Patients with type 2 diabetes (T2D) are at two-fold increased risk of cardiovascular disease (CVD). CVD is the leading cause of T2D morbidity and mortality. The aim of this study was to identify genetic risk factors associated with incident CVD in patients with T2D. We performed survival genome-wide association study (GWAS) with patients with T2D in the UK Biobank (UKBB), Partners HealthCare Biobank (PBB), and Korean Genome and Epidemiology (KoGES) studies. The primary outcome of the study was a composite of myocardial infarction and stroke that occurred at least one year after the diagnosis of T2D. We conducted survival GWAS using ’GWASTools’ R package adjusting for age, and sex. The results of the three cohorts were meta-analyzed using inverse variance weighted method. A total of 19,121 participants were included in the analyses (15,643 from UKBB, 1,161 from PBB and 2,317 from KoGES). The incidence rate of CVD was higher in the hospital-based study of PBB (33.5%) compared to population-based studies of UKBB (9.5%), and KoGES (8.0%). Although there was no genetic association reaching genome-wide significance, there were four genomic loci that had suggestive association evidence for incident CVD with P<1.0x10-6. These include distinct variants in rs113067014 (intergenic) on chromosome 1 (chr1), rs1367414 (intron in PAX3) on chr2, rs11762253 (intron in AC004160.1) on chr7, and rs2837174 (intron in IGSF5) on chr21. When we investigated 184 previously validated coronary artery disease loci, 17 reached nominal significance of P<0.05 with consistent direction of association. A polygenic score (PS) comprised of these 184 variants was significantly associated with risk of CVD in T2D patients (HR 1.20 per s.d. increase in PS, P=6.6x10-16).
In summary, we have implemented survival GWAS analysis to investigate genetic risk factors for incident CVD in patients with T2D. However, further increase in sample size is required to identify molecular features leading to increased CVD risk among individuals with T2D.
S. Kwak: None. J.M. Mercader: None. A. Leong: None. B. Porneala: None. P. Wu: None. J.B. Cole: None. J. Merino: None. K. Park: None. N.H. Cho: None. J. Dupuis: Consultant; Self; Merck Sharp & Dohme Corp. J.C. Florez: Advisory Panel; Self; Doris Duke Charitable Foundation. Other Relationship; Self; Novo Nordisk Inc., Park Street School. J.B. Meigs: Consultant; Self; Quest Diagnostics.