Incremental Prognostic Value of a Coronary Heart Disease Polygenic Risk Score in Type 2 Diabetes

Abstract

OBJECTIVE The recent availability of cardiovascular risk-reducing type 2 diabetes (T2D) therapies makes it imperative to optimally identify individuals who could derive benefit. Current clinical risk prediction may misclassify individuals as low risk and could be improved. Our aim was to determine the incremental prognostic value of a coronary heart disease (CHD) genome-wide polygenic risk score (PRS) to a clinical risk score in prediction of major adverse cardiovascular events (MACE) in patients with T2D. RESEARCH DESIGN AND METHODS We evaluated 10,556 individuals with T2D aged 40–79 without a prior cardiovascular hospitalization. We calculated 10-year clinical cardiovascular risk at the date of recruitment using the Pooled Cohort Equation (PCE Risk) and constructed a CHD PRS. The primary outcome was time to first MACE incidence, and we assessed the additional incremental predictive value of the CHD PRS to the PCE risk. RESULTS At 10 years, there were 1,477 MACE. After adjustment for clinical risk, the CHD PRS was significantly associated with MACE (hazard ratio [HR] 1.69 per SD increase, 95% CI 1.60–1.79). Individuals with PCE Risk <7.5% but in the top quintile of CHD PRS had a significantly increased likelihood of MACE (HR 10.69, 95% CI 5.07–22.55) compared with those in the lowest. The addition of the PRS to the clinical risk score led to significant improvements in risk prediction, particularly in those at low clinical risk. CONCLUSIONS The addition of a CHD PRS to clinical assessment improved MACE prediction in T2D individuals without prior cardiovascular disease, particularly in those at low clinical risk.