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Time-to-Event Genome-Wide Association Study for Incident Cardiovascular Disease in People with Type 2 Diabetes Mellitus

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posted on 2024-04-23, 16:28 authored by Soo Heon Kwak, Ryan B. Hernandez-Cancela, Daniel A DiCorpo, David E. Condon, Jordi Merino, Peitao Wu, Jennifer A Brody, Jie Yao, Xiuqing Guo, Fariba Ahmadizar, Mariah Meyer, Murat Sincan, Josep M. Mercader, Sujin Lee, Jeffrey Haessler, Ha My T. Vy, Zhaotong Lin, Nicole D. Armstrong, Shaopeng Gu, Noah L. Tsao, Leslie A. Lange, Ningyuan Wang, Kerri L. Wiggins, Stella Trompet, Simin Liu, Ruth J.F. Loos, Renae Judy, Philip H. Schroeder, Natalie R. Hasbani, Maxime M. Bos, Alanna C. Morrison, Rebecca D. Jackson, Alexander P. Reiner, JoAnn E. Manson, Ninad S. Chaudhary, Lynn K. Carmichael, Yii-Der Ida Chen, Kent D. Taylor, Mohsen Ghanbari, Joyce van Meurs, Achilleas N Pitsillides, Bruce M. Psaty, Raymond Noordam, Ron Do, Kyong Soo Park, J Wouter Jukema, Maryam Kavousi, Adolfo Correa, Stephen S. Rich, Scott M. Damrauer, Catherine Hajek, Nam H. Cho, Marguerite R. Irvin, James S. Pankow, Girish N. Nadkarni, Robert Sladek, Mark O. Goodarzi, Jose C. Florez, Daniel I. Chasman, Susan R. Heckbert, Charles Kooperberg, Josée Dupuis, Rajeev Malhotra, Paul S. de Vries, Ching-Ti Liu, Jerome I. Rotter, James B. Meigs

OBJECTIVE To identify genetic risk factors for incident cardiovascular disease (CVD) among people with type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS We conducted a multi-ancestry time-to-event genome-wide association study for incident CVD among people with T2D. We also tested 204 known coronary artery disease (CAD) variants for association with incident CVD. RESULTS Among 49,230 participants with T2D, 8,956 had incident CVD events (event rate 18.2%). We identified three novel genetic loci for incident CVD: rs147138607 (near CACNA1E/ZNF648, HR 1.23, P=3.6×10-9), rs11444867 (near HS3ST1, HR 1.89, P=9.9×10-9), and rs335407 (near TFB1M/NOX3, HR 1.25, P=1.5×10-8). Among 204 known CAD loci, 5 were associated with incident CVD in T2D (multiple comparison-adjusted P < 0.00024, 0.05/204). A standardized polygenic score of these 204 variants was associated with incident CVD with HR 1.14 (P=1.0×10-16). CONCLUSIONS The data point to novel and known genomic regions associated with incident CVD among individuals with T2D.

Funding

S.H.K is supported by the National Research Foundation of Korea grant funded by the Korean Ministry of Science and ICT (RS-2023-00262002) and by the Ministry of Food and Drug Safety grant (23212MFDS202) in 2023. J.M. was supported by American Diabetes Association grant No. 7-21-JDFM-005. J.M.M. is supported by American Diabetes Association Innovative and Clinical Translational Award 1-19-ICTS-068, American Diabetes Association grant #11-22-ICTSPM-16, and by NHGRI U01HG011723. M.O.G. was supported by the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Disease (R01-DK109588 and P30-DK063491), the National Center for Advancing Translational Sciences (UL1TR001420, UL1TR001881), and by the Eris M. Field Chair in Diabetes Research. R.H.C. was supported by the National Institute of General Medical Sciences of the National Institutes of Health under award number T32GM100842. S.M.D. receives research support from RenalytixAI, outside the current work and is supported by the US Department of Veterans Affairs Clinical Research and Development award IK2-CX001780. This publication does not represent the views of the Department of Veterans Affairs or the United States Government. R.M. was supported by the National Heart, Lung, and Blood Institute (R01HL142809 and R01HL159514), the American Heart Association (22TPA969625), and the Wild Family Foundation. Cardiovascular Health Study: This CHS research was supported by NHLBI contracts HHSN268201200036C, HHSN268200800007C, HHSN268201800001C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, 75N92021D00006; and NHLBI grants U01HL080295, R01HL085251, R01HL087652, R01HL105756, R01HL103612, R01HL120393, and U01HL130114 with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided through R01AG023629 from the National Institute on Aging (NIA). A full list of principal CHS investigators and inst

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