst Salud Carlos III, Biomed Network Res Ctr Mental Hlth CIBERSAM, Madrid, Spain.
    Ridker, Paul M.
    Brigham & Womens Hosp, Div Prevent & Cardiovasc Med, 75 Francis St, Boston, MA 02115 USA;Harvard Med Sch, Boston, MA USA.
    Rienstra, Michiel
    Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, Groningen, Netherlands.
    Risch, Lorenz
    Univ Bern, Univ Inst Clin Chem, Bern, Switzerland;Lab Med Zentrum Dr Risch, Schaan, Liechtenstein.
    Roden, Dan M.
    Vanderbilt Univ, Med Ctr, Dept Med, Nashville, TN USA.
    Rosand, Jonathan
    Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA USA;Massachusetts Gen Hosp, Ctr Genom Med, Boston, MA 02114 USA.
    Rosenberg, Michael A.
    Massachusetts Gen Hosp, Ctr Genom Med, Boston, MA 02114 USA;Univ Colorado, Sch Med, Aurora, CO USA.
    Rost, Natalia
    Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA USA;Massachusetts Gen Hosp, J Philip Kistler Stroke Res Ctr, Boston, MA 02114 USA.
    Rotter, Jerome I.
    Harbor UCLA Med Ctr, LABioMed, Inst Translat Genom & Populat Sci, Dept Pediat, Torrance, CA 90509 USA;Harbor UCLA Med Ctr, LABioMed, Dept Med, Torrance, CA 90509 USA.
    Saba, Samir
    Univ Pittsburgh, Div Cardiol, Pittsburgh, PA USA.
    Sandhu, Roopinder K.
    Univ Alberta, Div Cardiol, Edmonton, AB, Canada.
    Schnabel, Renate B.
    Univ Heart Ctr Hamburg, Dept Gen & Intervent Cardiol, Hamburg, Germany;DZHK German Ctr Cardiovasc Res, Partner Site Hamburg Kiel Lubeck, Hamburg, Germany.
    Schramm, Katharina
    Ludwig Maximilians Univ Munchen, Univ Hosp Munich, Dept Med 1, Munich, Germany;Helmholtz Zentrum Munchen German Res Ctr Environm, Inst Genet Epidemiol, Neuherberg, Germany.
    Schunkert, Heribert
    DZHK German Ctr Cardiovasc Res, Partner Site Munich Heart Alliance, Munich, Germany;Tech Univ Munich, Klin Herz & Kreislauferkrankungen, Deutsch Herzzentrum Munchen, Munich, Germany.
    Schurman, Claudia
    Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA;Icahn Sch Med Mt Sinai, Genet Obes & Related Metab Traits Program, New York, NY 10029 USA.
    Scott, Stuart A.
    Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA.
    Seppala, Ilkka
    Univ Tampere, Fac Med & Life Sci, Dept Clin Chem, Fimlab Labs, Tampere, Finland;Univ Tampere, Fac Med & Life Sci, Finnish Cardiovasc Res Ctr Tampere, Tampere, Finland.
    Shaffer, Christian
    Vanderbilt Univ, Med Ctr, Dept Med, Nashville, TN USA.
    Shah, Svati
    Duke Univ, Sch Med, Dept Med, Div Cardiol, Durham, NC 27706 USA.
    Shalaby, Alaa A.
    Univ Pittsburgh, Div Cardiol, Pittsburgh, PA USA;Pittsburgh VA Healthcare Syst, Cardiol Div, Pittsburgh, PA USA.
    Shim, Jaemin
    Korea Univ, Anam Hosp, Seoul, South Korea.
    Shoemaker, M. Benjamin
    Vanderbilt Univ, Med Ctr, Dept Med, Nashville, TN USA.
    Siland, Joylene E.
    Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, Groningen, Netherlands.
    Sinisalo, Juha
    Univ Helsinki, Cent Hosp, Heart & Lung Ctr HUS, Helsinki, Finland.
    Sinner, Moritz F.
    Ludwig Maximilians Univ Munchen, Univ Hosp Munich, Dept Med 1, Munich, Germany;DZHK German Ctr Cardiovasc Res, Partner Site Munich Heart Alliance, Munich, Germany.
    Slowik, Agnieszka
    Jagiellonian Univ, Med Coll, Fac Med, Dept Neurol, Krakow, Poland.
    Smith, Albert V.
    Icelandic Heart Assoc, Kopavogur, Iceland;Univ Iceland, Fac Med, Reykavik, Iceland.
    Smith, Blair H.
    Univ Dundee, Div Populat Hlth Sci, Dundee, Scotland.
    Smith, J. Gustav
    Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA USA;Lund Univ, Dept Cardiol Clin Sci, Lund, Sweden;Skane Univ Hosp, Lund, Sweden.
    Smith, Jonathan D.
    Cleveland Clin, Dept Cardiovasc Med, Cleveland, OH USA;Cleveland Clin, Dept Cellular & Mol Med, Cleveland, OH USA;Cleveland Clin, Dept Mol Cardiol, Cleveland, OH USA;Cleveland Clin, Dept Quantitat Hlth Sci, Cleveland, OH USA.
    Smith, Nicholas L.
    Univ Washington, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA;Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA;Kaiser Permanente, Washington Hlth Res Inst, Seattle, WA USA.
    Soliman, Elsayed Z.
    Wake Forest Sch Med, Epidemiol Cardiol Res Ctr EPICARE, Winston Salem, NC USA.
    Sotoodehnia, Nona
    Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA;Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA.
    Stricker, Bruno H.
    Erasmus Univ, Med Ctr Rotterdam, Dept Epidemiol & Internal Med, Rotterdam, Netherlands;Inspectorate Hlth Care, Utrecht, Netherlands.
    Sun, Albert
    Duke Univ, Sch Med, Dept Med, Div Cardiol, Durham, NC 27706 USA.
    Sun, Han
    Cleveland Clin, Dept Cardiovasc Med, Cleveland, OH USA;Cleveland Clin, Dept Cellular & Mol Med, Cleveland, OH USA;Cleveland Clin, Dept Mol Cardiol, Cleveland, OH USA;Cleveland Clin, Dept Quantitat Hlth Sci, Cleveland, OH USA.
    Svendsen, Jesper H.
    Copenhagen Univ Hosp, Dept Cardiol, Heart Ctr, Lab Mol Cardiol,Rigshosp, Copenhagen, Denmark;Univ Copenhagen, Fac Hlth & Med Sci, Dept Clin Med, Copenhagen, Denmark.
    Tanaka, Toshihiro
    Tokyo Med & Dent Univ, Grad Sch Med & Dent Sci, Dept Human Genet & Dis Div, Tokyo, Japan.
    Tanriverdi, Kahraman
    Univ Massachusetts, Med Sch Worcester, Worcester, MA 01605 USA.
    Taylor, Kent D.
    Harbor UCLA Med Ctr, Dept Pediat, LABioMed, Inst Translat Genom & Populat Sci, Torrance, CA 90509 USA.
    Teder-Laving, Maris
    Univ Tartu, Estonian Genome Ctr, Tartu, Estonia.
    Teumer, Alexander
    Partner Site Greifswald, DZHK German Ctr Cardiovasc Res, Greifswald, Germany;Univ Med Greifswald, Inst Community Med, Greifswald, Germany.
    Theriault, Sebastien
    McMaster Univ, Populat Hlth Res Inst, Hamilton, ON, Canada;McMaster Univ, Dept Pathol & Mol Med, Hamilton, ON, Canada.
    Trompet, Stella
    Leiden Univ, Med Ctr, Dept Cardiol, Leiden, Netherlands;Leiden Univ, Med Ctr, Dept Internal Med, Sect Gerontol & Geriatr, Leiden, Netherlands.
    Tucker, Nathan R.
    Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA USA;Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA.
    Tveit, Arnljot
    Vestre Viken Hosp Trust, Baerum Hosp, Dept Med Res, Drammen, Norway;Univ Oslo, Inst Clin Med, Oslo, Norway.
    Uitterlinden, Andre G.
    Erasmus Univ, Med Ctr Rotterdam, Dept Epidemiol & Internal Med, Rotterdam, Netherlands.
    Van Der Harst, Pim
    Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, Groningen, Netherlands.
    Van Gelder, Isabelle C.
    Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, Groningen, Netherlands.
    Van Wagoner, David R.
    Cleveland Clin, Dept Cardiovasc Med, Cleveland, OH USA;Cleveland Clin, Dept Cellular & Mol Med, Cleveland, OH USA;Cleveland Clin, Dept Mol Cardiol, Cleveland, OH USA;Cleveland Clin, Dept Quantitat Hlth Sci, Cleveland, OH USA.
    Verweij, Niek
    Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, Groningen, Netherlands.
    Vlachopoulou, Efthymia
    Univ Helsinki, Medicum, Transplantat Lab, Helsinki, Finland.
    Voelker, Uwe
    Partner Site Greifswald, DZHK German Ctr Cardiovasc Res, Greifswald, Germany;Univ Med Ernst Moritz Arndt Univ Greifswald, Interfac Inst Genet & Funct Gen, Greifswald, Germany.
    Wang, Biqi
    Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA.
    Weeke, Peter E.
    Copenhagen Univ Hosp, Dept Cardiol, Heart Ctr, Lab Mol Cardiol,Rigshosp, Copenhagen, Denmark;Vanderbilt Univ, Med Ctr, Dept Med, Nashville, TN USA.
    Weijs, Bob
    Maastricht Univ, Med Ctr, Maastricht, Netherlands;Maastricht Univ, Cardiovasc Res Inst Maastricht, Dept Cardiol, Maastricht, Netherlands.
    Weiss, Raul
    Ohio State Univ, Div Cardiovasc Med, Columbus, OH 43210 USA.
    Weiss, Stefan
    Partner Site Greifswald, DZHK German Ctr Cardiovasc Res, Greifswald, Germany;Univ Med Ernst Moritz Arndt Univ Greifswald, Interfac Inst Genet & Funct Gen, Greifswald, Germany.
    Wells, Quinn S.
    Vanderbilt Univ, Med Ctr, Dept Med, Nashville, TN USA.
    Wiggins, Kerri L.
    Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA.
    Wong, Jorge A.
    McMaster Univ, Div Cardiol Hamilton Hlth Sci, Hamilton, ON, Canada.
    Woo, Daniel
    Univ Cincinnati, Coll Med, Cincinnati, OH USA.
    Worrall, Bradford B.
    Univ Virginia Hlth Syst, Dept Neurol, Charlottesville, VA USA;Univ Virginia Hlth Syst, Dept Publ Hlth Sci, Charlottesville, VA USA.
    Yang, Pil-Sung
    Yonsei Univ Hlth Syst, Seoul, South Korea.
    Yao, Jie
    Harbor UCLA Med Ctr, Dept Pediat, LABioMed, Inst Translat Genom & Populat Sci, Torrance, CA 90509 USA.
    Yoneda, Zachary T.
    Vanderbilt Univ, Med Ctr, Dept Med, Nashville, TN USA.
    Zeller, Tanja
    Univ Heart Ctr Hamburg, Dept Gen & Intervent Cardiol, Hamburg, Germany;DZHK German Ctr Cardiovasc Res, Partner Site Hamburg Kiel Lubeck, Hamburg, Germany.
    Zeng, Lingyao
    Tech Univ Munich, Klin Herz & Kreislauferkrankungen, Deutsch Herzzentrum Munchen, Munich, Germany.
    Lubitz, Steven A.
    Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA USA;Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA;Massachusetts Gen Hosp, Cardiac Arrhythmia Serv, Boston, MA 02114 USA.
    Lunetta, Kathryn L.
    NHLBI, Framingham, MA USA;Boston Univ, Framingham Heart Study, Framingham, MA USA;Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA.
    Ellinor, Patrick T.
    Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA USA;Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA;Massachusetts Gen Hosp, Cardiac Arrhythmia Serv, Boston, MA 02114 USA.
    Multi-ethnic genome-wide association study for atrial fibrillation2018In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 50, no 9, p. 1225-1233Article in journal (Refereed)
    Abstract [en]

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

  • 254.
    Ruge, Toralph
    et al.
    Karolinska Inst, Dept Med, Stockholm, Sweden; Karolinska Inst, Dept Med, Stockholm, Sweden.
    Carlsson, Axel C
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Karolinska Inst, Dept Neurobiol Care Sci & Soc, Div Family Med & Primary Care, Huddinge, Sweden.
    Ingelsson, Erik
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Stanford Univ, Sch Med, Div Cardiovasc Med, Stanford, CA USA.
    Risérus, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Sundström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Ärnlöv, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Center for Clinical Research Dalarna. Karolinska Inst, Dept Neurobiol Care Sci & Soc, Div Family Med & Primary Care, Huddinge, Sweden.
    Circulating endostatin and the incidence of heart failure.2018In: Scandinavian Cardiovascular Journal, ISSN 1401-7431, E-ISSN 1651-2006, Vol. 52, no 5, p. 244-249Article in journal (Refereed)
    Abstract [en]

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

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

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

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

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

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

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

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

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

  • 256.
    Saleheen, Danish
    et al.
    Univ Penn, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA.;Ctr Noncommunicable Dis, Karachi, Pakistan..
    Zhao, Wei
    Univ Penn, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA..
    Young, Robin
    Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England..
    Nelson, Christopher P.
    Univ Leicester, Dept Cardiovascular Sci, Leicester, Leics, England..
    Ho, WeangKee
    Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England..
    Ferguson, Jane F.
    Vanderbilt Univ, Dept Med, Cardiol Div, Nashville, TN USA..
    Rasheed, Asif
    Ctr Noncommunicable Dis, Karachi, Pakistan..
    Ou, Kristy
    Vanderbilt Univ, Dept Med, Cardiol Div, Nashville, TN USA..
    Nurnberg, Sylvia T.
    Univ Penn, Perelman Sch Med, Dept Med, Div Translat Med & Human Genet, Philadelphia, PA 19104 USA..
    Bauer, Robert C.
    Columbia Univ, Med Ctr, Dept Med, Cardiol Div, New York, NY USA.;Columbia Univ, Med Ctr, Irving Inst Clin & Translat Res, New York, NY USA..
    Goel, Anuj
    Univ Oxford, Radcliffe Dept Med, Div Cardiovasc Med, Oxford, England.;Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England..
    Do, Ron
    Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA.;Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA..
    Stewart, Alexandre F. R.
    Univ Ottawa, Heart Inst, Ruddy Canadian Cardiovasc Genet Ctr, Ottawa, ON, Canada..
    Hartiala, Jaana
    Univ Southern Calif, Keck Sch Med, Inst Med Genet, Los Angeles, CA USA.;Univ Southern Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA USA..
    Zhang, Weihua
    Imperial Coll London, Dept Epidemiol & Biostat, London, England.;Ealing Hosp NHS Trust, Dept Cardiol, Southall, Middx, England..
    Thorleifsson, Gudmar
    deCODE Genet, Sturlugata 8, IS-101 Reykjavik, Iceland.;Univ Iceland, Sch Med, Reykjavik, Iceland..
    Strawbridge, Rona J.
    Karolinska Inst, Cardiovasc Med Unit, Dept Med Solna, Stockholm, Sweden..
    Sinisalo, Juha
    Helsinki Univ Cent Hosp HUCH Heart & Lung Ctr, Helsinki, Uusimaa, Finland..
    Kanoni, Stavroula
    William Harvey Res Inst, Barts, England.;Queen Mary Univ London, London Sch Med & Dent, London, England..
    Sedaghat, Sanaz
    Erasmus Univ, Med Ctr, Dept Epidemiol, Rotterdam, Netherlands..
    Marouli, Eirini
    William Harvey Res Inst, Barts, England.;Queen Mary Univ London, London Sch Med & Dent, London, England.;Harokopio Univ, Dept Dietet Nutr, Athens, Greece..
    Kristiansson, Kati
    Natl Inst Hlth & Welf, Helsinki, Finland..
    Zhao, Jing Hua
    Univ Cambridge, Sch Clin Med, Inst Metab Sci, MRC Epidemiol Unit, Cambridge Biomed Campus, Cambridge, England..
    Scott, Robert
    Univ Cambridge, Sch Clin Med, Inst Metab Sci, MRC Epidemiol Unit, Cambridge Biomed Campus, Cambridge, England..
    Gauguier, Dominique
    INSERM, UMRS1138, Ctr Rech Cordeliers, Paris, France..
    Shah, Svati H.
    Duke Univ, Med Ctr, Dept Med, Div Cardiol, Durham, NC 27710 USA..
    Smith, Albert Vernon
    Iceland Heart Assoc, Kopavogur, Iceland.;Univ Iceland, Fac Med, Reykjavik, Iceland..
    van Zuydam, Natalie
    Univ Dundee, Med Res Inst, Ninewells Hosp & Med Sch, Dundee, Scotland..
    Cox, Amanda J.
    Wake Forest Sch Med, Ctr Genom & Personalized Med Res, Winston Salem, NC USA..
    Willenborg, Christina
    Univ Lubeck, Inst Integrat & Experimentelle Genom, Lubeck, Germany.;DZHK German Res Ctr Cardiovasc Res, Hamburg, Germany..
    Kessler, Thorsten
    Tech Univ Munich, Deutsch Herzzentrum Munchen, Munich, Germany.;Klinikum Rechts Der Isar, Munich, Germany..
    Zeng, Lingyao
    Tech Univ Munich, Deutsch Herzzentrum Munchen, Munich, Germany.;DZHK German Res Ctr Cardiovasc Res, Partner Site Munich Heart Alliance, Munich, Germany..
    Province, Michael A.
    Washington Univ, Sch Med, Dept Genet, St Louis, MO USA..
    Ganna, Andrea
    Massachusetts Gen Hosp, Dept Med, Analyt & Translat Genet Unit, Boston, MA 02114 USA.;Harvard Med Sch, Boston, MA 02114 USA.;Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA USA..
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Pedersen, Nancy L.
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    White, Charles C.
    Boston Univ, Sch Publ Hlth Framingham Heart Study, Dept Biostat, Boston, MA 02215 USA..
    Joensuu, Anni
    Natl Inst Hlth & Welf, Helsinki, Finland.;Univ Helsinki, Inst Mol Med, Helsinki, Finland..
    Kleber, Marcus Edi
    Heidelberg Univ, Mannheim Med Fac, Dept Med, Heidelberg, Germany..
    Hall, Alistair S.
    Univ Leeds, Leeds Inst Genet Hlth & Therapeut, Leeds, W Yorkshire, England..
    Maerz, Winfried
    Synlab Serv GmbH, Synlab Acad, Mannheim, Germany.;Med Univ Graz, Clin Inst Med & Chem Lab Diagnost, Graz, Austria..
    Salomaa, Veikko
    Natl Inst Hlth & Welf, Helsinki, Finland..
    O'Donnell, Christopher
    NHLBI, Bldg 10, Bethesda, MD 20892 USA.;NIH, Framingham Heart Study, Bethesda, MD USA..
    Ingelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Feitosa, Mary F.
    Washington Univ, Sch Med, Dept Genet, St Louis, MO USA..
    Erdmann, Jeanette
    Univ Lubeck, Inst Integrat & Experimentelle Genom, Lubeck, Germany.;DZHK German Res Ctr Cardiovasc Res, Hamburg, Germany..
    Bowden, Donald W.
    Wake Forest Sch Med, Ctr Genom & Personalized Med Res, Winston Salem, NC USA..
    Palmer, Colin N. A.
    Univ Dundee, Med Res Inst, Ninewells Hosp & Med Sch, Dundee, Scotland..
    Gudnason, Vilmundur
    Iceland Heart Assoc, Kopavogur, Iceland.;Univ Iceland, Fac Med, Reykjavik, Iceland..
    De Faire, Ulf
    Karolinska Inst, Inst Environm Med, Div Cardiovasc Epidemiol, Stockholm, Sweden..
    Zalloua, Pierre
    Lebanese Amer Univ, Sch Med, Beirut, Lebanon..
    Wareham, Nicholas
    INSERM, UMRS1138, Ctr Rech Cordeliers, Paris, France..
    Thompson, John R.
    Univ Leicester, Dept Hlth Sci, Leicester, Leics, England..
    Kuulasmaa, Kari
    Natl Inst Hlth & Welf, Helsinki, Finland..
    Dedoussis, George
    Harokopio Univ, Dept Dietet Nutr, Athens, Greece..
    Perola, Markus
    Natl Inst Hlth & Welf, Helsinki, Finland.;Univ Helsinki, Inst Mol Med, Helsinki, Finland..
    Dehghan, Abbas
    Erasmus Univ, Med Ctr, Dept Epidemiol, Rotterdam, Netherlands..
    Chambers, John C.
    Imperial Coll London, Dept Epidemiol & Biostat, London, England.;Ealing Hosp NHS Trust, Dept Cardiol, Southall, Middx, England.;Imperial Coll Healthcare NHS Trust, London, England..
    Kooner, Jaspal
    Imperial Coll London, Dept Epidemiol & Biostat, London, England.;Imperial Coll Healthcare NHS Trust, London, England.;Imperial Coll London, Natl Heart & Lung Inst, Cardiovasc Sci, London, England..
    Allayee, Hooman
    Univ Southern Calif, Keck Sch Med, Inst Med Genet, Los Angeles, CA USA.;Univ Southern Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA USA..
    Deloukas, Panos
    William Harvey Res Inst, Barts, England.;Queen Mary Univ London, London Sch Med & Dent, London, England.;King Abdulaziz Univ, Princess Al Jawhara Al Brahim Ctr Excellence Res, Jeddah, Saudi Arabia..
    McPherson, Ruth
    Univ Ottawa, Heart Inst, Ruddy Canadian Cardiovasc Genet Ctr, Ottawa, ON, Canada..
    Stefansson, Kari
    deCODE Genet, Sturlugata 8, IS-101 Reykjavik, Iceland.;Univ Iceland, Sch Med, Reykjavik, Iceland..
    Schunkert, Heribert
    Tech Univ Munich, Deutsch Herzzentrum Munchen, Munich, Germany.;DZHK German Res Ctr Cardiovasc Res, Partner Site Munich Heart Alliance, Munich, Germany..
    Kathiresan, Sekar
    MIT, Broad Inst, Cambridge, MA 02139 USA.;Harvard Univ, Cambridge, MA 02138 USA.;Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA USA.;Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA.;Harvard Med Sch, Dept Med, Boston, MA USA..
    Farrall, Martin
    Univ Oxford, Radcliffe Dept Med, Div Cardiovasc Med, Oxford, England.;Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England..
    Frossard, Philippe Marcel
    Ctr Noncommunicable Dis, Karachi, Pakistan..
    Rader, Daniel J.
    Univ Penn, Dept Genet, Philadelphia, PA 19104 USA.;Univ Penn, Perelman Sch Med, Dept Med, Div Translat Med & Human Genet, Philadelphia, PA 19104 USA..
    Samani, Nilesh J.
    Univ Leicester, Dept Cardiovascular Sci, Leicester, Leics, England..
    Reilly, Muredach P.
    Columbia Univ, Med Ctr, Dept Med, Cardiol Div, New York, NY USA.;Columbia Univ, Med Ctr, Irving Inst Clin & Translat Res, New York, NY USA..
    Loss of Cardioprotective Effects at the ADAMTS7 Locus as a Result of Gene-Smoking Interactions2017In: Circulation, ISSN 0009-7322, E-ISSN 1524-4539, Vol. 135, no 24, p. 2336-2353Article in journal (Refereed)
    Abstract [en]

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

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

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

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

  • 257.
    Salihovic, Samira
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab. MTM Research Centre, School of Science and Technology, Örebro University.
    Fall, Tove
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Ganna, Andrea
    Broeckling, Corey D
    Prenni, Jessica E
    Hyötyläinen, Tuulia
    Kärrman, Anna
    Lind, P. Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Ingelsson, Erik
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Identification of metabolic profiles associated with human exposure to perfluoroalkyl substances.2019In: Journal of Exposure Science and Environmental Epidemiology, ISSN 1559-0631, E-ISSN 1559-064X, Vol. 29, no 2, p. 196-205Article in journal (Refereed)
    Abstract [en]

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

  • 258.
    Salihovic, Samira
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. MTM Research Centre, School of Science and Technology, Örebro University, SE-701 82 Örebro, Sweden.
    Kärrman, Anna
    MTM Research Centre, School of Science and Technology, Örebro University, SE-701 82 Örebro, Sweden.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Lind, P. Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Lindström, Gunilla
    MTM Research Centre, School of Science and Technology, Örebro University, SE-701 82 Örebro, Sweden.
    van Bavel, Bert
    MTM Research Centre, School of Science and Technology, Örebro University, SE-701 82 Örebro, Sweden.
    Perfluoroalkyl substances (PFAS) including structural PFOS isomers in plasma from elderly men and women from Sweden: Results from the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS)2015In: Environment International, ISSN 0160-4120, E-ISSN 1873-6750, Vol. 82, p. 21-27Article in journal (Refereed)
    Abstract [en]

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

  • 259.
    Salihovic, Samira
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Orebro Univ, Sch Sci & Technol, MTM Res Ctr, Orebro, Sweden.
    Stubleski, Jordan
    Orebro Univ, Sch Sci & Technol, MTM Res Ctr, Orebro, Sweden.
    Kärrman, Anna
    Orebro Univ, Sch Sci & Technol, MTM Res Ctr, Orebro, Sweden.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Fall, Tove
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Lind, P. Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Changes in markers of liver function in relation to changes in perfluoroalkyl substances - A longitudinal study2018In: Environment International, ISSN 0160-4120, E-ISSN 1873-6750, Vol. 117, p. 196-203Article in journal (Refereed)
    Abstract [en]

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

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

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

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

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

  • 260.
    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.

  • 261.
    Schmidt, Amand F.
    et al.
    UCL, Inst Cardiovasc Sci, London NW1 2DA, England.;UCL, UCL Inst Hlth Informat, Farr Inst Hlth Informat Res, London, England..
    Swerdlow, Daniel I.
    UCL, Inst Cardiovasc Sci, London NW1 2DA, England.;Imperial Coll London, Dept Med, Fac Med, London, England..
    Holmes, Michael V.
    Univ Oxford, Clin Trial Serv Unit, Nuffield Dept Populat Hlth, Oxford, England.;Univ Oxford, Epidemiol Studies Unit CTSU, Nuffield Dept Populat Hlth, Oxford, England.;Univ Oxford, Med Res Council, Populat Hlth Res Unit, Oxford, England..
    Patel, Riyaz S.
    UCL, Inst Cardiovasc Sci, London NW1 2DA, England.;UCL, UCL Inst Hlth Informat, Farr Inst Hlth Informat Res, London, England.;St Bartholomews Hosp, Barts Heart Ctr, London, England..
    Fairhurst-Hunter, Zammy
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England..
    Lyall, Donald M.
    Univ Glasgow, Inst Hlth & Wellbeing, Glasgow, Lanark, Scotland..
    Hartwig, Fernando Pires
    Univ Fed Pelotas, Postgrad Program Epidemiol, Pelotas, Brazil..
    Horta, Bernardo Lessa
    Univ Fed Pelotas, Postgrad Program Epidemiol, Pelotas, Brazil..
    Hypponen, Elina
    Univ South Australia, Ctr Populat Hlth Res, Sansom Inst Hlth Res, Adelaide, SA, Australia.;UCL Great Ormond St Inst Child Hlth, Populat Policy & Practice, London, England.;South Australian Hlth & Med Res Inst, Adelaide, SA, Australia..
    Power, Christine
    UCL Great Ormond St Inst Child Hlth, Populat Policy & Practice, London, England..
    Moldovan, Max
    Univ South Australia, Sch Hlth Sci, Adelaide, SA, Australia.;EMBL Australia, South Australian Hlth & Med Res Inst, Adelaide, SA, Australia..
    van Iperen, Erik
    Netherlands Heart Inst, Durrer Ctr Cardiovasc Res, Utrecht, Netherlands.;Acad Med Ctr, Dept Clin Epidemiol Biostat & Bioinformat, Amsterdam, Netherlands..
    Hovingh, G. Kees
    Acad Med Ctr, Dept Vasc Med, Amsterdam, Netherlands..
    Demuth, Ilja
    Charite Univ Med Berlin, Charite Res Grp Geriatr, Berlin, Germany.;Charite Univ Med Berlin, Inst Med & Human Genet, Berlin, Germany..
    Norman, Kristina
    Charite Univ Med Berlin, Charite Res Grp Geriatr, Berlin, Germany..
    Steinhagen-Thiessen, Elisabeth
    Charite Univ Med Berlin, Charite Res Grp Geriatr, Berlin, Germany..
    Demuth, Juri
    E CA Econ GmbH, Berlin, Germany..
    Bertram, Lars
    Imperial Coll London, Neuroepidemiol & Ageing Res Unit, Fac Med, London, England.;Univ Lubeck, Lubeck Interdisciplinary Platform Genome Analyt L, Inst Neurogenet, Lubeck, Germany.;Univ Lubeck, Lubeck Interdisciplinary Platform Genome Analyt L, Inst Integrat & Expt Genom, Lubeck, Germany..
    Liu, Tian
    Max Planck Inst Human Dev, Berlin, Germany.;Max Planck Inst Mol Genet, Berlin, Germany..
    Coassin, Stefan
    Med Univ Innsbruck, Dept Med Genet Mol & Clin Pharmacol, Div Genet Epidemiol Innsbruck, Innsbruck, Austria..
    Willeit, Johann
    Med Univ Innsbruck, Dept Neurol, Innsbruck, Austria..
    Kiechl, Stefan
    Med Univ Innsbruck, Dept Neurol, Innsbruck, Austria..
    Willeit, Karin
    Med Univ Innsbruck, Dept Neurol, Innsbruck, Austria..
    Mason, Dan
    Bradford Royal Infirm, Bradford Inst Hlth Res, Bradford, W Yorkshire, England..
    Wright, John
    Bradford Royal Infirm, Bradford Inst Hlth Res, Bradford, W Yorkshire, England..
    Morris, Richard
    Univ Bristol, Sch Social & Community Med, Bristol, Avon, England..
    Wanamethee, Goya
    UCL, Dept Primary Care & Populat Hlth, London, England..
    Whincup, Peter
    St Georges Univ London, Populat Hlth Res Inst, London, England..
    Ben-Shlomo, Yoav
    Univ Bristol, Sch Social & Community Med, Bristol, Avon, England..
    McLachlan, Stela
    Univ Edinburgh, Ctr Populat Hlth Sci, Usher Inst Populat Hlth Sci & Informat, Edinburgh, Midlothian, Scotland..
    Price, Jackie F.
    Univ Edinburgh, Ctr Populat Hlth Sci, Usher Inst Populat Hlth Sci & Informat, Edinburgh, Midlothian, Scotland..
    Kivimaki, Mika
    UCL, UCL Inst Epidemiol & Hlth Care, Dept Epidemiol & Publ Hlth, London, England..
    Welch, Catherine
    UCL, UCL Inst Epidemiol & Hlth Care, Dept Epidemiol & Publ Hlth, London, England..
    Sanchez-Galvez, Adelaida
    UCL, UCL Inst Epidemiol & Hlth Care, Dept Epidemiol & Publ Hlth, London, England..
    Marques-Vidal, Pedro
    Univ Lausanne Hosp, Dept Med, Internal Med Unit, Lausanne, Switzerland..
    Nicolaides, Andrew
    Imperial Coll London, Dept Vasc Surg, Fac Med, London, England.;Univ Nicosia, Nicosia Med Sch, Dept Surg, Nicosia, Cyprus..
    Panayiotou, Andrie G.
    Cyprus Univ Technol, Cyprus Int Inst Environm & Publ Hlth, Limassol, Cyprus..
    Onland-Moret, N. Charlotte
    Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, Utrecht, Netherlands..
    van der Schouw, Yvonne T.
    Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, Utrecht, Netherlands..
    Matullo, Giuseppe
    Human Genet Fdn, Turin, Italy.;Univ Turin, Dept Med Sci, Turin, Italy..
    Fiorito, Giovanni
    Human Genet Fdn, Turin, Italy.;Univ Turin, Dept Med Sci, Turin, Italy..
    Guarrera, Simonetta
    Human Genet Fdn, Turin, Italy.;Univ Turin, Dept Med Sci, Turin, Italy..
    Sacerdote, Carlotta
    San Giovanni Battista Hosp, Canc Epidemiol Unit, Turin, Italy.;CPO Piemonte, Ctr Oncol Prevent, Turin, Italy..
    Wareham, Nicholas J.
    Univ Cambridge, Sch Clin Med, MRC Epidemiol Unit, Inst Metab Sci, Cambridge, England..
    Langenberg, Claudia
    Univ Cambridge, Sch Clin Med, MRC Epidemiol Unit, Inst Metab Sci, Cambridge, England..
    Scott, Robert
    Univ Cambridge, Sch Clin Med, MRC Epidemiol Unit, Inst Metab Sci, Cambridge, England..
    Luan, Jian'an
    Univ Cambridge, Sch Clin Med, MRC Epidemiol Unit, Inst Metab Sci, Cambridge, England..
    Bobak, Martin
    UCL, UCL Inst Epidemiol & Hlth Care, Dept Epidemiol & Publ Hlth, London, England..
    Malyutina, Sofi A.
    Novosibirsk State Med Univ, Novosibirsk, Russia.;Russian Acad Med Sci, Inst Internal & Prevent Med, Siberian Branch, Novosibirsk, Russia..
    Pajak, Andrzej
    Jagiellonian Univ, Coll Med, Krakow, Poland..
    Kubinova, Ruzena
    Natl Inst Publ Hlth, Prague, Czech Republic..
    Tamosiunas, Abdonas
    Lithuanian Univ Hlth Sci, Kaunas, Lithuania..
    Pikhart, Hynek
    UCL, UCL Inst Epidemiol & Hlth Care, Dept Epidemiol & Publ Hlth, London, England..
    Husemoen, Lise Lotte Nystrup
    Capital Reg Denmark, Res Ctr Prevent & Hlth, Copenhagen, Denmark..
    Grarup, Niels
    Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn, Ctr Basic Metab Res, Copenhagen, Denmark..
    Pedersen, Oluf
    Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn, Ctr Basic Metab Res, Copenhagen, Denmark..
    Hansen, Torben
    Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn, Ctr Basic Metab Res, Copenhagen, Denmark..
    Linneberg, Allan
    Capital Reg Denmark, Res Ctr Prevent & Hlth, Copenhagen, Denmark.;Rigshosp, Dept Clin Expt Res, Copenhagen, Denmark.;Univ Copenhagen, Fac Hlth & Med Sci, Dept Clin Med, Copenhagen, Denmark..
    Simonsen, Kenneth Starup
    Capital Reg Denmark, Res Ctr Prevent & Hlth, Copenhagen, Denmark..
    Cooper, Jackie
    UCL, Ctr Cardiovasc Genet, London, England..
    Humphries, Steve E.
    UCL, Ctr Cardiovasc Genet, London, England..
    Brilliant, Murray
    Marshfield Clin Res Fdn, Ctr Human Genet, Marshfield, WI USA..
    Kitchner, Terrie
    Marshfield Clin Res Fdn, Ctr Human Genet, Marshfield, WI USA..
    Hakonarson, Hakon
    Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA..
    Carrell, David S.
    Grp Hlth Res Inst, Seattle, WA USA..
    McCarty, Catherine A.
    Essentia Inst Rural Hlth, Duluth, MN USA..
    Kirchner, H. Lester
    Geisinger Med Clin, Ctr Hlth Res, Danville, PA USA..
    Larson, Eric B.
    Grp Hlth Res Inst, Seattle, WA USA..
    Crosslin, David R.
    Grp Hlth Res Inst, Seattle, WA USA..
    de Andrade, Mariza
    Mayo Clin, Div Biomed Stat & Informat, Rochester, MN USA..
    Roden, Dan M.
    Vanderbilt Univ, Sch Med, Dept Med, Nashville, TN 37212 USA.;Vanderbilt Univ, Sch Med, Dept Pharmacol, Nashville, TN 37212 USA..
    Denny, Joshua C.
    Vanderbilt Univ, Sch Med, Dept Biomed Informat, Nashville, TN 37212 USA..
    Carty, Cara
    George Washington Univ, Washington, DC USA..
    Hancock, Stephen
    Univ Newcastle, Newcastle, NSW, Australia..
    Attia, John
    Univ Newcastle, Newcastle, NSW, Australia..
    Holliday, Elizabeth
    Univ Newcastle, Newcastle, NSW, Australia..
    Donnell, Martin O'
    Populat Hlth Res Inst, Hamilton, ON, Canada..
    Yusuf, Salim
    Populat Hlth Res Inst, Hamilton, ON, Canada..
    Chong, Michael
    Populat Hlth Res Inst, Hamilton, ON, Canada..
    Pare, Guillaume
    Populat Hlth Res Inst, Hamilton, ON, Canada..
    van der Harst, Pim
    Netherlands Heart Inst, Durrer Ctr Cardiovasc Res, Utrecht, Netherlands.;Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, Groningen, Netherlands.;Univ Groningen, Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands..
    Said, M. Abdullah
    Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, Groningen, Netherlands..
    Eppinga, Ruben N.
    Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, Groningen, Netherlands..
    Verweij, Niek
    Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, Groningen, Netherlands..
    Snieder, Harold
    Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, Groningen, Netherlands..
    Christen, Tim
    Leiden Univ, Med Ctr, Dept Clin Epidemiol, Leiden, Netherlands..
    Mook-Kanamori, Dennis O.
    Leiden Univ, Med Ctr, Dept Clin Epidemiol, Leiden, Netherlands..
    Gustafsson, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Ingelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Stanford Univ, Dept Med, Sch Med, Div Cardiovasc Med, Stanford, CA 94305 USA..
    Pazoki, Raha
    Erasmus Univ, Med Ctr, Dept Epidemiol, Rotterdam, Netherlands..
    Franco, Oscar
    Erasmus Univ, Med Ctr, Dept Epidemiol, Rotterdam, Netherlands..
    Hofman, Albert
    Erasmus Univ, Med Ctr, Dept Epidemiol, Rotterdam, Netherlands..
    Uitterlinden, Andre
    Erasmus Univ, Med Ctr, Dept Internal Med, Rotterdam, Netherlands..
    Dehghan, Abbas
    Imperial Coll London, Sch Publ Hlth, MRC PHE Ctr Environm & Hlth, Dept Biostat & Epidemiol, London, England.;Erasmus Univ, Med Ctr, Dept Epidemiol, Rotterdam, Netherlands..
    Teumer, Alexander
    Univ Med Greifswald, Inst Community Med, Greifswald, Germany.;German Ctr Cardiovasc Res DZHK, Greifswald, Germany..
    Baumeister, Sebastian
    Univ Med Greifswald, Inst Community Med, Greifswald, Germany.;Univ Regensburg, Dept Epidemiol & Prevent Med, Regensburg, Germany..
    Doerr, Marcus
    Univ Med Greifswald, Dept Internal Med B, Greifswald, Germany.;German Ctr Cardiovasc Res DZHK, Greifswald, Germany..
    Lerch, Markus M.
    Univ Med Greifswald, Dept Med A, Greifswald, Germany..
    Voelker, Uwe
    Univ Med Greifswald, Interfac Inst Genet & Funct Genom, Greifswald, Germany.;German Ctr Cardiovasc Res DZHK, Greifswald, Germany..
    Voelzke, Henry
    Univ Med Greifswald, Inst Community Med, Greifswald, Germany.;German Ctr Cardiovasc Res DZHK, Greifswald, Germany..
    Ward, Joey
    Univ Glasgow, Inst Hlth & Wellbeing, Glasgow, Lanark, Scotland..
    Pell, Jill P.
    Univ Glasgow, Inst Hlth & Wellbeing, Glasgow, Lanark, Scotland..
    Smith, Daniel J.
    Univ Glasgow, Inst Hlth & Wellbeing, Glasgow, Lanark, Scotland..
    Meade, Tom
    London Sch Hyg & Trop Med, Dept Noncommunicable Dis Epidemiol, London, England..
    Maitland-van der Zee, Anke H.
    Acad Med Ctr, Dept Resp Med, Amsterdam, Netherlands.;Univ Utrecht, Fac Sci, Utrecht Inst Pharmaceut Sci, Div Pharmacoepidemiol & Clin Pharmacol, Utrecht, Netherlands..
    Baranova, Ekaterina V.
    Univ Utrecht, Fac Sci, Utrecht Inst Pharmaceut Sci, Div Pharmacoepidemiol & Clin Pharmacol, Utrecht, Netherlands..
    Young, Robin
    Univ Glasgow, Robertson Ctr Biostat, Glasgow, Lanark, Scotland..
    Ford, Ian
    Univ Glasgow, Robertson Ctr Biostat, Glasgow, Lanark, Scotland..
    Campbell, Archie
    Univ Edinburgh, Inst Genet & Mol Med, Edinburgh, Midlothian, Scotland..
    Padmanabhan, Sandosh
    Univ Glasgow, Cardiovasc & Med Sci, Glasgow, Lanark, Scotland..
    Bots, Michiel L.
    Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, Utrecht, Netherlands..
    Grobbee, Diederick E.
    Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, Utrecht, Netherlands..
    Froguel, Philippe
    Imperial Coll London, Fac Med, Dept Genom Common Dis, London, England.;Univ Lille, Inst Pasteur Lille, EGID, CNRS,UMR 8199, Lille, France..
    Thuillier, Dorothee
    Univ Lille, Inst Pasteur Lille, EGID, CNRS,UMR 8199, Lille, France..
    Balkau, Beverley
    INSERM, U1018, Ctr Rech Epidemiol & Sante Populat CESP, Renal & Cardiovasc Epidemiol, Villejuif, France..
    Bonnefond, Amelie
    Imperial Coll London, Fac Med, Dept Genom Common Dis, London, England.;Univ Lille, Inst Pasteur Lille, EGID, CNRS,UMR 8199, Lille, France..
    Cariou, Bertrand
    Univ Nantes, CHU Nantes, Inst Thorax, INSERM,CNRS, Nantes, France..
    Smart, Melissa
    Univ Essex, Inst Social & Econ Res, Colchester, Essex, England..
    Bao, Yanchun
    Univ Essex, Inst Social & Econ Res, Colchester, Essex, England..
    Kumari, Meena
    Univ Essex, Inst Social & Econ Res, Colchester, Essex, England..
    Mahajan, Anubha
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England..
    Ridker, Paul M.
    Harvard Med Sch, Brigham & Womens Hosp, Ctr Cardiovasc Dis Prevent, Boston, MA USA..
    Chasman, Daniel I.
    Harvard Med Sch, Brigham & Womens Hosp, Ctr Cardiovasc Dis Prevent, Boston, MA USA..
    Reiner, Alex P.
    Univ Washington, Fred Hutchinson Canc Res Ctr, Dept Epidemiol, Seattle, WA 98195 USA..
    Lange, Leslie A.
    Univ Colorado, Anschutz Med Campus, Denver, CO 80202 USA..
    Ritchie, Marylyn D.
    Geisinger Hlth Syst, Biomed & Translat Informat, Danville, PA USA.;Penn State Univ, Huck Inst Life Sci, Dept Biochem & Mol Biol, University Pk, PA 16802 USA..
    Asselbergs, Folkert W.
    UCL, Inst Cardiovasc Sci, London NW1 2DA, England.;UCL, UCL Inst Hlth Informat, Farr Inst Hlth Informat Res, London, England.;Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, Utrecht, Netherlands.;Univ Med Ctr Utrecht, Dept Cardiol, Div Heart & Lungs, Utrecht, Netherlands..
    Casas, Juan-Pablo
    UCL, UCL Inst Hlth Informat, Farr Inst Hlth Informat Res, London, England..
    Keating, Brendan J.
    Univ Penn, Dept Surg, Philadelphia, PA 19104 USA..
    Preiss, David
    Univ Oxford, Clin Trial Serv Unit, Nuffield Dept Populat Hlth, Oxford, England.;Univ Oxford, Epidemiol Studies Unit CTSU, Nuffield Dept Populat Hlth, Oxford, England.;Univ Oxford, Med Res Council, Populat Hlth Res Unit, Oxford, England..
    Hingorani, Aroon D.
    UCL, Inst Cardiovasc Sci, London NW1 2DA, England.;UCL, UCL Inst Hlth Informat, Farr Inst Hlth Informat Res, London, England..
    Sattar, Naveed
    Univ Glasgow, Cardiovasc & Med Sci, Glasgow, Lanark, Scotland..
    PCSK9 genetic variants and risk of type 2 diabetes: a mendelian randomisation study2017In: The Lancet Diabetes and Endocrinology, ISSN 2213-8587, E-ISSN 2213-8595, Vol. 5, no 2, p. 97-105Article in journal (Refereed)
    Abstract [en]

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

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

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

  • 264.
    Scott, Robert A.
    et al.
    Univ Cambridge, Sch Clin Med, MRC, Epidemiol Unit,Inst Metab Sci, Cambridge Biomedical Campus, Cambridge CB2 0QQ, England..
    Freitag, Daniel F.
    Univ Cambridge, Strangeways Res Lab, Dept Publ Hlth & Primary Care, Cambridge CB1 8RN, England.;Wellcome Trust Sanger Inst, Cambridge CB10 1SA, England..
    Li, Li
    GlaxoSmithKline, Stat Genet Projects Clin Platforms & Sci PCPS, Res Triangle Pk, NC 27709 USA..
    Chu, Audrey Y.
    Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02115 USA..
    Surendran, Praveen
    Univ Cambridge, Strangeways Res Lab, Dept Publ Hlth & Primary Care, Cambridge CB1 8RN, England..
    Young, Robin
    Univ Cambridge, Strangeways Res Lab, Dept Publ Hlth & Primary Care, Cambridge CB1 8RN, England..
    Grarup, Niels
    Univ Copenhagen, NovoNordisk Fdn, Fac Hlth & Med Sci, Ctr Basic Metab Res, DK-2200 Copenhagen, Denmark..
    Stancakova, Alena
    Univ Eastern Finland, Inst Clin Med, Internal Med, FI-70211 Kuopio, Finland..
    Chen, Yuning
    Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA..
    Varga, Tibor V.
    Lund Univ, Genet & Mol Epidemiol Unit, Dept Clin Sci, SE-205 Malmo, Sweden..
    Yaghootkar, Hanieh
    Univ Exeter, Sch Med, Genet Complex Traits, Exeter EX1 2LU, Devon, England..
    Luan, Jian'an
    Univ Cambridge, Sch Clin Med, MRC, Epidemiol Unit,Inst Metab Sci, Cambridge Biomedical Campus, Cambridge CB2 0QQ, England..
    Zhao, Jing Hua
    Univ Cambridge, Sch Clin Med, MRC, Epidemiol Unit,Inst Metab Sci, Cambridge Biomedical Campus, Cambridge CB2 0QQ, England..
    Willems, Sara M.
    Univ Cambridge, Sch Clin Med, MRC, Epidemiol Unit,Inst Metab Sci, Cambridge Biomedical Campus, Cambridge CB2 0QQ, England.;Erasmus Univ, Med Ctr, Dept Epidemiol, Genet Epidemiol Unit, NL-3000 CE Rotterdam, Netherlands..
    Wessel, Jennifer
    Fairbanks Sch Publ Hlth, Dept Epidemiol, Indianapolis, IN 46202 USA.;Indiana Univ Sch Med, Dept Med, Indianapolis, IN 46202 USA..
    Wang, Shuai
    Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA..
    Maruthur, Nisa
    Johns Hopkins Univ, Sch Med, Div Gen Internal Med, Baltimore, MD 21205 USA.;Johns Hopkins Univ, Welch Ctr Prevent Epidemol & Clin Res, Baltimore, MD 21205 USA.;Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA..
    Michailidou, Kyriaki
    Univ Cambridge, Ctr Canc Genet Epidemiol, Dept Publ Hlth & Primary Care, Strangeways Lab, Cambridge CB1 8RN, England..
    Pirie, Ailith
    Univ Cambridge, Ctr Canc Genet Epidemiol, Dept Publ Hlth & Primary Care, Strangeways Lab, Cambridge CB1 8RN, England..
    van der Lee, Sven J.
    Erasmus Univ, Dept Epidemiol, Med Ctr, NL-3000 CA Rotterdam, Netherlands..
    Gillson, Christopher
    Univ Cambridge, Sch Clin Med, MRC, Epidemiol Unit,Inst Metab Sci, Cambridge Biomedical Campus, Cambridge CB2 0QQ, England..
    Al Olama, Ali Amin
    Univ Cambridge, Ctr Canc Genet Epidemiol, Dept Publ Hlth & Primary Care, Strangeways Lab, Cambridge CB1 8RN, England..
    Amouyel, Philippe
    Univ Lille, Ctr Hosp Reg Univ Lille, INSERM, Inst Pasteur Lille,UMR 1167,RID AGE, F-59000 Lille, France..
    Arriola, Larraitz
    Publ Hlth Div Gipuzkoa, San Sebastian 20013, Spain.;Basque Govt, Inst BIOdonostia, San Sebastian 20014, Spain.;CIBER Epidemiol & Salud Publ CIBERESP, Madrid 28029, Spain..
    Arveiler, Dominique
    Univ Strasbourg, Dept Epidemiol & Publ Hlth EA3430, F-67085 Strasbourg, France..
    Aviles-Olmos, Iciar
    UCL Inst Neurol, Sobell Partment Motor Neurosci, London WC1N 3BG, England..
    Balkau, Beverley
    INSERM, Ctr Rech Epidemiol & Sante Populat CESP, F-94807 Villejuif, France.;Univ Paris 11, F-94805 Villejuif, France..
    Barricarte, Aurelio
    CIBER Epidemiol & Salud Publ CIBERESP, Madrid 28029, Spain.;Navarre Publ Hlth Inst ISPN, Pamplona 31003, Spain..
    Barroso, Ines
    Wellcome Trust Sanger Inst, Cambridge CB10 1SA, England.;Univ Paris 11, F-94805 Villejuif, France..
    Garcia, Sara Benlloch
    Univ Cambridge, Ctr Canc Genet Epidemiol, Dept Publ Hlth & Primary Care, Strangeways Lab, Cambridge CB1 8RN, England..
    Bis, Joshua C.
    Univ Washington, Cardiovasc Hlth Res Unit, Dept Med, Seattle, WA 98101 USA..
    Blankenberg, Stefan
    Univ Heart Ctr Hamburg, Dept Gen & Intervent Cardiol, D-20246 Hamburg, Germany..
    Boehnke, Michael
    Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA.;Univ Michigan, Ctr Stat Genet, Ann Arbor, MI 48109 USA..
    Boeing, Heiner
    German Inst Human Nutr, Potsdam Rehbruecke, D-14558 Nuthetal, Germany..
    Boerwinkle, Eric
    Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Human Genet Ctr, Houston, TX 77025 USA.;Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA..
    Borecki, Ingrid B.
    Washington Univ, Sch Med, Div Stat Genom, Dept Genet, St Louis, MO 63108 USA..
    Bork-Jensen, Jette
    Univ Copenhagen, NovoNordisk Fdn, Fac Hlth & Med Sci, Ctr Basic Metab Res, DK-2200 Copenhagen, Denmark..
    Bowden, Sarah
    Univ Birmingham, Inst Canc Studies, Canc Res UK Clin Trials Unit, Birmingham B15 2TT, W Midlands, England..
    Caldas, Carlos
    Univ Cambridge, Canc Res UK Cambridge Inst, Cambridge CB2 0RE, England.;Univ Cambridge, Li Ka Shing Ctr, Dept Oncol, Cambridge CB2 0RE, England..
    Caslake, Muriel
    Univ Glasgow, Glasgow G12 8QQ, Lanark, Scotland..
    Cupples, L. Adrienne
    Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA.;NHLBI, Framingham Heart Study, Framingham, MA 01702 USA..
    Cruchaga, Carlos
    Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA..
    Czajkowski, Jacek
    Washington Univ, Sch Med, Dept Genet, Div Stat Genom, St Louis, MO 63108 USA.;Washington Univ, Sch Med, Ctr Genome Sci & Syst Biol, St Louis, MO 63108 USA..
    den Hoed, Marcel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Dunn, Janet A.
    Univ Warwick, Warwick Clin Trials Unit, Gibbet Hill Rd, Coventry CV4 7AL, W Midlands, England..
    Earl, Helena M.
    Univ Cambridge, Cambridge CB2 0QQ, England.;Cambridge Univ Hosp Natl Hlth Serv Fdn Trust, Natl Inst Hlth Res, Cambridge Biomed Res Ctr, Cambridge CB2 0QQ, England..
    Ehret, Georg B.
    Johns Hopkins Univ, McKusick Nathans Inst Genet Med, Baltimore, MD 21205 USA..
    Ferrannini, Ele
    CNR, Inst Clin Physiol, I-56124 Pisa, Italy..
    Ferrieres, Jean
    Ctr Hosp Univ CHU Toulouse, Dept Epidemiol, INSERM, UMR 1027, F-31000 Toulouse, France..
    Foltynie, Thomas
    UCL Inst Neurol, Sobell Partment Motor Neurosci, London WC1N 3BG, England..
    Ford, Ian
    Univ Glasgow, Glasgow G12 8QQ, Lanark, Scotland..
    Forouhi, Nita G.
    Univ Cambridge, Sch Clin Med, MRC, Epidemiol Unit,Inst Metab Sci, Cambridge Biomedical Campus, Cambridge CB2 0QQ, England..
    Gianfagna, Francesco
    Univ Insubria, Dept Clin & Expt Med, Res Ctr Epidemiol & Prevent Med, I-21100 Varese, Italy.;IRCCS, Dept Epidemiol & Prevent, Ist Neurol Mediterraneo Neuromed, I-86077 Pozzilli, Italy..
    Gonzalez, Carlos
    Catalan Inst Oncol ICO, Barcelona 08908, Spain..
    Grioni, Sara
    Epidemiol & Prevent Unit, I-20133 Milan, Italy..
    Hiller, Louise
    Univ Warwick, Warwick Clin Trials Unit, Gibbet Hill Rd, Coventry CV4 7AL, W Midlands, England..
    Jansson, Jan-Hakan
    Res Unit, S-93141 Skelleftea, Sweden.;Umea Univ, Dept Publ Hlth & Clin Med, S-90185 Umea, Sweden..
    Jorgensen, Marit E.
    Steno Diabet Ctr, DK-2820 Gentofte, Denmark.;Southern Denmark Univ, Natl Inst Publ Hlth, DK-1353 Odense, Denmark..
    Jukema, J. Wouter
    Umea Univ, Dept Publ Hlth & Clin Med, S-90185 Umea, Sweden..
    Kaaks, Rudolf
    German Canc Res Ctr, D-69120 Heidelberg, Germany..
    Kee, Frank
    Queens Univ Belfast, UK Clin Res Collaborat UKCRC, Ctr Excellence Publ Hlth, Belfast BT12 6BJ, Antrim, North Ireland..
    Kerrison, Nicola D.
    Univ Cambridge, Sch Clin Med, MRC, Epidemiol Unit,Inst Metab Sci, Cambridge Biomedical Campus, Cambridge CB2 0QQ, England..
    Key, Timothy J.
    Univ Oxford, S Parks Rd, Oxford OX1 2JD, England..
    Kontto, Jukka
    Natl Inst Hlth & Welfare, FI-00271 Helsinki, Finland..
    Kote-Jarai, Zsofia
    Inst Canc Res, Sutton SM2 5NG, Surrey, England..
    Kraja, Aldi T.
    Washington Univ, Sch Med, Dept Genet, Div Stat Genom, St Louis, MO 63108 USA.;Washington Univ, Sch Med, Ctr Genome Sci & Syst Biol, St Louis, MO 63108 USA..
    Kuulasmaa, Kari
    Natl Inst Hlth & Welfare, FI-00271 Helsinki, Finland..
    Kuusisto, Johanna
    Univ Eastern Finland, Inst Clin Med, Internal Med, FI-70211 Kuopio, Finland..
    Linneberg, Allan
    Res Ctr Prevent & Hlth, DK-2600 Copenhagen, Denmark.;Rigshosp, Dept Clin Expt, DK-2100 Copenhagen, Denmark.;Univ Copenhagen, Fac Hlth & Med Sci, Dept Clin Med, DK-2200 Copenhagen, Denmark..
    Liu, Chunyu
    NHLBI, Framingham Heart Study, Populat Sci Branch, NIH, Bethesda, MD 20892 USA..
    Marenne, Galle
    Wellcome Trust Sanger Inst, Cambridge CB10 1SA, England..
    Mohlke, Karen L.
    Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA..
    Morris, Andrew P.
    Univ Liverpool, Dept Biostat, Liverpool L69 3GL, Merseyside, England.;Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England..
    Muir, Kenneth
    Univ Manchester, Inst Populat Hlth, Ctr Epidemiol, Oxford Rd, Manchester M13 9PT, Lancs, England.;Univ Warwick, Coventry CV4 7AL, W Midlands, England..
    Mueller-Nurasyid, Martina
    German Res Ctr Environm Hlth, Inst Genet Epidemiol, Helmholtz Zentrum Munchen, D-85764 Neuherberg, Germany.;Univ Munich, Dept Med 1, D-80336 Munich, Germany.;DZHK German Ctr Cardiovasc Res, Partner Site Munich Heart Alliance, D-80802 Munich, Germany..
    Munroe, Patricia B.
    Queen Mary Univ London, Barts & London Sch Med & Dent, William Harvey Res Inst, Clin Pharmacol, London EC1M 6BQ, England..
    Navarro, Carmen
    CIBER Epidemiol & Salud Publ CIBERESP, Madrid 28029, Spain.;Murcia Reg Hlth Council, Dept Epidemiol, IMIB Arrixaca, Murcia 30008, Spain..
    Nielsen, Sune F.
    Univ Copenhagen, Copenhagen Univ Hosp, Herlev Hosp, Dept Clin Biochem, DK-2730 Copenhagen, Denmark..
    Nilsson, Peter M.
    Lund Univ, S-20502 Malmo, Sweden..
    Nordestgaard, Borge G.
    Univ Copenhagen, Copenhagen Univ Hosp, Herlev Hosp, Dept Clin Biochem, DK-2730 Copenhagen, Denmark..
    Packard, Chris J.
    Univ Glasgow, Glasgow G12 8QQ, Lanark, Scotland..
    Palli, Domenico
    Canc Res & Prevent Inst ISPO, I-50141 Florence, Italy..
    Panico, Salvatore
    Univ Naples Federico II, Dipartimento Med Clin & Chirurg, I-80131 Naples, Italy..
    Peloso, Gina M.
    Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA.;Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA.;Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA..
    Perola, Markus
    Canc Res & Prevent Inst ISPO, I-50141 Florence, Italy.;Univ Helsinki, Inst Mol Med Finland FIMM, FI-00014 Helsinki, Finland..
    Peters, Annette
    DZHK German Ctr Cardiovasc Res, Partner Site Munich Heart Alliance, D-80802 Munich, Germany.;German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol 2, D-85764 Neuherberg, Germany..
    Poole, Christopher J.
    Univ Warwick, Coventry CV4 7AL, W Midlands, England.;Univ Hosp Coventry & Warwickshire, Arden Canc Ctr, Dept Med Oncol, Coventry CV2 2DX, W Midlands, England..
    Quiros, J. Ramn
    Publ Hlth Directorate, Oviedo 33006, Asturias, Spain..
    Rolandsson, Olov
    Umea Univ, S-90187 Umea, Sweden..
    Sacerdote, Carlotta
    Univ Turin, Citta Salute & Sci Hosp, Unit Canc Epidemiol, I-10126 Turin, Italy.;Ctr Canc Prevent CPO, I-10126 Turin, Italy.;Human Genet Fdn, I-10126 Turin, Italy..
    Salomaa, Veikko
    Natl Inst Hlth & Welfare, FI-00271 Helsinki, Finland..
    Sanchez, Mara-Jose
    CIBER Epidemiol & Salud Publ CIBERESP, Madrid 28029, Spain.;Univ Granada, Hosp Univ Granada, Inst Invest Biosanitaria Ibs GRANADA, Escuela Andaluza Salud Publ, Granada 18012, Spain..
    Sattar, Naveed
    Univ Glasgow, Glasgow G12 8QQ, Lanark, Scotland..
    Sharp, Stephen J.
    Univ Cambridge, Sch Clin Med, MRC, Epidemiol Unit,Inst Metab Sci, Cambridge Biomedical Campus, Cambridge CB2 0QQ, England..
    Sims, Rebecca
    Cardiff Univ, MRC Ctr, Inst Psychol Med & Clin Neurosci, Cardiff CF24 4HQ, S Glam, Wales..
    Slimani, Nadia
    Int Agcy Res Canc, F-69372 Lyon, France..
    Smith, Jennifer A.
    Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA..
    Thompson, Deborah J.
    Univ Cambridge, Ctr Canc Genet Epidemiol, Dept Publ Hlth & Primary Care, Strangeways Lab, Cambridge CB1 8RN, England..
    Trompet, Stella
    Leiden Univ, Med Ctr, NL-2333 AA Leiden, Netherlands..
    Tumino, Rosario
    ASP Ragusa, Civ MP Arezzo Hosp, Canc Registry & Histopathol Unit, I-97100 Ragusa, Italy..
    van der A, Daphne L.
    Natl Inst Publ Hlth & Environm RIVM, NL-3720 BA Bilthoven, Netherlands..
    van der Schouw, Yvonne T.
    Univ Med Ctr Utrecht, NL-3508 GA Utrecht, Netherlands..
    Virtamo, Jarmo
    Natl Inst Hlth & Welfare, FI-00271 Helsinki, Finland..
    Walker, Mark
    Newcastle Univ, Inst Cellular Med, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England..
    Walter, Klaudia
    Wellcome Trust Sanger Inst, Cambridge CB10 1SA, England..
    Abraham, Jean E.
    Univ Cambridge, Dept Oncol, Strangeways Lab, Ctr Canc Genet Epidemiol, Worts Causeway, Cambridge CB1 8RN, England..
    Amundadottir, Laufey T.
    NCI, Lab Translat Genom, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA..
    Aponte, Jennifer L.
    GlaxoSmithKline, PCPS, Genet, Res Triangle Pk, NC 27709 USA..
    Butterworth, Adams.
    Univ Cambridge, Strangeways Res Lab, Dept Publ Hlth & Primary Care, Cambridge CB1 8RN, England..
    Dupuis, Josee
    Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA..
    Easton, Douglas F.
    Univ Cambridge, Ctr Canc Genet Epidemiol, Dept Publ Hlth & Primary Care, Strangeways Lab, Cambridge CB1 8RN, England.;Univ Cambridge, Dept Oncol, Strangeways Lab, Ctr Canc Genet Epidemiol, Worts Causeway, Cambridge CB1 8RN, England..
    Eeles, Rosalind A.
    Inst Canc Res, Sutton SM2 5NG, Surrey, England.;Royal Marsden NHS Fdn Trust, London SW3 6JJ, England.;Royal Marsden NHS Fdn Trust, Surrey SW3 6JJ, England..
    Erdmann, Jeanette
    Med Univ Lubeck, Inst Integrat & Expt Genom, D-23562 Lubeck, Germany..
    Franks, Paul W.
    Lund Univ, Genet & Mol Epidemiol Unit, Dept Clin Sci, SE-205 Malmo, Sweden.;Umea Univ, Dept Publ Hlth & Clin Med, S-90185 Umea, Sweden.;Harvard Univ, TH Chan Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA..
    Frayling, Timothy M.
    Univ Exeter, Sch Med, Genet Complex Traits, Exeter EX1 2LU, Devon, England..
    Hansen, Torben
    Univ Copenhagen, NovoNordisk Fdn, Fac Hlth & Med Sci, Ctr Basic Metab Res, DK-2200 Copenhagen, Denmark..
    Howson, Joanna M. M.
    Univ Cambridge, Strangeways Res Lab, Dept Publ Hlth & Primary Care, Cambridge CB1 8RN, England..
    Jorgensen, Torben
    Res Ctr Prevent & Hlth, DK-2600 Capital Region, Denmark.;Univ Copenhagen, Inst Hlth Sci, Dept Publ Hlth, DK-1014 Copenhagen, Denmark.;Aalborg Univ, Fac Med, DK-9220 Aalborg, Denmark..
    Kooner, Jaspal
    Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, London SW3 6LY, England.;Imperial Coll Healthcare NHS Trust, London W2 1NY, England.;Ealing Hosp NHS Trust, Southall UB1 3HW, Middx, England..
    Laakso, Markku
    Univ Kuopio, Dept Med, FI-70211 Kuopio, Finland..
    Langenberg, Claudia
    Univ Cambridge, Sch Clin Med, MRC, Epidemiol Unit,Inst Metab Sci, Cambridge Biomedical Campus, Cambridge CB2 0QQ, England..
    McCarthy, Mark I.
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England.;Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab OCDEM, Oxford OX3 7LE, England..
    Pankow, James S.
    Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN 55455 USA..
    Pedersen, Oluf
    Univ Copenhagen, NovoNordisk Fdn, Fac Hlth & Med Sci, Ctr Basic Metab Res, DK-2200 Copenhagen, Denmark..
    Riboli, Elio
    Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, London W2 1PG, England..
    Rotter, Jerome I.
    Harbor Univ Calif Los Angeles, Med Ctr, Los Angeles Biomed Res Inst, Inst Translat Genom & Populat Sci, Torrance, CA 90502 USA..
    Saleheen, Danish
    Univ Penn, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA..
    Samani, Nilesh J.
    Univ Leicester, Glenfield Hosp, Dept Cardiovasc Sci, Leicester LE3 9QP, Leics, England.;Glenfield Hosp, Natl Inst Hlth Res, Leicester Cardiovasc Biomed Res Unit, Leicester LE3 9QP, Leics, England..
    Schunkert, Heribert
    DZHK German Ctr Cardiovasc Res, Partner Site Munich Heart Alliance, D-80802 Munich, Germany.;Tech Univ Munich, Deutsch Herzzentrum Munchen, D-80636 Munich, Germany..
    Vollenweider, Peter
    Lausanne Univ Hosp CHUV, Dept Internal Med, Internal Med, BH10-462, CH-1011 Lausanne, Switzerland..
    O'Rahilly, Stephen
    Univ Cambridge, Wellcome Trust MRC Inst Metab Sci, Metab Res Labs, Cambridge CB2 0QQ, England.;MRC Metab Dis Unit, Cambridge CB2 0QQ, England.;Natl Inst Hlth Res, Cambridge Biomed Res Ctr, Cambridge CB2 0QQ, England..
    Deloukas, Panos
    Queen Mary Univ London, Barts & London Sch Med & Dent, William Harvey Res Inst, London EC1M 6BQ, England..
    Danesh, John
    Univ Cambridge, Strangeways Res Lab, Dept Publ Hlth & Primary Care, Cambridge CB1 8RN, England.;Wellcome Trust Sanger Inst, Cambridge CB10 1SA, England..
    Goodarzi, Mark O.
    Cedars Sinai Med Ctr, Div Endocrinol Diabet & Metab, Los Angeles, CA 90048 USA..
    Kathiresan, Sekar
    Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA.;Broad Inst Harvard & MIT, Cambridge, MA 02142 USA.;Massachusetts Gen Hosp, Ctr Human Genet Res, Cardiol Div, Boston, MA 02114 USA.;Harvard Univ, Sch Med, Boston, MA 02114 USA..
    Meigs, James B.
    Massachusetts Gen Hosp, Dept Med, Div Gen Internal Med, Boston, MA 02114 USA.;Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA..
    Ehm, Margaret G.
    GlaxoSmithKline, PCPS, Genet, Res Triangle Pk, NC 27709 USA..
    Wareham, Nicholas J.
    Univ Cambridge, Sch Clin Med, MRC, Epidemiol Unit,Inst Metab Sci, Cambridge Biomedical Campus, Cambridge CB2 0QQ, England..
    Waterworth, Dawn M.
    GlaxoSmithKline, PCPS, Genet, Philadelphia, PA 19104 USA..
    A genomic approach to therapeutic target validation identifies a glucose-lowering GLP1R variant protective for coronary heart disease2016In: Science Translational Medicine, ISSN 1946-6234, E-ISSN 1946-6242, Vol. 8, no 341, article id 341ra76Article in journal (Refereed)
    Abstract [en]

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

  • 265.
    Scott, Robert A.
    et al.
    Univ Cambridge, MRC Epidemiol Unit, Cambridge, England..
    Scott, Laura J.
    Univ Michigan, Dept Biostatist & Ctr Stat Genet, Ann Arbor, MI USA..
    Maegi, Reedik
    Univ Tartu, Estonian Genome Ctr, Tartu, Estonia..
    Marullo, Letizia
    Univ Ferrara, Dept Life Sci & Biotechnol, Ferrara, Italy..
    Gaulton, Kyle J.
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.;Stanford Univ, Dept Genet, Stanford, CA USA..
    Kaakinen, Marika
    Imperial Coll London, Dept Genom Common Dis, London, England..
    Pervjakova, Natalia
    Univ Tartu, Estonian Genome Ctr, Tartu, Estonia..
    Pers, Tune H.
    Broad Inst & Harvard, Program Med & Populat Genet, Cambridge, MA USA.;Boston Childrens Hosp, Div Endocrinol, Ctr Basic & Translat Obes Res, Boston, MA USA.;Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Copenhagen, Denmark.;Statens Serum Inst, Dept Epidemiol Res, Copenhagen, Denmark..
    Johnson, Andrew D.
    Natl Heart Lung & Blood Inst, Div Intramural Res, Framingham Heart Study Populat Sci Branch, Framingham, MA USA..
    Eicher, John D.
    Natl Heart Lung & Blood Inst, Div Intramural Res, Framingham Heart Study Populat Sci Branch, Framingham, MA USA..
    Jackson, Anne U.
    Univ Michigan, Dept Biostatist & Ctr Stat Genet, Ann Arbor, MI USA..
    Ferreira, Teresa
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England..
    Lee, Yeji
    Univ Michigan, Dept Biostatist & Ctr Stat Genet, Ann Arbor, MI USA..
    Ma, Clement
    Univ Michigan, Dept Biostatist & Ctr Stat Genet, Ann Arbor, MI USA..
    Steinthorsdottir, Valgerdur
    Amgen Inc, DECODE genet, Reykjavik, Iceland..
    Thorleifsson, Gudmar
    Amgen Inc, DECODE genet, Reykjavik, Iceland..
    Qi, Lu
    Harvard T H Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA.;Harvard T H Chan Sch Publ Hlth, Dept Nutr, Boston, MA USA.;Brigham & Womens Hosp, Channing Div Network Med, Dept Med, Boston, MA USA.;Harvard Med Sch, Boston, MA USA..
    Van Zuydam, Natalie R.
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England..
    Mahajan, Anubha
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England..
    Chen, Han
    Univ Texas Hlth Sci Ctr, Sch Publ Hlth, Human Genet Ctr & Dept Epidemiol, Human Genet Environm Sci, Houston, TX USA.;Univ Texas Hlth Sci Ctr, Sch Biomed Informat, Sch Biomed Informat, Ctr Precis Hlth, Houston, TX USA..
    Almgren, Peter
    Lund Univ, Univ Hosp Scania, Dept Clin Sci Malmo, Lund Univ Diabet Ctr, Lund, Sweden..
    Voight, Ben F.
    Univ Penn sylvania, Perelman Sch Med, Dept Pharm, Philadelphia, PA USA.;Univ Pennsylvania, Perelman Sch Med, Dept Genet, Philadelphia, PA USA.;Univ Pennsylvania, Perelman Sch Medi cine, Inst Translat Med & Therapeut, Philadelphia, PA USA..
    Grallert, Harald
    Res Unit Mol Epidemiol, German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Neuherberg, Germany.;German Ctr Diabet Res, Neuherberg, Germany..
    Mueller-Nurasyid, Martina
    German Res Ctr Environm Hlth, Inst Genet Epidemiol, Helmholtz Zentrum Munchen, Neuherberg, Germany.;Univ Hosp Grosshadern, Ludwig Maximilians Univ, Dep Med I, Munich, Germany.;Ludwig Maximilians Univ Munchen, Inst Med Informat, Genet Epidemiol, Biometry & Epidemiol, Munich, Germany.;Munich Heart Alliance, German Ctr Cardiovascular Dis, Munich, Germany..
    Ried, Janina S.
    German Res Ctr Environm Hlth, Inst Genet Epidemiol, Helmholtz Zentrum Munchen, Neuherberg, Germany..
    Rayner, Nigel W.
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Oxford, Oxford Ctr Diabet, Endocrinol & Metab, Oxford, England.;Wellcome Trust Sanger Inst, Hinxton, England..
    Robertson, Neil
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Oxford, Oxford Ctr Diabet, Endocrinol & Metab, Oxford, England..
    Karssen, Lennart C.
    Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands.;Polyomica S Hertogenbosch, Amsterdam, Netherlands..
    Van Leeuwen, Elisabeth M.
    Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands..
    Willems, Sara M.
    Univ Cambridge, MRC Epidemiol Unit, Cambridge, England.;Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands..
    Fuchsberger, Christian
    Univ Michigan, Dept Biostatist & Ctr Stat Genet, Ann Arbor, MI USA..
    Kwan, Phoenix
    Univ Michigan, Dept Biostatist & Ctr Stat Genet, Ann Arbor, MI USA..
    Teslovich, Tanya M.
    Univ Michigan, Dept Biostatist & Ctr Stat Genet, Ann Arbor, MI USA..
    Chanda, Pritam
    Johns Hopkins Univ Sch Med, High Throughput Biol Ctr, Baltimore, MD USA..
    Li, Man
    Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA..
    Lu, Yingchang
    Charles Bronfman Inst Personalized Med, Icahn Sch Med, Mt Sinai, New York, NY USA.;Icahn Sch Med, Genet Obes & Related Metab Traits Program, Mt Sinai, New York, NY USA..
    Dina, Christian
    Univ Nantes, CNRS, Inst Thorax, Ctr Hosp Univ Nantes, Nantes, France..
    Thuillier, Dorothee
    Lille Inst Biol, European Genom Inst Diabet, Lille, France.;Univ Lille, CNRS UMR 8199, European Genom Inst Diabet EGID, Inst Pasteur Lille, Lille, France..
    Yengo, Loic
    Lille Inst Biol, European Genom Inst Diabet, Lille, France.;Univ Lille, CNRS UMR 8199, European Genom Inst Diabet EGID, Inst Pasteur Lille, Lille, France..
    Jiang, Longda
    Imperial Coll London, Dept Genom Common Dis, London, England..
    Sparso, Thomas
    Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Copenhagen, Denmark..
    Kestler, Hans A.
    Fritz Lipmann Inst, Leibniz Inst Aging, Jena, Germany.;Univ Ulm, Inst Med Syst Biol, Ulm, Germany..
    Chheda, Himanshu
    Univ Helsinki, Inst Mol Med Finland, Helsinki, Finland..
    Eisele, Lewin
    Univ Hosp Essen, Inst Med Informat, Biometry & Epidemiol, Essen, Germany..
    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.
    Franberg, Mattias
    Karolinska Inst, Dept Med Solna, Cardiovascular Med Unit, Stockholm, Sweden.;Sci Life Lab, Stockholm, Sweden.;Stockholm Univ, Dept Numer Anal & Comp Sci, Stockholm, Sweden..
    Strawbridge, Rona J.
    Karolinska Inst, Dept Med Solna, Cardiovascular Med Unit, Stockholm, Sweden..
    Benediktsson, Rafn
    Univ Iceland, Fac Med, Reykjavik, Iceland.;Landspitali Univ Hosp, Reykjavik, Iceland..
    Hreidarsson, Astradur B.
    Landspitali Univ Hosp, Reykjavik, Iceland..
    Kong, Augustine
    Amgen Inc, DECODE genet, Reykjavik, Iceland..
    Sigurdsson, Gunnar
    Landspitali Univ Hosp, Reykjavik, Iceland.;Iceland Heart Assoc, Kopavogur, Iceland..
    Kerrison, Nicola D.
    Univ Cambridge, MRC Epidemiol Unit, Cambridge, England..
    Luan, Jian'an
    Univ Cambridge, MRC Epidemiol Unit, Cambridge, England..
    Liang, Liming
    Harvard T H Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA.;Harvard T H Chan Sch Publ Hlth, Dept Biostatist, Boston, MA USA..
    Meitinger, Thomas
    Munich Heart Alliance, German Ctr Cardiovascular Dis, Munich, Germany.;Fritz Lipmann Inst, Leibniz Inst Aging, Jena, Germany.;Inst Human Genet, Helmholtz Zentrum Munchen, Neuherberg, Germany. Tech Univ Munich, Inst Human Genet, Munich, Germany..
    Roden, Michael
    German Ctr Diabet Res, Neuherberg, Germany.;Heinrich Heine Univ, Fac Med, Dept Endocrinol & Diabet, Dusseldorf, Germany.;Heinrich Heine Univ Dusseldorf, Leibniz Inst Diabet Res, German Diabet Ctr, Inst Clin Diabetol, Dusseldorf, Germany..
    Thorand, Barbara
    German Ctr Diabet Res, Neuherberg, Germany..
    Esko, Tonu
    Univ Tartu, Estonian Genome Ctr, Tartu, Estonia.;Broad Inst & Harvard, Program Med & Populat Genet, Cambridge, MA USA.;Boston Childrens Hosp, Divis Genet & Endocrinol, Boston, MA USA.;Natl Heart Lung & Blood Inst, Framingham Heart Study, Framingham, MA USA..
    Mihailov, Evelin
    Univ Tartu, Estonian Genome Ctr, Tartu, Estonia..
    Fox, Caroline
    Harvard Med Sch, Divis Endocrinol, Diabet & Hypertens, Brigham & Womens Hosp, Boston, MA USA..
    Liu, Ching-Ti
    Boston Univ Sch Publ Hlth, Dept Biostat, Boston, MA USA..
    Rybin, Denis
    Boston Univ Sch Publ Hlth, Data Coordinating Ctr, Boston, MA USA..
    Isomaa, Bo
    Folkhalsan Res Ctr, Helsinki, Finland.;Dept Social Serv & Hlth Care, Pietarsaari, Finland..
    Lyssenko, Valeriya
    Lund Univ, Univ Hosp Scania, Dept Clin Sci Malmo, Lund Univ Diabet Ctr, Lund, Sweden..
    Tuomi, Tiinamaija
    Folkhalsan Res Ctr, Helsinki, Finland.;Univ Helsinki, Helsinki Univ Hosp, Dept Med, Helsinki, Finland..
    Couper, David J.
    Univ N Carolina, Dept Biostatist, Collaborat Studies Coordinating Ctr, Chapel Hill, NC USA..
    Pankow, James S.
    Univ Minnesota, Divis Epidemiol Community Hlth, Minneapolis, MN USA..
    Grarup, Niels
    Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Copenhagen, Denmark..
    Have, Christian T.
    Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Copenhagen, Denmark..
    Jorgensen, Marit E.
    Steno Diabet Ctr, Gentofte, Denmark..
    Jorgensen, Torben
    Capital Region Denmark, Res Ctr Prevent & Hlth, Copenhagen, Denmark.;Univ Copenhagen, Fac Hlth & Med Sci, Copenhagen, Denmark.;Aalborg Univ, Fac Med, Aalborg, Denmark..
    Linneberg, Allan
    Capital Region Denmark, Res Ctr Prevent & Hlth, Copenhagen, Denmark.;Copenhagen Univ Hosp, Rigshospitalet, Copenhagen, Denmark. Univ Copenhagen, Fac Hlth & Med Sci, Dept Clin Med, DK-1168 Copenhagen, Denmark..
    Cornelis, Marilyn C.
    NW Univ Feinberg Sch Med, Dept Prevent Med, Chicago, IL USA..
    Van Dam, Rob M.
    Harvard T H Chan Sch Publ Hlth, Dept Nutr, Boston, MA USA.;Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore, Singapore..
    Hunter, David J.
    Harvard T H Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA.;Harvard T H Chan Sch Publ Hlth, Dept Nutr, Boston, MA USA.;Brigham & Womens Hosp, Channing Div Network Med, Dept Med, Boston, MA USA.;Harvard Med Sch, Boston, MA USA.;Harvard T H Chan Sch Publ Hlth, Program Genet Epidemiol & Stat Genet, Boston, MA USA..
    Kraft, Peter
    Harvard T H Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA.;Harvard T H Chan Sch Publ Hlth, Dept Biostatist, Boston, MA USA.;Harvard T H Chan Sch Publ Hlth, Program Genet Epidemiol & Stat Genet, Boston, MA USA..
    Sun, Qi
    Harvard T H Chan Sch Publ Hlth, Dept Nutr, Boston, MA USA.;Brigham & Womens Hosp, Channing Div Network Med, Dept Med, Boston, MA USA.;Harvard Med Sch, Boston, MA USA..
    Edkins, Sarah
    Wellcome Trust Sanger Inst, Hinxton, England..
    Owen, Katharine R.
    Univ Oxford, Oxford Ctr Diabet, Endocrinol & Metab, Oxford, England.;Natl Inst Hlth Res Oxford Biomed Res Ctr, Churchill Hosp, Oxford, England..
    Perry, John R. B.
    Univ Cambridge, MRC Epidemiol Unit, Cambridge, England..
    Wood, Andrew R.
    Univ Exeter Med Sch, Univ Exeter, Genet Complex Traits, Exeter, Devon, England..
    Zeggini, Eleftheria
    Wellcome Trust Sanger Inst, Hinxton, England..
    Tajes-Fernandes, Juan
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England..
    Abecasis, Goncalo R.
    Univ Michigan, Dept Biostatist & Ctr Stat Genet, Ann Arbor, MI USA..
    Bonnycastle, Lori L.
    Natl Human Genome Res Inst, Natl Inst Hlth, Bethesda, MD USA..
    Chines, Peter S.
    Natl Human Genome Res Inst, Natl Inst Hlth, Bethesda, MD USA..
    Stringham, Heather M.
    Univ Michigan, Dept Biostatist & Ctr Stat Genet, Ann Arbor, MI USA..
    Koistinen, Heikki A.
    Natl Inst Hlth & Welf, Dept Hlth, Helsinki, Finland.;Univ Helsinki, Helsinki Univ Cent Hosp, Dept Med & Abdominal Ctr, Endocrinol, Helsinki, Finland.;Biomedicum Helsinki 2U, Minerva Fdn Inst Med Res, Helsinki, Finland..
    Kinnunen, Leena
    Natl Inst Hlth & Welf, Dept Hlth, Helsinki, Finland.;Univ Helsinki, Helsinki Univ Cent Hosp, Dept Med & Abdominal Ctr, Endocrinol, Helsinki, Finland.;Biomedicum Helsinki 2U, Minerva Fdn Inst Med Res, Helsinki, Finland..
    Sennblad, Bengt
    Karolinska Inst, Dept Med Solna, Cardiovascular Med Unit, Stockholm, Sweden.;Sci Life Lab, Stockholm, Sweden..
    Muehleisen, Thomas W.
    Univ Bonn, Inst Human Genet, Bonn, Germany.;Univ Bonn, Dept Genom, Life Brain Ctr, Bonn, Germany..
    Noethen, Markus M.
    Univ Bonn, Inst Human Genet, Bonn, Germany.;Univ Bonn, Dept Genom, Life Brain Ctr, Bonn, Germany..
    Pechlivanis, Sonali
    Univ Hosp Essen, Inst Med Informat, Biometry & Epidemiol, Essen, Germany..
    Baldassarre, Damiano
    Ist Ricovero Cura Carattere Sci, Ctr Cardiologico Monzino, Milan, Italy.;Univ Milan, Dipartimento Sci Farmacol Biomol, Milan, Italy..
    Gertow, Karl
    Karolinska Inst, Dept Med Solna, Cardiovascular Med Unit, Stockholm, Sweden..
    Humphries, Steve E.
    UCL, Inst Cardiovascular Sci, BHF Labs, Cardiovascular Genet, London, England..
    Tremoli, Elena
    Ist Ricovero Cura Carattere Sci, Ctr Cardiologico Monzino, Milan, Italy.;Univ Milan, Dipartimento Sci Farmacol Biomol, Milan, Italy..
    Klopp, Norman
    Res Unit Mol Epidemiol, German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Neuherberg, Germany.;Hannover Med Sch, Hannover Unified Biobank, Hannover, Germany..
    Meyer, Julia
    German Res Ctr Environm Hlth, Inst Genet Epidemiol, Helmholtz Zentrum Munchen, Neuherberg, Germany..
    Steinbach, Gerald
    Univ Ulm, Dept Clin Chem & Cent Lab, Ulm, Germany..
    Wennauer, Roman
    Erasmus MC, Dept Internal Med, Rotterdam, Netherlands..
    Eriksson, Johan G.
    Folkhalsan Res Ctr, Helsinki, Finland.;Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland.;Univ Helsinki, Dept Gen Practice & Primary Hlth Care, Helsinki, Finland.;Helsinki Univ Cent Hosp, Unit Gen Practice, Helsinki, Finland..
    Mannisto, Satu
    Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland..
    Peltonen, Leena
    Wellcome Trust Sanger Inst, Hinxton, England.;Univ Helsinki, Inst Mol Med Finland, Helsinki, Finland.;Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland.;Broad Inst & Harvard, Cambridge, MA USA..
    Tikkanen, Emmi
    Univ Helsinki, Inst Mol Med Finland, Helsinki, Finland.;Univ Helsinki, Hjelt Inst, Dept Publ Hlth, Helsinki, Finland..
    Charpentier, Guillaume
    Corbeil Essonnes Hosp, Endocrinol Diabetol Unit, Corbeil Essonnes, France..
    Eury, Elodie
    Univ Lille, CNRS UMR 8199, European Genom Inst Diabet EGID, Inst Pasteur Lille, Lille, France..
    Lobbens, Stephane
    Univ Lille, CNRS UMR 8199, European Genom Inst Diabet EGID, Inst Pasteur Lille, Lille, France..
    Gigante, Bruna
    Inst Environm Medi cine, Karolinska Inst, Divis Cardiovascular Epidemiol, Stockholm, Sweden..
    Leander, Karin
    Inst Environm Medi cine, Karolinska Inst, Divis Cardiovascular Epidemiol, Stockholm, Sweden..
    McLeod, Olga
    Karolinska Inst, Dept Med Solna, Cardiovascular Med Unit, Stockholm, Sweden..
    Bottinger, Erwin P.
    Charles Bronfman Inst Personalized Med, Icahn Sch Med, Mt Sinai, New York, NY USA..
    Gottesman, Omri
    Charles Bronfman Inst Personalized Med, Icahn Sch Med, Mt Sinai, New York, NY USA..
    Ruderfer, Douglas
    Icahn Sch Med, Dept Psychiat, Divis Psychiat Genom, Mt Sinai, New York, NY USA..
    Blueher, Matthias
    Univ Leipzig, IFB Adiposity Dis, Leipzig, Germany.;Univ Leipzig, Dept Med, Leipzig, Germany..
    Kovacs, Peter
    Univ Leipzig, IFB Adiposity Dis, Leipzig, Germany.;Univ Leipzig, Dept Med, Leipzig, Germany..
    Tonjes, Anke
    Univ Leipzig, IFB Adiposity Dis, Leipzig, Germany.;Univ Leipzig, Dept Med, Leipzig, Germany..
    Maruthur, Nisa M.
    Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA.;Johns Hopkins Bloomberg Sch Med, Dept Med, Divis Gen Internal Med, Baltimore, MD USA.;Johns Hopkins Univ, Welch Ctr Prevent, Epidemiol & Clin Res, Baltimore, MD USA..
    Scapoli, Chiara
    Univ Ferrara, Dept Life Sci & Biotechnol, Ferrara, Italy..
    Erbel, Raimund
    Univ Hosp Essen, Inst Med Informat, Biometry & Epidemiol, Essen, Germany..
    Joeckel, Karl-Heinz
    Univ Hosp Essen, Inst Med Informat, Biometry & Epidemiol, Essen, Germany..
    Moebus, Susanne
    Univ Hosp Essen, Inst Med Informat, Biometry & Epidemiol, Essen, Germany..
    De Faire, Ulf
    Inst Environm Medi cine, Karolinska Inst, Divis Cardiovascular Epidemiol, Stockholm, Sweden..
    Hamsten, Anders
    Karolinska Inst, Dept Med Solna, Cardiovascular Med Unit, Stockholm, Sweden..
    Stumvoll, Michael
    Univ Leipzig, IFB Adiposity Dis, Leipzig, Germany.;Univ Leipzig, Dept Med, Leipzig, Germany..
    Deloukas, Panagiotis
    Wellcome Trust Sanger Inst, Hinxton, England.;Queen Mary Univ London, William Harvey Res Inst, Barts & London Sch Med & Dent, London, England..
    Donnelly, Peter J.
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Oxford, Dept Stat, Oxford, England..
    Frayling, Timothy M.
    Univ Exeter Med Sch, Univ Exeter, Genet Complex Traits, Exeter, Devon, England..
    Hattersley, Andrew T.
    Univ Exeter Med Sch, Inst Biomed & Clin Sci, Exeter, Devon, England..
    Ripatti, Samuli
    Wellcome Trust Sanger Inst, Hinxton, England.;Univ Helsinki, Inst Mol Med Finland, Helsinki, Finland.;Univ Helsinki, Hjelt Inst, Dept Publ Hlth, Helsinki, Finland.;Natl Inst Hlth & Welf, Publ Hlth Genom Unit, Helsinki, Finland..
    Salomaa, Veikko
    Natl Inst Hlth & Welf, Dept Hlth, Helsinki, Finland..
    Pedersen, Nancy L.
    Karolinska Inst tutet, Dept Med Epidemiol & Biostatist, Stockholm, Sweden..
    Boehm, Bernhard O.
    Univ Med Ctr Ulm, Dept Internal Med, Divis Endocrinol & Diabet, Ulm, Germany.;Nanyang Technol Univ, Imperial Coll London, Lee Kong Chian Sch Med, Singapore, Singapore..
    Bergman, Richard N.
    Cedars Sinai Med Ctr, Diabetes & Obes Res Inst, Los Angeles, CA USA..
    Collins, Francis S.
    Natl Human Genome Res Inst, Natl Inst Hlth, Bethesda, MD USA..
    Mohlke, Karen L.
    Univ N Carolina, Dept Genet, Chapel Hill, NC USA..
    Tuomilehto, Jaakko
    Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland.;Dasman Diabet Inst, Dasman, Kuwait.;Danube Univ Krems, Ctr Vasc Prevent, Krems, Austria.;King Abdulaziz Univ, Diabetes Res Grp, Jeddah, Saudi Arabia..
    Hansen, Torben
    Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Copenhagen, Denmark.;Univ So Denmark, Fac Hlth Sci, Odense, Denmark..
    Pedersen, Oluf
    Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Copenhagen, Denmark..
    Barroso, Ines
    Wellcome Trust Sanger Inst, Hinxton, England.;Addenbrookes Hosp Cambridge, Wellcome Trust MRC Inst Metab Sci, Hlth Res Cambridge Biomed Res Ctr, Cambridge, England.;Univ Cambridge Metab Res Labs, Wellcome Trust MRC Inst Metab Sci, Hlth Res Cambridge Biomed Res Ctr, Cambridge, England..
    Lannfelt, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Ingelsson, Erik
    Uppsala University, 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.
    Lindgren, Cecilia M.
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.;Broad Inst & Harvard, Cambridge, MA USA..
    Cauchi, Stephane
    Lille Inst Biol, European Genom Inst Diabet, Lille, France..
    Froguel, Philippe
    Imperial Coll London, Dept Genom Common Dis, London, England.;Lille Inst Biol, European Genom Inst Diabet, Lille, France.;Univ Lille, CNRS UMR 8199, European Genom Inst Diabet EGID, Inst Pasteur Lille, Lille, France..
    Loos, Ruth J. F.
    Charles Bronfman Inst Personalized Med, Icahn Sch Med, Mt Sinai, New York, NY USA.;Icahn Sch Med, Genet Obes & Related Metab Traits Program, Mt Sinai, New York, NY USA.;Mindich Child Hlth & Dev Inst, Icahn Sch Med, Mt Sinai, New York, NY USA..
    Balkau, Beverley
    INSERM, CESP, UMR 1018, Villejuif, France.;Univ Paris Sud, UMR 1018, Villejuif, France..
    Boeing, Heiner
    German Inst Human Nutr Potsdam Rehbrucke, Nuthetal, Germany..
    Franks, Paul W.
    Lund Univ, Malmo, Sweden.;Umea Univ, Umea, Sweden..
    Gurrea, Aurelio Barricarte
    Navarra Publ Hlth Inst, Pamplona, Spain.;Navarra Inst Hlth Res, Pamplona, Spain.;CIBER Epidemiol & Publ Hlth, Madrid, Spain..
    Palli, Domenico
    Canc Res & Prevent Inst, Florence, Italy..
    Van der Schouw, Yvonne T.
    Univ Med Ctr Utrecht, Utrecht, Netherlands..
    Altshuler, David
    Broad Inst & Harvard, Cambridge, MA USA.;Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA USA.;Harvard Med Sch, Dept Med, Boston, MA USA.;Harvard Med Sch, Dept Genet, Boston, MA USA.;Harvard Med Sch, Dept Mol Biol, Boston, MA USA.;Massachusetts Gen Hosp, Diabet Unit, Boston, MA USA..
    Groop, Leif C.
    Lund Univ, Univ Hosp Scania, Dept Clin Sci Malmo, Lund Univ Diabet Ctr, Lund, Sweden.;Univ Helsinki, Inst Mol Med Finland, Helsinki, Finland..
    Langenberg, Claudia
    Univ Cambridge, MRC Epidemiol Unit, Cambridge, England..
    Wareham, Nicholas J.
    Univ Cambridge, MRC Epidemiol Unit, Cambridge, England..
    Sijbrands, Eric
    Erasmus MC, Dept Internal Med, Rotterdam, Netherlands..
    Van Duijn, Cornelia M.
    Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands.;Healthy Ageing & Ctr Med Syst Biol, Netherlands Consortium, Netherlands Genom Initiat, Rotterdam, Netherlands..
    Florez, Jose C.
    Broad Inst & Harvard, Program Med & Populat Genet, Cambridge, MA USA.;Harvard Med Sch, Dept Med, Boston, MA USA.;Massachusetts Gen Hosp, Ctr Human Genet Res, Diabet Unit, Boston, MA USA..
    Meigs, James B.
    Broad Inst & Harvard, Program Med & Populat Genet, Cambridge, MA USA.;Amgen Inc, DECODE genet, Reykjavik, Iceland.;Harvard Med Sch, Dept Med, Boston, MA USA.;Massachusetts Gen Hosp, Gen Med Divis, Boston, MA USA..
    Boerwinkle, Eric
    Univ Texas Hlth Sci Ctr, Human Genet Ctr, Houston, TX USA.;Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX USA..
    Gieger, Christian
    Res Unit Mol Epidemiol, German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Neuherberg, Germany.;German Res Ctr Environm Hlth, Inst Epidemiol II, Helmholtz Zentrum Munchen, Neuherberg, Germany..
    Strauch, Konstantin
    German Res Ctr Environm Hlth, Inst Genet Epidemiol, Helmholtz Zentrum Munchen, Neuherberg, Germany.;Ludwig Maximilians Univ Munchen, Inst Med Informat, Genet Epidemiol, Biometry & Epidemiol, Munich, Germany..
    Metspalu, Andres
    Univ Tartu, Estonian Genome Ctr, Tartu, Estonia.;Univ Tartu, Inst Mol & Cell Biol, Tartu, Estonia..
    Morris, Andrew D.
    Univ Edinburgh, Usher Inst Populat Hlth Sci & Informat, Edinburgh, Midlothian, Scotland..
    Palmer, Colin N. A.
    Univ Dundee, Biomed Res Inst, Ninewells Hosp, Cardiovascular & Diabet Med, Dundee, Scotland..
    Hu, Frank B.
    Harvard T H Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA.;Harvard T H Chan Sch Publ Hlth, Dept Nutr, Boston, MA USA.;Brigham & Womens Hosp, Channing Div Network Med, Dept Med, Boston, MA USA.;Harvard Med Sch, Boston, MA USA..
    Thorsteinsdottir, Unnur
    Amgen Inc, DECODE genet, Reykjavik, Iceland.;Univ Iceland, Fac Med, Reykjavik, Iceland..
    Stefansson, Kari
    Amgen Inc, DECODE genet, Reykjavik, Iceland.;Univ Iceland, Fac Med, Reykjavik, Iceland..
    Dupuis, Josee
    Boston Univ Sch Publ Hlth, Dept Biostat, Boston, MA USA..
    Morris, Andrew P.
    Univ Tartu, Estonian Genome Ctr, Tartu, Estonia.;Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Liverpool, Dept Biostat, Liverpool, Merseyside, England.;Univ Liverpool, Dept Mol & Clin Pharmacol, Liverpool, Merseyside, England..
    Boehnke, Michael
    Univ Michigan, Dept Biostatist & Ctr Stat Genet, Ann Arbor, MI USA..
    McCarthy, Mark I.
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Oxford, Oxford Ctr Diabet, Endocrinol & Metab, Oxford, England.;Natl Inst Hlth Res Oxford Biomed Res Ctr, Churchill Hosp, Oxford, England..
    Prokopenko, Inga
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.;Imperial Coll London, Dept Genom Common Dis, London, England.;Univ Oxford, Oxford Ctr Diabet, Endocrinol & Metab, Oxford, England..
    An Expanded Genome-Wide Association Study of Type 2 Diabetes in Europeans2017In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 66, no 11, p. 2888-2902Article in journal (Refereed)
    Abstract [en]

    To characterize type 2 diabetes (T2D)-associated variation across the allele frequency spectrum, we conducted a meta-analysis of genome-wide association data from 26,676 T2D case and 132,532 control subjects of European ancestry after imputation using the 1000 Genomes multiethnic reference panel. Promising association signals were followed up in additional data sets (of 14,545 or 7,397 T2D case and 38,994 or 71,604 control subjects). We identified 13 novel T2D-associated loci (P < 5 x 10(-8)), including variants near the GLP2R, GIP, and HLA-DQA1 genes. Our analysis brought the total number of independent T2D associations to 128 distinct signals at 113 loci. Despite substantially increased sample size and more complete coverage of low-frequency variation, all novel associations were driven by common single nucleotide variants. Credible sets of potentially causal variants were generally larger than those based on imputation with earlier reference panels, consistent with resolution of causal signals to common risk haplotypes. Stratification of T2D-associated loci based on T2D-related quantitative trait associations revealed tissue-specific enrichment of regulatory annotations in pancreatic islet enhancers for loci influencing insulin secretion and in adipocytes, monocytes, and hepatocytes for insulin action-associated loci. These findings highlight the predominant role played by common variants of modest effect and the diversity of biological mechanisms influencing T2D pathophysiology.

  • 266.
    Shungin, Dmitry
    et al.
    Lund Univ, Diabet Ctr, Skane Univ Hosp, Dept Clin Sci,Genet & Mol Epidemiol Unit, Malmo, Sweden.;Umea Univ, Dept Odontol, Umea, Sweden.;Umea Univ, Dept Publ Hlth & Clin Med, Unit Med, Umea, Sweden.;MIT, Broad Inst, 77 Massachusetts Ave, Cambridge, MA 02139 USA.;Harvard Univ, Cambridge, MA 02138 USA..
    Deng, Wei Q.
    Univ Toronto, Dept Stat Sci, Toronto, ON, Canada..
    Varga, Tibor V.
    Lund Univ, Diabet Ctr, Skane Univ Hosp, Dept Clin Sci,Genet & Mol Epidemiol Unit, Malmo, Sweden.;Univ Copenhagen, Fac Hlth & Med Sci, Translat Dis Syst Biol Grp, Novo Nordisk Fdn Ctr Prot Res, Copenhagen, Denmark.;Lund Univ, Exercise Physiol Grp, Dept Hlth Sci, Lund, Sweden..
    Luan, Jian'an
    Univ Cambridge, Inst Metab Sci, Addenbrookes Hosp, MRC Epidemiol Unit, Cambridge, England..
    Mihailov, Evelin
    Univ Tartu, Estonian Genome Ctr, Tartu, Estonia..
    Metspalu, Andres
    Univ Tartu, Estonian Genome Ctr, Tartu, Estonia.;Univ Tartu, Inst Mol & Cell Biol, Tartu, Estonia..
    Morris, Andrew P.
    Univ Tartu, Estonian Genome Ctr, Tartu, Estonia.;Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Liverpool, Dept Biostat, Liverpool, Merseyside, England..
    Forouhi, Nita G.
    Univ Cambridge, Inst Metab Sci, Addenbrookes Hosp, MRC Epidemiol Unit, Cambridge, England..
    Lindgren, Cecilia
    MIT, Broad Inst, 77 Massachusetts Ave, Cambridge, MA 02139 USA.;Harvard Univ, Cambridge, MA 02138 USA.;Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England..
    Magnusson, Patrik K. E.
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Pedersen, Nancy L.
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Hallmans, Göran
    Umea Univ, Dept Biobank Res, Umea, Sweden..
    Chu, Audrey Y.
    Harvard Med Sch, Boston, MA USA..
    Justice, Anne E.
    Univ North Carolina Chapel Hill, Dept Epidemiol, Chapel Hill, NC USA..
    Graff, Mariaelisa
    Univ North Carolina Chapel Hill, Dept Epidemiol, Chapel Hill, NC USA..
    Winkler, Thomas W.
    Univ Regensburg, Dept Genet Epidemiol, Regensburg, DE, Germany..
    Rose, Lynda M.
    Brigham & Womens Hosp, Div Prevent Med, 75 Francis St, Boston, MA 02115 USA..
    Langenberg, Claudia
    Univ Cambridge, Inst Metab Sci, Addenbrookes Hosp, MRC Epidemiol Unit, Cambridge, England.;UCL, Dept Epidemiol & Publ Hlth, London, England..
    Cupples, L. Adrienne
    Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA.;NHLBI Framingham Heart Study, Framingham, MA USA..
    Ridker, Paul M.
    Harvard Med Sch, Boston, MA USA.;Brigham & Womens Hosp, Div Prevent Med, 75 Francis St, Boston, MA 02115 USA..
    Wareham, Nicholas J.
    Univ Cambridge, Inst Metab Sci, Addenbrookes Hosp, MRC Epidemiol Unit, Cambridge, England..
    Ong, Ken K.
    Univ Cambridge, Inst Metab Sci, Addenbrookes Hosp, MRC Epidemiol Unit, Cambridge, England..
    Loos, Ruth J. F.
    Icahn Sch Med Mt Sinai, Genet Obes & Related Metab Traits Program, New York, NY USA.;Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY USA.;Icahn Sch Med Mt Sinai, Mindich Child Hlth & Dev Inst, New York, NY USA..
    Chasman, Daniel I.
    Harvard Med Sch, Boston, MA USA.;Brigham & Womens Hosp, Div Prevent Med, 75 Francis St, Boston, MA 02115 USA..
    Ingelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Stanford Univ, Sch Med, Dept Med, Div Cardiovasc Med, Stanford, CA 94305 USA..
    Kilpeläinen, Tuomas O.
    Univ Copenhagen, Fac Hlth & Med Sci, Sect Metab Genet, Novo Nordisk Fdn Ctr Basic Metab Res, Copenhagen, Denmark..
    Scott, Robert A.
    Univ Cambridge, Inst Metab Sci, Addenbrookes Hosp, MRC Epidemiol Unit, Cambridge, England..
    Magi, Reedik
    Univ Tartu, Estonian Genome Ctr, Tartu, Estonia.;Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England..
    Pare, Guillaume
    McMaster Univ, Dept Pathol & Mol Med, Hamilton, ON, Canada..
    Franks, Paul W.
    Lund Univ, Diabet Ctr, Skane Univ Hosp, Dept Clin Sci,Genet & Mol Epidemiol Unit, Malmo, Sweden.;Umea Univ, Dept Publ Hlth & Clin Med, Unit Med, Umea, Sweden.;Harvard TH Chan Sch Publ Hlth, Dept Nutr, Boston, MA USA.;Univ Oxford, Radcliff Dept Med, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England..
    Ranking and characterization of established BMI and lipid associated loci as candidates for gene-environment interactions2017In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 13, no 6, article id e1006812Article in journal (Refereed)
    Abstract [en]

    Phenotypic variance heterogeneity across genotypes at a single nucleotide polymorphism (SNP) may reflect underlying gene-environment (GxE) or gene-gene interactions. We modeled variance heterogeneity for blood lipids and BMI in up to 44,211 participants and investigated relationships between variance effects (P-v), GxE interaction effects (with smoking and physical activity), and marginal genetic effects (P-m). Correlations between P-v and P-m were stronger for SNPs with established marginal effects (Spearman's rho = 0.401 for triglycerides, and rho = 0.236 for BMI) compared to all SNPs. When P-v and P-m were compared for all pruned SNPs, only BMI was statistically significant (Spearman's rho = 0.010). Overall, SNPs with established marginal effects were overrepresented in the nominally significant part of the P-v distribution (P-binomial < 0.05). SNPs from the top 1% of the P-m distribution for BMI had more significant P-v values (Pmann-Whitney = 1.46x10(-5)), and the odds ratio of SNPs with nominally significant (< 0.05) P-m and P-v was 1.33 (95% CI: 1.12, 1.57) for BMI. Moreover, BMI SNPs with nominally significant GxE interaction P-values (Pint < 0.05) were enriched with nominally significant P-v values (P-binomial = 8.63x10(-9) and 8.52x10(-7) for SNP x smoking and SNP x physical activity, respectively). We conclude that some loci with strong marginal effects may be good candidates for GxE, and variance-based prioritization can be used to identify them.

  • 267. Shungin, Dmitry
    et al.
    Winkler, Thomas W
    Croteau-Chonka, Damien C
    Ferreira, Teresa
    Locke, Adam E
    Mägi, Reedik
    Strawbridge, Rona J
    Pers, Tune H
    Fischer, Krista
    Justice, Anne E
    Workalemahu, Tsegaselassie
    Wu, Joseph M W
    Buchkovich, Martin L
    Heard-Costa, Nancy L
    Roman, Tamara S
    Drong, Alexander W
    Song, Ci
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    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.
    Day, Felix R
    Esko, Tonu
    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.
    Kutalik, Zoltán
    Luan, Jian'an
    Randall, Joshua C
    Scherag, André
    Vedantam, Sailaja
    Wood, Andrew R
    Chen, Jin
    Fehrmann, Rudolf
    Karjalainen, Juha
    Kahali, Bratati