Polygenic risk, lifestyle, and cardiovascular mortality: a prospective population-based UK Biobank study
Authors: Yun Jae-Seung , Jung Sang-Hyuk , Shivakumar Manu , Xiao Brenda , Khera Amit V. , Park Woong-Yang , Won Hong-Hee , Kim Dokyoon 
Published: February 2021

AbstractOBJECTIVETo assess the prognostic ability of polygenic risk scores (PRSs) for coronary artery disease (CAD) and type 2 diabetes mellitus (T2DM) for cardiovascular (CV) mortality, independent of traditional risk factors, and further investigate the additive effect between lifestyle behavior and PRS on CV mortality.DESIGNProspective population-based cohort study.SETTINGUK Biobank.PARTICIPANTSA total 377,909 unrelated participants of white British descent were included in the analyses from the UK Biobank cohort.MAIN OUTCOME MEASURESGenome-wide PRSs were constructed using >6 million genetic variants. We stratified patients into four PRS risk groups: low (0 to 19th percentile), intermediate (20 to 79th percentile), high (80 to 98th percentile), and very high (99th percentile). We defined a favorable and unfavorable lifestyle with four modifiable lifestyle components, including smoking, obesity, physical activity, and diet. 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.RESULTSOf 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 to 3.36]) and T2DM PRS (HR 2.08 [1.58 to 2.73]), respectively. These relationships remained significant even after 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 versus unfavorable lifestyle with very high genetic risk for CAD PRS, HR 8.31 [5.12 to 13.49]; T2DM PRS, HR 5.84 [3.39 to 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 to 35.3%]) and 14.1% was attributable to smoking (PAF 14.1% [95% CI 12.4 to 15.7%]). There was no evidence of significant interaction between PRSs and age, sex, or lifestyle behavior in predicting the risk of CV mortality.CONCLUSIONPRSs for CAD or T2DM and lifestyle behaviors are independent predictive factors for future CV mortality in the white, middle-aged population. PRS-based risk assessment could be useful to identify individuals who need intensive behavioral or therapeutic interventions to reduce the risk of CV mortality.Summary BoxWhat is already known on this topicPolygenic risk scores quantify the inherited risk conferred by the cumulative impact of common variants into a quantitative risk estimate.Previous studies primarily targeted the ability of polygenic risk scores to predict a specific disease, and only a few studies have investigated the association between genetic risk scores and cardiovascular mortality.The majority of previous analyses calculated polygenic risk scores from only a small number of genetic variants or adjusted for only a few risk factors, and no studies have examined whether the association of polygenic risk score with cardiovascular mortality differs by lifestyle behavior.What this study addsGenetic risk and lifestyle are independent predictive factors for cardiovascular mortality, even after adjustment for a comprehensive range of demographic and clinical factors.A healthy lifestyle is associated with relative risk reduction for cardiovascular mortality across all genetic risk categories, a finding that indicates the potential benefit of intensive lifestyle modification in overcoming genetic risk for cardiovascular mortality.