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

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; Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium

doi:10.2337/dc23-2274

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

Diabetes Care. 2024 Apr 23:dc232274. doi: 10.2337/dc23-2274. Online ahead of print.

Authors

Soo Heon Kwak^{1

2

3}, Ryan B Hernandez-Cancela⁴, Daniel A DiCorpo⁴, David E Condon⁵, Jordi Merino^{2

3

6

7}, Peitao Wu⁴, Jennifer A Brody⁸, Jie Yao⁹, Xiuqing Guo⁹, Fariba Ahmadizar^{10

11}, Mariah Meyer¹², Murat Sincan⁴, Josep M Mercader^{2

3

6}, Sujin Lee¹³, Jeffrey Haessler¹⁴, Ha My T Vy¹⁵, Zhaotong Lin¹⁶, Nicole D Armstrong¹⁷, Shaopeng Gu¹⁸, Noah L Tsao¹⁹, Leslie A Lange¹², Ningyuan Wang⁴, Kerri L Wiggins⁸, Stella Trompet^{20

21}, Simin Liu²², Ruth J F Loos¹⁵, Renae Judy¹⁹, Philip H Schroeder^{2

3

6}, Natalie R Hasbani²³, Maxime M Bos¹⁰, Alanna C Morrison²³, Rebecca D Jackson²⁴, Alexander P Reiner^{14

25}, JoAnn E Manson²⁶, Ninad S Chaudhary¹⁷, Lynn K Carmichael¹⁸, Yii-Der Ida Chen⁹, Kent D Taylor⁹, Mohsen Ghanbari¹⁰, Joyce van Meurs¹⁰, Achilleas N Pitsillides⁴, Bruce M Psaty^{8

25

27}, Raymond Noordam²⁰, Ron Do¹⁵, Kyong Soo Park¹, J Wouter Jukema^{21

28}, Maryam Kavousi¹⁰, Adolfo Correa²⁹, Stephen S Rich³⁰, Scott M Damrauer^{19

31}, Catherine Hajek¹⁸, Nam H Cho³², Marguerite R Irvin¹⁷, James S Pankow³³, Girish N Nadkarni¹⁵, Robert Sladek³⁴, Mark O Goodarzi³⁵, Jose C Florez^{2

3

6}, Daniel I Chasman²⁶, Susan R Heckbert^{8

25}, Charles Kooperberg¹⁴, Josée Dupuis^{4

36}, Rajeev Malhotra³⁷, Paul S de Vries²³, Ching-Ti Liu⁴, Jerome I Rotter⁹, James B Meigs^{2

6

38}; Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium

Affiliations

¹ Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea.
² Broad Metabolism Program and Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA.
³ Diabetes Unit and Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA.
⁴ Department of Biostatistics, Boston University School of Public Health, Boston, MA.
⁵ Sanford Imagenetics, Sanford Health, Sioux Falls, SD.
⁶ Department of Medicine, Harvard Medical School, Boston, MA.
⁷ Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.
⁸ Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA.
⁹ Department of Pediatrics, Institute for Translational Genomics and Population Sciences, The Lundquist Institute for Biomedical Innovation, Harbor-UCLA Medical Center, Torrance, CA.
¹⁰ Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, the Netherlands.
¹¹ Department of Data Science and Biostatistics, Julius Global Health, University Medical Center Utrecht, Utrecht, the Netherlands.
¹² Department of Biomedical Informatics, University of Colorado Anschutz Medical Campus, Aurora, CO.
¹³ Division of Vascular Surgery and Endovascular Therapy, Massachusetts General Hospital, Boston, MA.
¹⁴ Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA.
¹⁵ Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY.
¹⁶ Department of Biostatistics, University of Minnesota, Minneapolis, MN.
¹⁷ Department of Epidemiology, The University of Alabama at Birmingham, Birmingham, AL.
¹⁸ Department of Internal Medicine, Sanford Health, Sioux Falls, SD.
¹⁹ Corporal Michael J. Crescenz VA Medical Center and Department of Surgery, Perelman School of Medicine, Philadelphia, PA.
²⁰ Section of Gerontology and Geriatrics, Department of Internal Medicine, Leiden University Medical Center, Leiden, the Netherlands.
²¹ Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands.
²² Department of Epidemiology, Brown University, Providence, RI.
²³ Human Genetics Center, Department of Epidemiology, Human Genetics and Environmental Sciences, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX.
²⁴ Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, Ohio State University, Columbus, OH.
²⁵ Department of Epidemiology, University of Washington, Seattle, WA.
²⁶ Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
²⁷ Department of Health Systems and Population Health, University of Washington, Seattle, WA.
²⁸ Netherlands Heart Institute, Utrecht, the Netherlands.
²⁹ Department of Medicine, University of Mississippi Medical Center, Jackson, MS.
³⁰ Center for Public Health Genomics, University of Virginia, Charlottesville, VA.
³¹ Department of Genetics, Perelman School of Medicine, Philadelphia, PA.
³² Department of Preventive Medicine, Ajou University School of Medicine, Suwon, Korea.
³³ Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN.
³⁴ Department of Medicine and Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
³⁵ Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA.
³⁶ Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, Quebec, Canada.
³⁷ Cardiovascular Research Center, Cardiology Division, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA.
³⁸ Department of General Internal Medicine, Harvard Medical School and Massachusetts General Hospital, Boston, MA.

PMID: 38652672
DOI: 10.2337/dc23-2274

Abstract

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 multiancestry 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, hazard ratio [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.

Abstract

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