Genetics could help the identification of coronary artery disease in smoker patients with few other cardiovascular risk factors

Abstract Introduction Coronary arterial disease (CAD) poses a significant public health challenge, with tobacco recognized as the most predominant modifiable risk factor in young individuals. Despite a strong correlation between tobacco use and cardiovascular (CV) events, many smokers remain event-free. This fact raises questions about the complex interplay of environmental, epigenetic, and genetic factors contributing to CAD. Objective To identify genetic polymorphisms potentially responsible for CAD in smokers without other cardiovascular risk factors. Methods A case-control study involved individuals with low-density lipoprotein (LDL) levels 100mg/dl who were non-diabetic and non-hypertensive. 134 individuals (83% men; age 48.9±8.4 years) were enrolled, comprising 97 CAD patients (defined as having at least 70% stenosis in one major coronary artery) and 37 controls without CAD. Eight polymorphisms previously associated with CAD but not with traditional risk factors (TRFs) were genotyped using TaqMan real-time PCR: CDKN2B-AS1 (rs1333049/rs4977574), TCF21 (rs12190287), PHACTR1 (rs1332844), MIA3 (rs17465637), ADAMTS7 (rs3825807), ZC3HC1 (rs11556924), SMAD3 (rs17228212), and GJA4 (rs618675). Bivariate and multivariate analyses compared genotypic proportions between CAD and non-CAD groups. Results The PHACTR1 polymorphism (rs1332844 TT/TC) was significantly more prevalent in the CAD cohort, with 86.6% of CAD patients exhibiting this genotype compared to 70.3% of controls (p=0.028). After multivariate analysis of the eight polymorphisms, the PHACTR1 variant remained associated with CAD (OR 2.7; p=0.031). No other genetic variant examined was associated with CAD in this population. Conclusion The PHACTR1 variant is linked to an increased risk of CAD in smokers without other main CV risk factors. This gene encodes a phosphatase and actin regulator protein involved in endothelial cell stabilization, suggesting a synergistic effect of smoking and the PHACTR1 endothelial dysfunction.