Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
[Preprint]. 2023 Jul 28:2023.07.25.23293180.
doi: 10.1101/2023.07.25.23293180.

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

Soo Heon Kwak  1   2   3 , Ryan B Hernandez-Cancela  4 , Daniel A DiCorpo  4 , David E Condon  5 , Jordi Merino  2   3   6   7 , Peitao Wu  4 , Jennifer A Brody  8 , Jie Yao  9 , Xiuqing Guo  9 , Fariba Ahmadizar  10   11 , Mariah Meyer  12 , Murat Sincan  4 , Josep M Mercader  2   3   6 , Sujin Lee  13 , Jeffrey Haessler  14 , Ha My T Vy  15 , Zhaotong Lin  16 , Nicole D Armstrong  17 , Shaopeng Gu  18 , Noah L Tsao  19 , Leslie A Lange  12 , Ningyuan Wang  4 , Kerri L Wiggins  8 , Stella Trompet  20   21 , Simin Liu  22 , Ruth J F Loos  15 , Renae Judy  19 , Philip H Schroeder  2   3   6 , Natalie R Hasbani  23 , Maxime M Bos  10 , Alanna C Morrison  23 , Rebecca D Jackson  24 , Alexander P Reiner  14   25 , JoAnn E Manson  26 , Ninad S Chaudhary  17 , Lynn K Carmichael  18 , Yii-Der Ida Chen  9 , Kent D Taylor  9 , Mohsen Ghanbari  10 , Joyce van Meurs  10 , Achilleas N Pitsillides  4 , Bruce M Psaty  8   25   27 , Raymond Noordam  20 , Ron Do  15 , Kyong Soo Park  1 , J Wouter Jukema  21   28 , Maryam Kavousi  10 , Adolfo Correa  29 , Stephen S Rich  30 , Scott M Damrauer  19   31 , Catherine Hajek  18 , Nam H Cho  32 , Marguerite R Irvin  17 , James S Pankow  16 , Girish N Nadkarni  15 , Robert Sladek  33 , Mark O Goodarzi  34 , Jose C Florez  2   3   6 , Daniel I Chasman  26 , Susan R Heckbert  8   25 , Charles Kooperberg  14 , Josée Dupuis  4   35 , Rajeev Malhotra  36 , Paul S de Vries  23 , Ching-Ti Liu  4 , Jerome I Rotter  9 , James B Meigs  2   6   37
Affiliations

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

Soo Heon Kwak et al. medRxiv. .

Update in

  • Time-to-Event Genome-Wide Association Study for Incident Cardiovascular Disease in People With Type 2 Diabetes.
    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; Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Kwak SH, et al. Diabetes Care. 2024 Jun 1;47(6):1042-1047. doi: 10.2337/dc23-2274. Diabetes Care. 2024. PMID: 38652672 Free PMC article.

Abstract

Background: Type 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.

Methods: From 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.

Results: A 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 (P<5.0×10-8): rs147138607 (intergenic variant between CACNA1E and ZNF648) with a hazard ratio (HR) 1.23, 95% confidence interval (CI) 1.15 - 1.32, P=3.6×10-9, rs11444867 (intergenic variant near HS3ST1) with HR 1.89, 95% CI 1.52 - 2.35, P=9.9×10-9, and rs335407 (intergenic variant between TFB1M and NOX3) HR 1.25, 95% CI 1.16 - 1.35, P=1.5×10-8. Among 204 known CAD loci, 32 were associated with incident CVD in people with T2D with P<0.05, and 5 were significant after Bonferroni correction (P<0.00024, 0.05/204). A polygenic score of these 204 variants was significantly associated with incident CVD with HR 1.14 (95% CI 1.12 - 1.16) per 1 standard deviation increase (P=1.0×10-16).

Conclusions: The data point to novel and known genomic regions associated with incident CVD among individuals with T2D.

PubMed Disclaimer

Figures

Figure 1.
Figure 1.. QQ plot and Manhattan plot of the time-to-event GWAS for incident CVD in people with T2D.
A, QQ plot showing the distribution of the observed P values from the meta-analysis of GWAS result against the expected distribution under the null hypothesis. The gray zone indicates the 95% CI. λGC was 1.093 for variants with MAF ≥ 1% and λGC was 1.058 for variants with MAF ≥ 5%. B, Manhattan plot depicting the significance of all the variants after meta-analysis of GWAS results. SNP locations are plotted on the x-axis according to their chromosomal position. The negative log10 of P values of time-to-event analysis based on Cox proportional hazard model under the additive model are plotted on the y-axis. Dark dots highlight the significance of association for the previously known 204 CAD variants identified in the general population.
Figure 2.
Figure 2.. 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 panel represent the position of each SNP that was genotyped or imputed. The negative log10 of P values from the Cox regression are shown in the y-axis. Estimated recombination rates are plotted to reflect recombination hot spots. The SNPs in LD with the most significant SNP are color coded to represent their strength of LD based on Europeans for A, and C, and Africans for B.
Figure 3.
Figure 3.. Association of previously identified 204 CAD variants with incident CVD in people with T2D.
A, QQ 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. The red dots highlight five variants that were significantly associated with incident CVD after Bonferroni correction. B, Comparison of the effect size of known 204 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) are plotted. There was a significant correlation between the effect sizes (Spearman coefficient 0.509, P=7.2×10−15). The red dots highlight 32 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

References

    1. Haffner SM, Lehto S, Ronnemaa T, Pyorala K and Laakso M. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med. 1998;339:229–34. - PubMed
    1. Kannel WB and McGee DL. Diabetes and cardiovascular disease. The Framingham study. JAMA. 1979;241:2035–8. - PubMed
    1. Rosenquist KJ and Fox CS. Mortality Trends in Type 2 Diabetes. In: rd, Cowie C. C., Casagrande S. S, Menke A, Cissell M. A, Eberhardt M. S, Meigs J. B, Gregg E. W, Knowler W. C, Barrett-Connor E, Becker D. J., Brancati F. L, Boyko E. J, Herman W. H, Howard B. V, Narayan K. M. V, Rewers Mand Fradkin J. E, eds. Diabetes in America Bethesda (MD); 2018. - PubMed
    1. Rawshani A, Rawshani A, Franzen S, Eliasson B, Svensson AM, Miftaraj M, McGuire DK, Sattar N, Rosengren A and Gudbjornsdottir S. Mortality and Cardiovascular Disease in Type 1 and Type 2 Diabetes. N Engl J Med. 2017;376:1407–1418. - PubMed
    1. Goff DC Jr., Lloyd-Jones DM, Bennett G, Coady S, D’Agostino RB, Gibbons R, Greenland P, Lackland DT, Levy D, O’Donnell CJ, Robinson JG, Schwartz JS, Shero ST, Smith SC Jr., Sorlie P, Stone NJ, Wilson PW, Jordan HS, Nevo L, Wnek J, Anderson JL, Halperin JL, Albert NM, Bozkurt B, Brindis RG, Curtis LH, DeMets D, Hochman JS, Kovacs RJ, Ohman EM, Pressler SJ, Sellke FW, Shen WK, Smith SC Jr, Tomaselli GF and American College of Cardiology/American Heart Association Task Force on Practice G. 2013 ACC/AHA guideline on the assessment of cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;129:S49–73. - PubMed

Publication types

Grants and funding