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

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
PMCID: PMC11116923
DOI: 10.2337/dc23-2274

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

Soo Heon Kwak et al. Diabetes Care. 2024.

. 2024 Jun 1;47(6):1042-1047.

doi: 10.2337/dc23-2274.

Authors

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
PMCID: PMC11116923
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), rs77142250 (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.

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Figures

**Figure 1**
Regional association plots for the three genome-wide significant variants. A: rs147138607, near *CACNA1E* and *ZNF648*. B: rs77142250, near *HS3ST1*. C: rs335407, near *TFB1M* and *NOX3*. The hash marks above the panels represent the position of each SNP that was genotyped or imputed. The negative log₁₀ of P values from the Cox regression is shown on the y-axis. Estimated recombination rates are plotted to reflect recombination hot spots. The single nucleotide polymorphisms (SNPs) in linkage disequilibrium with the most significant single nucleotide polymorphism are color coded to represent their strength of linkage disequilibrium based on European ancestry for A and C and African ancestry for B.

**Figure 2**
Association of 204 previously identified CAD variants with incident CVD in people with T2D. A: Quantile-quantile plot showing the distribution of the observed P values for the 204 CAD variants with risk of incident CVD in people with T2D against the expected distribution under the null hypothesis. Red dots highlight five variants that were significantly associated with incident CVD after Bonferroni correction. B: Comparison of the effect size of 204 known CAD variants in the general population and incident CVD in people with T2D. Effect size of the known 204 CAD variants for prevalent CAD in the general population (x-axis, β-coefficient from logistic regression analysis) and incident CVD in people with T2D (y-axis, β-coefficient from Cox regression analysis) is plotted. Red dots highlight 35 variants that were nominally (P < 0.05) associated with incident CVD and had same direction of association in the general population.

See this image and copyright information in PMC

Update of

Time-to-Event Genome-Wide Association Study for Incident Cardiovascular Disease in People with Type 2 Diabetes Mellitus.
Kwak SH, Hernandez-Cancela RB, DiCorpo DA, Condon DE, Merino J, Wu P, Brody JA, Yao J, Guo X, Ahmadizar F, Meyer M, Sincan M, Mercader JM, Lee S, Haessler J, Vy HMT, Lin Z, Armstrong ND, Gu S, Tsao NL, Lange LA, Wang N, Wiggins KL, Trompet S, Liu S, Loos RJF, Judy R, Schroeder PH, Hasbani NR, Bos MM, Morrison AC, Jackson RD, Reiner AP, Manson JE, Chaudhary NS, Carmichael LK, Chen YI, Taylor KD, Ghanbari M, van Meurs J, Pitsillides AN, Psaty BM, Noordam R, Do R, Park KS, Jukema JW, Kavousi M, Correa A, Rich SS, Damrauer SM, Hajek C, Cho NH, Irvin MR, Pankow JS, Nadkarni GN, Sladek R, Goodarzi MO, Florez JC, Chasman DI, Heckbert SR, Kooperberg C, Dupuis J, Malhotra R, de Vries PS, Liu CT, Rotter JI, Meigs JB. Kwak SH, et al. medRxiv [Preprint]. 2023 Jul 28:2023.07.25.23293180. doi: 10.1101/2023.07.25.23293180. medRxiv. 2023. Update in: Diabetes Care. 2024 Jun 1;47(6):1042-1047. doi: 10.2337/dc23-2274. PMID: 37546893 Free PMC article. Updated. Preprint.

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

Affiliations

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

Authors

Affiliations

Abstract

Figures

Update of

References

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Miscellaneous