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

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.

To test selected variants for association with early-onset CAD.

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.

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).

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.