Interplay between lifestyle factors and polygenic risk for incident coronary heart disease in a large multiethnic cohort.

Introduction: The objective of this study was to examine the interplay of polygenic risk and individual lifestyle factors (and a composite score of lifestyle) as antecedents of CHD in a large multiethnic cohort. Methods: We used Genetic Epidemiology Resource in Adult Health and Aging (GERA) cohort participants free of CHD at baseline (n = 60,568; 67 % female; 18 % non-European). The individual and joint associations of smoking, Mediterranean diet pattern, level of physical activity and polygenic risk with incident CHD were assessed using Cox regression adjusting for genetic ancestry and non-mediating risk factors. Hazard ratios (HRs) and number needed to treat (NNT) were estimated according to these lifestyle factors and polygenic risk categories. Strengths included large sample size, long-follow-up, ethnic diversity, a clinically-validated polygenic risk score (PRS), and rich phenotype information. Results: After 14 years of follow-up, there were 3159 incident CHD events. We observed no statistically significant interactions between individual lifestyle factors and polygenic risk (all p > 0.23). For individuals with a high genetic risk, moving from the worse lifestyle combination (no favorable lifestyle factors) to the best lifestyle combination (all three) is associated with 52 % lower rate of CHD. The NNT was highest in the low polygenic risk group (34), lowest in the high polygenic risk group [19] and in-between (Jin et al., 2011) [24] in the intermediate polygenic risk group. Conclusions: Lifestyle and polygenic risk together influence the risk of incident CHD. Our results support consideration of polygenic risk in lifestyle interventions because those with high polygenic risk are likely to derive the most benefit.