Lifestyle factors, genetic susceptibility to obesity and their interactions on coronary artery disease risk: A cohort study in the UK Biobank

Objective: We aimed to evaluate potential modifying effects of genetic susceptibility to obesity on the association of lifestyle factors with coronary artery disease (CAD) risk. Methods: A total of 328,606 participants (54% women) were included using data from the UK Biobank. We evaluated the risk of developing CAD associated with obesity -related polygenic scores (PGSs) and healthy lifestyle scores (HLSs). HLSs were constructed using six lifestyle factors. Obesity PGSs were created using genetic variants identified by genome-wide association studies, including 941 variants for body mass index (BMI) and 457 for waist -to -hip ratio (WHR). Both HLSs and PGSs were categorized into three groups. Results: During a 9 -year median follow-up, 14,541 participants developed CAD. An unhealthy lifestyle was significantly associated with an increased CAD risk (hazard ratio [HR] = 2.24, 95% confidence interval [CI] = 2.09-2.40). High BMI and WHR PGSs were each significantly associated with an increased CAD risk (HRBMI = 1.23, 1.17-1.29; HRWHR = 1.15, 1.09-1.21). Lifestyle factors explained 41% (95% CI = 38%-45%) of CAD, while genetic variants for BMI explained only 10% (7%-14%). Risks of CAD were increased with poorer HLS independent of obesity -related PGSs. Individuals with the most unhealthy lifestyle and highest BMI PGS had the highest risk of CAD risk (HR = 2.59, 95% CI = 2.26-2.97), compared with participants with the healthiest lifestyle and lowest BMI PGS. Conclusions: While the observational nature of the study precludes the establishment of causality, our study provides supports for a causal association between obesity and CAD risk and the importance of lifestyle modification in the prevention of CAD.