Time-to-Event Genome-Wide Association Study for Incident Cardiovascular Disease in People with Type 2 Diabetes Mellitus
Author:
Kwak Soo HeonORCID, Hernandez-Cancela Ryan B., DiCorpo Daniel AORCID, Condon David E., Merino Jordi, Wu Peitao, Brody Jennifer AORCID, Yao JieORCID, Guo XiuqingORCID, Ahmadizar FaribaORCID, Meyer MariahORCID, Sincan Murat, Mercader Josep M.ORCID, Lee SujinORCID, Haessler Jeffrey, Vy Ha My T.ORCID, Lin Zhaotong, Armstrong Nicole D., Gu Shaopeng, Tsao Noah L.ORCID, Lange Leslie A., Wang NingyuanORCID, Wiggins Kerri L.ORCID, Trompet StellaORCID, Liu SiminORCID, Loos Ruth J.F.ORCID, Judy Renae, Schroeder Philip H., Hasbani Natalie R.ORCID, Bos Maxime M., Morrison Alanna C.ORCID, Jackson Rebecca D., Reiner Alexander P.ORCID, Manson JoAnn E.ORCID, Chaudhary Ninad S.ORCID, Carmichael Lynn K., Chen Yii-Der IdaORCID, Taylor Kent D.ORCID, Ghanbari MohsenORCID, van Meurs Joyce, Pitsillides Achilleas NORCID, Psaty Bruce M.ORCID, Noordam RaymondORCID, Do RonORCID, Park Kyong Soo, Jukema J WouterORCID, Kavousi MaryamORCID, Correa AdolfoORCID, Rich Stephen S.ORCID, Damrauer Scott M.ORCID, Hajek Catherine, Cho Nam H., Irvin Marguerite R., Pankow James S.ORCID, Nadkarni Girish N.ORCID, Sladek Robert, Goodarzi Mark O.ORCID, Florez Jose C., Chasman Daniel I.ORCID, Heckbert Susan R.ORCID, Kooperberg CharlesORCID, Dupuis Josée, Malhotra RajeevORCID, de Vries Paul S.ORCID, Liu Ching-TiORCID, Rotter Jerome I.ORCID, Meigs James B.ORCID
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 (P<5.0×10-8): rs147138607 (intergenic variant betweenCACNA1EandZNF648) with a hazard ratio (HR) 1.23, 95% confidence interval (CI) 1.15 – 1.32,P=3.6×10-9, rs11444867 (intergenic variant nearHS3ST1) with HR 1.89, 95% CI 1.52 – 2.35,P=9.9×10-9, and rs335407 (intergenic variant betweenTFB1MandNOX3) 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 withP<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).CONCLUSIONSThe data point to novel and known genomic regions associated with incident CVD among individuals with T2D.CLINICAL PERSPECTIVEWhat is new?We conducted a large-scale multi-ancestry time-to-event GWAS to identify genetic variants associated with CVD among people with T2D.Three variants were significantly associated with incident CVD in people with T2D: rs147138607 (intergenic variant betweenCACNA1EandZNF648), rs11444867 (intergenic variant nearHS3ST1), and rs335407 (intergenic variant betweenTFB1MandNOX3).A polygenic score composed of known CAD variants identified in the general population was significantly associated with the risk of CVD in people with T2D.What are the clinical implications?There are genetic risk factors specific to T2D that could at least partially explain the excess risk of CVD in people with T2D.In addition, we show that people with T2D have enrichment of known CAD association signals which could also explain the excess risk of CVD.
Publisher
Cold Spring Harbor Laboratory
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