ArticlemedRxiv : the preprint server for health sciences2023
Time-to-Event Genome-Wide Association Study for Incident Cardiovascular Disease in People with Type 2 Diabetes Mellitus.
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67 authors at 20 institutions in 5 countries.
Soo Heon KwakDepartment of Internal Medicine, Seoul National University Hospital, Seoul, Korea.
Ryan B Hernandez-CancelaDepartment of Biostatistics, Boston University School of Public Health, Boston, MA.
Daniel A DiCorpoDepartment of Biostatistics, Boston University School of Public Health, Boston, MA.
David E CondonSanford Imagenetics, Sanford Health, Sioux Falls, SD.
Jordi MerinoPrograms in Metabolism and Medical & Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA.
Peitao WuDepartment of Biostatistics, Boston University School of Public Health, Boston, MA.
Jennifer A BrodyCardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA.
Jie YaoDepartment of Pediatrics, Institute for Translational Genomics and Population Science, Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA.
Xiuqing GuoDepartment of Pediatrics, Institute for Translational Genomics and Population Science, Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA.
Fariba AhmadizarDepartment of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands.
Mariah MeyerDepartment of Biomedical Informatics, University of Colorado Anschutz Medical Campus, Aurora, CO.
Murat SincanDepartment of Biostatistics, Boston University School of Public Health, Boston, MA.
Josep M MercaderPrograms in Metabolism and Medical & Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA.
Sujin LeeDivision of Vascular Surgery and Endovascular Therapy, Massachusetts General Hospital, Boston, MA.
Jeffrey HaesslerDivision of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA.
Ha My T VyCharles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY.
Zhaotong LinDepartment of Biostatistics, University of Minnesota, Minneapolis, MN.
Nicole D ArmstrongDepartment of Epidemiology, University of Alabama at Birmingham, Birmingham, AL.
Shaopeng GuDepartment of Internal Medicine, Sanford Health, Sioux Falls, SD.
Noah L TsaoCorporal Michael Crescenz VA Medical Center, and Department of Surgery, Perelman School of Medicine, Philadelphia, PA.
Leslie A LangeDepartment of Biomedical Informatics, University of Colorado Anschutz Medical Campus, Aurora, CO.
Ningyuan WangDepartment of Biostatistics, Boston University School of Public Health, Boston, MA.
Kerri L WigginsCardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA.
Stella TrompetDepartment of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands.
Simin LiuDepartment of Epidemiology, Brown University, Providence, RI.
Ruth J F LoosCharles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY.
Renae JudyCorporal Michael Crescenz VA Medical Center, and Department of Surgery, Perelman School of Medicine, Philadelphia, PA.
Philip H SchroederPrograms in Metabolism and Medical & Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA.
Natalie R HasbaniHuman Genetics Center, Department of Epidemiology Human Genetics and Environmental Sciences, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX.
Maxime M BosDepartment of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands.
Alanna C MorrisonHuman Genetics Center, Department of Epidemiology Human Genetics and Environmental Sciences, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX.
Rebecca D JacksonDivision of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, Ohio State University, Columbus, OH.
Alexander P ReinerDivision of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA.
JoAnn E MansonDepartment of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
Ninad S ChaudharyDepartment of Epidemiology, University of Alabama at Birmingham, Birmingham, AL.
Lynn K CarmichaelDepartment of Internal Medicine, Sanford Health, Sioux Falls, SD.
Yii-Der Ida ChenDepartment of Pediatrics, Institute for Translational Genomics and Population Science, Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA.
Kent D TaylorDepartment of Pediatrics, Institute for Translational Genomics and Population Science, Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA.
Mohsen GhanbariDepartment of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands.
Joyce van MeursDepartment of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands.
Achilleas N PitsillidesDepartment of Biostatistics, Boston University School of Public Health, Boston, MA.
Bruce M PsatyCardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA.
Raymond NoordamDepartment of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands.
Ron DoCharles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY.
Kyong Soo ParkDepartment of Internal Medicine, Seoul National University Hospital, Seoul, Korea.
J Wouter JukemaDepartment of Cardiology, Leiden University Medical Center, Leiden, the Netherlands.
Maryam KavousiDepartment of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands.
Adolfo CorreaDepartment of Medicine, University of Mississippi Medical Center, Jackson, MS.
Stephen S RichCenter for Public Health Genomics, University of Virginia, Charlottesville, VA.
Scott M DamrauerCorporal Michael Crescenz VA Medical Center, and Department of Surgery, Perelman School of Medicine, Philadelphia, PA.
Catherine HajekDepartment of Internal Medicine, Sanford Health, Sioux Falls, SD.
Nam H ChoDepartment of Preventive Medicine, Ajou University School of Medicine, Suwon, Korea.
Marguerite R IrvinDepartment of Epidemiology, University of Alabama at Birmingham, Birmingham, AL.
James S PankowDepartment of Biostatistics, University of Minnesota, Minneapolis, MN.
Girish N NadkarniCharles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY.
Robert SladekDepartment of Medicine and Department of Human Genetics, McGill University, Montréal, QC, Canada.
Mark O GoodarziDivision of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Cedars-Sinai Medical Center.
Jose C FlorezPrograms in Metabolism and Medical & Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA.
Daniel I ChasmanDepartment of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
Susan R HeckbertCardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA.
Charles KooperbergDivision of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA.
Josée DupuisDepartment of Biostatistics, Boston University School of Public Health, Boston, MA.
Rajeev MalhotraCardiovascular Research Center, Cardiology Division of the Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA.
Paul S de VriesHuman Genetics Center, Department of Epidemiology Human Genetics and Environmental Sciences, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX.
Ching-Ti LiuDepartment of Biostatistics, Boston University School of Public Health, Boston, MA.
Jerome I RotterDepartment of Pediatrics, Institute for Translational Genomics and Population Science, Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA.
James B MeigsPrograms in Metabolism and Medical & Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA.
Boston University · USBroad Institute · USErasmus MC · NLUCLA Medical Center · USUniversity of Washington · USIcahn School of Medicine at Mount Sinai · USSanford Health · USLeiden University Medical Center · NLPhiladelphia VA Medical Center · USThe University of Texas Health Science Center at Houston · USUniversity of Alabama at Birmingham · USBrigham and Women's Hospital · USFred Hutch Cancer Center · USUniversity of Colorado Anschutz Medical Campus · USUniversity of Minnesota · USAjou University · KRBrown University · USCedars-Sinai Medical Center · USHarvard University · USMassachusetts General Hospital · US
Funding
UCLA Clinical Translational Science InstituteUL1TR001881 · NCATS · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI ARLEEN F. BROWN, ARASH NAEIM · 2016 to 2026
$118.1MPhenotypic Diversity in COVID-19UL1TR001878 · NCATS · UNIVERSITY OF PENNSYLVANIA · PI FITZGERALD, GARRET A · 2016 to 2025
$102.4MVCID and Stroke in a Bi-racial National CohortU01NS041588 · NINDS · UNIVERSITY OF ALABAMA AT BIRMINGHAM · PI CUSHMAN, MARY, HOWARD, GEORGE · 2002 to 2022
$96.0MInstitute for Clinical and Translational ResearchUL1TR001079 · NCATS · JOHNS HOPKINS UNIVERSITY · PI FORD, DANIEL ERNEST · 2013 to 2017
$60.1MWOMEN'S HEALTH INITIATIVE - CLINICAL COORDINATING CENTER: TASK AREA B - LONG LIFE STUDY VISIT 2 LIMITED HOME VISIT75N92021D00001 · NHLBI · FRED HUTCHINSON CANCER RESEARCH CENTER · PI ANDERSON, GARNET L. · 2021 to 2025
$52.0MTransgenic & Knock-out MouseP30DK063491 · NIDDK · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI PETER J TONTONOZ · 2003 to 2026
$40.4MWake Forest Clinical and Translational Science AwardUL1TR001420 · NCATS · WAKE FOREST UNIVERSITY HEALTH SCIENCES · PI ARD, JAMY D, FOLEY, KRISTIE L · 2015 to 2023
$32.3MFRAMINGHAM HEART STUDY - YEAR 5 EXAM75N92019D00031 · NHLBI · BOSTON UNIVERSITY MEDICAL CAMPUS · 2019 to 2024
$29.8MWomen's Health Study: Continued Follow-upR01CA047988 · NCI · BRIGHAM AND WOMEN'S HOSPITAL · PI BURING, JULIE E., LEE, I-MIN · 1991 to 2014
$28.2MClinical and Translational Science AwardUL1TR000040 · NCATS · COLUMBIA UNIVERSITY HEALTH SCIENCES · PI GINSBERG, HENRY N · 2012 to 2015
$26.2MTask Area A Core Study Operations.Task Area A shall encompass annual follow-up of cohort members, clinical endpoints ascertainment, study coordination activities, maintenance of the database and biosp75N92020D00001 · NHLBI · UNIVERSITY OF WASHINGTON · PI MCCLELLAND, ROBYN LEAGH · 2020 to 2025
$17.2MExceptional Survival: Trajectories to Functional Aging (CHS All Stars)R01AG023629 · NIA · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI NEWMAN, ANNE B. · 2004 to 2016
$9.5MCSRD VA IK2 CX001780NCATS NIH HHS UL1 TR000040NCATS NIH HHS UL1 TR001079NCATS NIH HHS UL1 TR001420NCATS NIH HHS UL1 TR001878NCATS NIH HHS UL1 TR001881NCI NIH HHS R01 CA047988NCI NIH HHS UM1 CA182913NHGRI NIH HHS U01 HG011723NHLBI NIH HHS 75N92019D00031NHLBI NIH HHS 75N92020D00001NHLBI NIH HHS 75N92020D00002NHLBI NIH HHS 75N92020D00003NHLBI NIH HHS 75N92020D00004NHLBI NIH HHS 75N92020D00005NHLBI NIH HHS 75N92020D00006NHLBI NIH HHS 75N92020D00007NHLBI NIH HHS 75N92021D00001NHLBI NIH HHS 75N92021D00002NHLBI NIH HHS 75N92021D00006NHLBI NIH HHS HHSN268200800007CNHLBI NIH HHS HHSN268201200036CNHLBI NIH HHS HHSN268201500001CNHLBI NIH HHS HHSN268201500001INHLBI NIH HHS HHSN268201500003CNHLBI NIH HHS HHSN268201500003INHLBI NIH HHS HHSN268201800001CNHLBI NIH HHS HHSN268201800010INHLBI NIH HHS HHSN268201800011CNHLBI NIH HHS HHSN268201800011INHLBI NIH HHS HHSN268201800012CNHLBI NIH HHS HHSN268201800012INHLBI NIH HHS HHSN268201800014CNHLBI NIH HHS HHSN268201800014INHLBI NIH HHS HHSN268201800015INHLBI NIH HHS N01 HC025195NHLBI NIH HHS N01 HC055222NHLBI NIH HHS N01 HC085079NHLBI NIH HHS N01 HC085080NHLBI NIH HHS N01 HC085081NHLBI NIH HHS N01 HC085082NHLBI NIH HHS N01 HC085083NHLBI NIH HHS N01 HC085086NHLBI NIH HHS N01 HC095159NHLBI NIH HHS N01 HC095160NHLBI NIH HHS N01 HC095161NHLBI NIH HHS N01 HC095162NHLBI NIH HHS N01 HC095163NHLBI NIH HHS N01 HC095164NHLBI NIH HHS N01 HC095165NHLBI NIH HHS N01 HC095166NHLBI NIH HHS N01 HC095167NHLBI NIH HHS N01 HC095168NHLBI NIH HHS N01 HC095169NHLBI NIH HHS N02 HL064278NHLBI NIH HHS R01 HL043851NHLBI NIH HHS R01 HL080467NHLBI NIH HHS R01 HL085251NHLBI NIH HHS R01 HL087652NHLBI NIH HHS R01 HL103612NHLBI NIH HHS R01 HL105756NHLBI NIH HHS R01 HL120393NHLBI NIH HHS R01 HL136666NHLBI NIH HHS R01 HL142809NHLBI NIH HHS R01 HL146860NHLBI NIH HHS R01 HL151855NHLBI NIH HHS R01 HL159514NHLBI NIH HHS R01 HL162928NHLBI NIH HHS T32 HL007457NHLBI NIH HHS U01 HL080295NHLBI NIH HHS U01 HL130114NIA NIH HHS R01 AG023629NIDDK NIH HHS P30 DK063491NIDDK NIH HHS R01 DK109588NIDDK NIH HHS UM1 DK078616NIGMS NIH HHS T32 GM100842NIH HHS S10 OD028685NIMHD NIH HHS HHSN268201800013ININDS NIH HHS U01 NS041588WHI NIH HHS 75N92021D00003WHI NIH HHS 75N92021D00004WHI NIH HHS 75N92021D00005
Abstract
backgroundType 2 diabetes mellitus (T2D) confers a two- to three-fold increased risk of cardiovascular disease (CVD). However, the mechanisms underlying increased CVD risk among people with T2D are only partially understood. We hypothesized that a genetic association study among people with T2D at risk for developing incident cardiovascular complications could provide insights into molecular genetic aspects underlying CVD.
methodsFrom 16 studies of the Cohorts for Heart & Aging Research in Genomic Epidemiology (CHARGE) Consortium, we conducted a multi-ancestry time-to-event genome-wide association study (GWAS) for incident CVD among people with T2D using Cox proportional hazards models. Incident CVD was defined based on a composite of coronary artery disease (CAD), stroke, and cardiovascular death that occurred at least one year after the diagnosis of T2D. Cohort-level estimated effect sizes were combined using inverse variance weighted fixed effects meta-analysis. We also tested 204 known CAD variants for association with incident CVD among patients with T2D.
resultsA total of 49,230 participants with T2D were included in the analyses (31,118 European ancestries and 18,112 non-European ancestries) which consisted of 8,956 incident CVD cases over a range of mean follow-up duration between 3.2 and 33.7 years (event rate 18.2%). We identified three novel, distinct genetic loci for incident CVD among individuals with T2D that reached the threshold for genome-wide significance (
conclusionsThe data point to novel and known genomic regions associated with incident CVD among individuals with T2D.
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