24-OR: Time-to-Event GWAS for Incident Cardiovascular Disease in Type 2 Diabetes Patients

Abstract

Patients with type 2 diabetes (T2D) are at two-fold increased risk of cardiovascular disease (CVD), which is the leading cause of T2D morbidity and mortality. Here, we conducted a time-to-event genome-wide association study (GWAS) to identify genetic variants associated with incident CVD among patients with T2D in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium. Incident CVD was defined based on a composite of myocardial infarction, stroke, and cardiovascular death that occurred at least one year after the diagnosis of T2D. In each participating prospective cohort, we performed GWAS using a Cox proportional hazard survival model adjusting for age, and sex to identify genetic variants associated with incident CVD, and cohort-level estimated effect sizes were combined using inverse variance weighted fixed effects meta-analysis. A total of 37,327 participants were included in the analyses (26,928 European ancestry and 10,399 non-European ancestry) which comprised 6,012 primary event cases. We identified three distinct genetic loci associated with incident CVD among individuals with T2D that reached the threshold for genome-wide significance: rs231964 (intronic variant in NOX3, hazard ratio [HR] 1.4, P=8.3x10-9), rs139753656 (intronic variant in DCC, HR 2.0, P=2.4x10-8), and rs77202398 (intronic variant in TNS3, HR 1.4, P=4.4x10-8). Among 204 known coronary artery disease risk loci, 27 were associated with incident CVD with P<0.05 and rs6842241 upstream of EDNRA was associated with increased risk of CVD after Bonferroni correction (HR 1.1, P=1.2x10-4). The data provide evidence of novel and known genomic regions associated with incident CVD among individuals with T2D that require validation but point to novel targets. Disclosure S. Kwak: None. P. Wu: None. J. B. Meigs: Consultant; Self; Quest Diagnostics. On behalf of the charge diabetes working group: n/a. Funding National Institutes of Health (1R01HL151855-01)