Genetic contribution to CAD in patients with few traditional risk factors but a sedentary lifestyle

Introduction Physical inactivity has mainly been recognised as a risk factor for coronary arterial disease (CAD), an essential modifiable risk impacting public health. Although there is a significant correlation between physical inactivity and the incidence of cardiovascular disease (CV), a considerable proportion of people with sedentary lifestyles remain CAD-free. This disparity prompts fascinating inquiries into the intricate interactions among environmental, epigenetic, and genetic factors contributing to CAD. Objective Evaluate which genetic polymorphisms are responsible for a higher probability of occurrence of CAD in individuals with physical inactivity but without other CV risk factors. Methods A case-control study was conducted involving individuals with physical inactivity, with a few traditional risk factors: density lipoprotein (LDL) levels<100 mg/dL, non-diabetic, and non-hypertensive. Of 3.157 participants, 152 (77.6% men; aged 50.8±8.9) were enrolled and subdivided into two groups: 100 patients with CAD (defined as having at least 70% stenosis in one major coronary artery) and 52 controls without CAD. Four polymorphisms previously associated with CAD by GWAS but not with TRFs (CDKN2B-AS1 G>C, PHACTR1 C>T, ACE I>D and SLC30A8 T>C) were genotyped using TaqMan real-time PCR. Then, we performed a bivariate analysis to evaluate genotype distribution in cases and controls and a multivariate regression analysis to assess what genotype or genetic models were significant and independently associated with CAD. Results After bivariate analysis, PHACTR1 rs1332844 variant, ACE I/D rs4340, CDKN2B-AS1 rs1333049 and rs497757 variants, and SLC30A8 rs1326634 were significantly more prevalent in the CAD cohort. After multivariate regression analysis entering the four variants in the recessive genetic models, PHACTR1 C>T remained in the equation significantly associated with CAD (OR 2.82; p=0.019) together with SLC30A8 T>C (OR 3.05; p=0.003) and CDKN2B-AS1 T>C (OR 2.49; p=0.028). Conclusion Although the variation in physical activity and sedentariness is likely to be determined by many factors, the influence of genetics is significant. Our findings suggest three genetic variants related to the cellular cycle, apoptosis, endothelial dysfunction, and inflammation, which are significantly associated with CAD in sedentary people with few traditional risk factors. A synergistic effect of a sedentary lifestyle and genetic influence may explain CAD susceptibility.