Polymorphism of the VEGFA Gene and Coronary Artery Disease: Sex Dimorphism in Relationship between the Gene and Disease Predisposition

Polymorphisms of vascular endothelial growth factor A (VEGFA) gene represent attractive markers for genetic studies of coronary artery disease (CAD). The aim of the study was to investigate relationship between four single nucleotide polymorphisms (SNPs) rs3025039, rs833061, rs3025000 and rs833068 of the VEGFA gene and the risk of CAD in Central Russia. Genotyping of SNPs was done using the MassARRAY-4 system. SNPs rs3025039, rs833061, and rs3025000 were associated with CAD risk solely in men (P = 0.05). Haplotypes H3 (rs833061-T–rs833068-A–rs3025000-T–rs3025039-C) and H2 (rs833061-T–rs833068-G–rs3025000-C–rs3025039-С) were associated with decreased risk of CAD in men, P = 0.01 and P = 0.05, respectively. In contrast, in women, the H4 haplotype (rs833061-C–rs833068-G–rs3025000-C–rs3025039-T) was associated with an increased risk of CAD (P = 0.01). Linkage disequilibrium (LD) analysis between SNPs stratified by sex revealed that the rs833061-T allele was in negative LD with the rs833068-G and rs3025000-C alleles in men and in positive LD in women (P = 2.0 × 10–16), whereas SNP rs3025039 was in a weak positive LD with SNP rs3025039 in men. The miRBase database allowed identifying that the rs3025039-T allele creates a binding site for miRNA hsa-mir-591, which can inhibit the translation of the VEGFA gene by blocking and degrading its DNA transcripts. An analysis of the GTEx portal data showed that haplotypes associated with CAD may affect the expression of the VEGFA gene. For the first time, sex-specific features of linkage disequilibrium between SNPs of VEGFA and their link with coronary artery disease are a subject of interest and require further investigations.