Utility of a polygenic risk score for incident CHD: interplay with lifestyle in a multi-ethnic cohort of more than 60,000 individuals

Abstract

Abstract Background The degree to which benefits of healthy eating, physical activity and not smoking are protective for coronary heart disease (CHD) based on levels of polygenic risk remains an important question. We set out to investigate whether and to what degree a favorable lifestyle could reduce the effect of high genetic risk. Methods We utilized data from the Genetic Epidemiology Resource in Adult Health and Aging (GERA) Multi-Ethnic cohort of 60,682 (mean ± SD age = 59 ± 9 years; 67% female; 18% non-European ancestry) Kaiser Permanente of Northern California (KPNC) members. We characterized the cohort at baseline in 2003-2007 by smoking status (never, former or current smoker), Mediterranean-pattern diet (MedDiet) and meeting current AHA physical activity recommendations (PAR) of at least 150 min of moderate activity or 75 min of vigorous activity per week. We stratified the cohort into three groups of CHD genetic risk (low: quintile 1, intermediate: quintiles 2, 3 and 4 combined, and high: quintile 5) using a validated 12-SNP Polygenic Risk Score (PRS) for CHD (CARDIO inCode-Score, GENinCode Plc). Incident CHD consisted of primary in-patient codes for angina pectoris, myocardial infarction, revascularization procedures or CHD death (n=2,220) through 12/31/2014; mean follow-up was 9.5 years. Results Age-adjusted CHD rates per 10,000 person-years were estimated using Poisson regression (accounting for death and health plan disenrollment) by number of favorable lifestyle factors (LF) and, within each level, by genetic risk groups (see Figure below). Genetic background provided further CHD risk stratification within each lifestyle group. The most favorable lifestyle (never smoking, MedDiet, meeting PAR) reduced the effect of high genetic risk by 59% (age-adjusted rates per 10,000 person-years 40 vs. 99) and similar reductions were observed at intermediate or low genetic risk. Conclusions Our results are consistent with an additive model of genetic risk and lifestyle as determinants of CHD. These results underscore the importance of favorable lifestyle and the need to prioritize those individuals with the highest CHD risk (most unfavorable lifestyle and high genetic risk), who will benefit the most from lifestyle advice.