138-OR: Earlier Onset of Type 2 Diabetes Increases Genetic Risk of Cardiovascular Complication

Abstract

Earlier age at diagnosis of type 2 diabetes (T2D) is associated with increased risk of cardiovascular disease (CVD) . However, genetic risk factors associated with accelerated CVD in people with early onset T2D remain elusive. We aimed to investigate if the impact of polygenic risk for developing CVD differs according to age at diagnosis of T2D. Using prospective cohorts of UK Biobank (T2D, N=15,915) and Seoul National University Hospital (SNUH) T2D cohort (N=1,228) , we compared the incidence of newly developed CVD among four groups based on age at diagnosis of T2D (30-39, 40-49, 50-59, and 60-69 years of age) using time to event analysis. Polygenic risk scores (PRSs) for T2D and coronary artery disease (CAD) were calculated by PRS-CS, Bayesian regression using continuous shrinkage priors, using 1.1 million SNPs each from summary statistics of DIAGRAM and CARDIoGRAMplusC4D Consortium. In UK Biobank, people diagnosed as T2D between age 30-39 had 5.8 (95% CI 4.04-8.42) fold increased risk of CVD compared to those who developed T2D between 60-69. Higher T2D PRS was associated with earlier onset of T2D but not with risk of myocardial infarction (MI) . On the other hand, higher CAD PRS was associated with increased risk of MI but not with earlier age at diagnosis of T2D. The effect of CAD PRS on MI was largest in people diagnosed between age 30-39 and its effect size decreased as the age at diagnosis increased: HR 2.34 (1.47-3.71) for age 30-39, 1.42 (1.20-1.68) for 40-49, 1.39 (1.25-1.54) for 50-59, and 1.28 (1.11-1.48) for 60-69. Interaction analysis between age at diagnosis and CAD PRS showed additional 10% increase in risk of MI for year earlier onset of T2D (P=0.0056) . These findings were replicated in the SNUH T2D cohort, which is a hospital based cohort of East Asians. In summary, people with earlier onset T2D had higher risks for CVD, and the impact of CAD PRS for incident MI increased as age at diagnosis decreased. Genetic information in people with early onset T2D could be used to identify those with increased risk of CVD. Disclosure H.Lee: None. J.Choi: None. N.Kim: None. S.Lee: None. K.Park: None. S.Kwak: None.