Associations between polygenic risk of coronary artery disease and type 2 diabetes, lifestyle, and cardiovascular mortality: A prospective UK Biobank study.

Background: Previous studies primarily targeted the ability of polygenic risk scores (PRSs) to predict a specific disease, and only a few studies have investigated the association between genetic risk scores and cardiovascular (CV) mortality. We assessed PRSs for coronary artery disease (CAD) and type 2 diabetes (T2DM) as the predictive factors for CV mortality, independent of traditional risk factors, and further investigated the additive effect between lifestyle behavior and PRS on CV mortality. Methods: We used genetic and phenotypic data from UK Biobank participants aged 40-69 years at baseline, collected with standardized procedures. Genome-wide PRSs were constructed using >6 million genetic variants. Cox proportional hazard models were used to analyze the relationship between PRS and CV mortality with stratification by age, sex, disease status, and lifestyle behavior. Results: Of 377,909 UK Biobank participants having European ancestry, 3,210 (0.8%) died due to CV disease during a median follow-up of 8.9 years. CV mortality risk was significantly associated with CAD PRS [low vs. very high genetic risk groups, CAD PRS hazard ratio (HR) 2.61 (2.02-3.36)] and T2DM PRS [HR 2.08 (1.58-2.73)], respectively. These relationships remained significant even after an adjustment for a comprehensive range of demographic and clinical factors. In the very high genetic risk group, adherence to an unfavorable lifestyle was further associated with a substantially increased risk of CV mortality [favorable vs. unfavorable lifestyle with very high genetic risk for CAD PRS, HR 8.31 (5.12-13.49); T2DM PRS, HR 5.84 (3.39-10.04)]. Across all genetic risk groups, 32.1% of CV mortality was attributable to lifestyle behavior [population attributable fraction (PAF) 32.1% (95% CI 28.8-35.3%)] and 14.1% was attributable to smoking [PAF 14.1% (95% CI 12.4-15.7%)]. There was no evidence of significant interaction between PRSs and age, sex, or lifestyle behavior in predicting the risk of CV mortality. Conclusion: PRSs for CAD or T2DM and lifestyle behaviors are the independent predictive factors for future CV mortality in the white, middle-aged population. PRS-based risk assessment could be useful to identify the individuals who need intensive behavioral or therapeutic interventions to reduce the risk of CV mortality.