Assessing genetic risk factors for early-onset coronary artery disease in Iranians

Background: Coronary artery disease (CAD) is a leading cause of death worldwide. Evidence of genetic predisposition is derived mostly from studies of Europeans and East Asians. Objectives: To test selected variants for association with early-onset CAD. Methods: We performed a case-control study of 697 young angiography-defined CAD cases (women aged <55 years, men <45) and 911 age- and sex-matched controls in Iran. We tested 24 variants (12 established CAD loci, 12 candidates in hemostasis genes) using age- and sex-adjusted logistic regression, stratified by ethnicity. A 6-variant unweighted genetic risk score (GRS) was built from the top loci. Additive interaction with cardiovascular risk factors was assessed by relative excess risk due to interaction. Results: Of 12 established loci, HCG27–HLA-C, CDKN2A/CDKN2B, and SORT1 showed nominal or near-nominal replication and 4 were directionally aligned with prior literature, whereas 5 showed no association. Among hemostasis candidates, F5 rs4524 was nominally associated with increased risk, and TSPAN15 rs78707713 and F11 rs2289252 suggested reduced risk. Ethnicity-stratified analyses indicated nominal or suggestive ancestry-specific effects at SORT1, HCG27–HLA-C, CDKN2A/CDKN2B, LPA, VWF, MIA3, and CXCL12. The GRS (range, 2-11 alleles/person) yielded a per-allele odds ratio of 1.20 (95% CI, 1.12-1.29), ie, a 5.2-fold higher risk across the observed range. Combining GRS with metabolic comorbidities showed super-additive effects (relative excess risk due to interaction, 6.66; 95% CI, 2.04-11.28). Conclusion: Ten variants, including 3 previously linked to venous thrombosis, showed nominal or suggestive association with early-onset CAD in Iranians or specific ethnic groups. Genetic burden substantially amplified risk in the presence of metabolic comorbidities. Our findings underscore the need for ancestry-aware studies in multiethnic populations.