The study was designed to evaluate putative mechanisms by which lipid-associated loci identified by genome-wide association studies (GWAS) are involved in the molecular pathogenesis of coronary artery disease (CAD) using a comprehensive statistical and bioinformatics analysis. A total of 1700 unrelated individuals of Slavic origin from the Central Russia, including 991 CAD patients and 709 healthy controls were examined. Sixteen lipid-associated GWAS loci were selected from European studies and genotyped using the MassArray-4 system. The polymorphisms were associated with plasma lipids such as total cholesterol (rs12328675, rs4846914, rs55730499, and rs838880), LDL-cholesterol (rs3764261, rs55730499, rs1689800, and rs838880), HDL-cholesterol (rs3764261) as well as carotid intima-media thickness/CIMT (rs12328675, rs11220463, and rs1689800). Polymorphisms such as rs4420638 of APOC1 (p = 0.009), rs55730499 of LPA (p = 0.0007), rs3136441 of F2 (p < 0.0001), and rs6065906 of PLTP (p = 0.002) showed significant associations with the risk of CAD, regardless of sex, age, and body mass index. A majority of the observed associations were successfully replicated in large independent cohorts. Bioinformatics analysis allowed establishing (1) phenotype-specific and shared epistatic gene–gene and gene–smoking interactions contributing to all studied cardiovascular phenotypes; (2) lipid-associated GWAS loci might be allele-specific binding sites for transcription factors from gene regulatory networks controlling multifaceted molecular mechanisms of atherosclerosis.

The influence of single nucleotide polymorphism (SNP) of genes encoding intracellular cholesterol transporters, such as rs1883025 of ABCA1, rs217406 of NPC1L1, and rs881844 of STARD3, on blood lipid levels, carotid intima-media thickness (CIMT), and the risk of coronary heart disease (CHD) has been studied. SNP genotyping was performed using the MassARRAY 4 system. The effects of polymorphic genes on transformed values of blood lipids and CIMT were evaluated by linear regression analysis separately in men and women and adjusted for age and body mass index. SNP rs881844 of the STARD3 gene was associated with decreased risk of CHD in men (OR = 0.67, 95% CI 0.46–0.96, P = 0.02). In women, SNP rs1883025 of ABCA1 showed an association with decreased risk of CHD (OR = 0.65, 95% CI 0.44–0.95, P = 0.02). In men, SNP rs1883025 of the ABCA1 gene was associated with the levels of low density lipoprotein cholesterol (P = 0.05), whereas SNP rs217406 was associated with triglyceride levels (P = 0.02). Polymorphisms such as rs217406 of NPC1L1 and rs881844 of STARD3 in women and rs1883025 of ABCA1 in men were associated with CIMT. The present study has identified for the first time that rs1883025 of ABCA1 and rs881844 of STARD3 are associated with susceptibility to coronary heart disease and showed clear sex-specific differences in the associations between the genes and the studied phenotypes. Thus, polymorphic variants of genes encoding intracellular cholesterol transporters are potentially involved in the formation of the atherosclerotic process through the mechanisms that seem to be not directly related to the metabolism of cholesterol and cholesterol of low density lipoproteins.