Multi‐Trait Polygenic Risk Score, Nongenetic Determinants, and Cardiovascular Disease Death: A Cohort Study of 14 086 Japanese Individuals

BACKGROUND: Although utility of composite trait-specific polygenic risk score (multi-trait PRS) has been examined among European ancestries, few studies investigated among East Asians and incorporated modifiable risk factors. We examined the associations of multi-trait PRS for cardiometabolic factors with cardiovascular disease mortality by integrating nongenetic determinants. METHODS: A total of 14 086 Japanese participants (mean age, 55±9; 55.8% women) of the J-MICC (Japan Multi-Institutional Collaborative Cohort) study were analyzed in this study. We calculated 6 PRSs for cardiometabolic traits (systolic blood pressure, body mass index, triglycerides, low-density lipoprotein cholesterol, estimated glomerular filtration rate, and hemoglobin A1c). Based on these PRSs, we developed multi-trait PRS and considered as a primary exposure. Three nongenetic factors (smoking, alcohol drinking, and educational attainment) from the self-reported questionnaire were also examined. RESULTS: During a median 12.1-year follow-up period, a total of 472 all-cause and 79 cardiovascular disease mortality cases were documented. Compared with 0% to 90% of multi-trait PRSs, an adjusted hazard ratio (HR) among the top 10% of multi-trait PRSs was 1.32 (95% CI, 1.00-1.73) for all-cause death and 2.63 (95% CI, 1.48-4.67) for cardiovascular disease death. Incorporation of educational attainment with multi-trait PRSs showed null associations in those who went beyond high school (HR, 2.07 [95% CI, 0.44-9.66]) even in the top 10% of multi-trait PRS. CONCLUSIONS: Our analysis combining both genetic and nongenetic determinants highlighted that lifestyle factors and educational attainment can slightly reduce an individual's composite genetic risk for cardiovascular disease death.