Exploring sex-specific genetic architecture of coronary artery disease in Tehran: a cardiometabolic genetic study

The development of coronary artery disease (CAD) is influenced by sex and genetic factors. Genome-wide association studies (GWAS) have linked genetic loci to CAD, mostly in European populations. The study aims to find sex-related genetic differences in the Iranian population. We conducted a sex-stratified GWAS with 4519 subjects (1832 males and 2687 females) in the discovery group and 922 subjects (495 males and 427 females) in the confirmation group of an Iranian cohort. We analyzed 9,141,124 variants using a genome-wide complex trait analysis (GCTA) tool. We detected distinct genetic variants associated with CAD in males: rs34952209 [OR = 1.79; <i>p</i> = 5.216E–8], rs1432687863 [OR = 1.95; <i>p</i> = 8.477E–8], and in females, rs7314741 [OR = 1.67; <i>p</i> = 7.142-8E] positively influenced CAD risk. The CAD-associated SNPs that were obtained have been confirmed using independent samples. Rs3495229 May impact histone mark and Pou2f2 motifs, while rs7314741 in the LEM Domain Containing 3 (LEMD3) promoter may affect a regulatory motif for the STAT transcription factor. According to Roadmap and ENCODE data, Rs1432687863 is a new variant affecting CAD in males, potentially through H3K9me3 in the heart. Our findings highlight the role of sex-specific genetic differences in CAD development, providing novel insights into disease pathways which is not appropriate using a sex-combined strategy.