Abstract

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.

中文翻译：

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VEGFA基因多态性与冠状动脉疾病：基因与疾病易感性之间的性别差异

摘要

血管内皮生长因子A（VEGFA）基因的多态性代表了冠心病（CAD）遗传研究的诱人标记。该研究的目的是调查俄罗斯中部的VEGFA基因的四个单核苷酸多态性（SNP）rs3025039，rs833061，rs3025000和rs833068与CAD风险之间的关系。使用MassARRAY-4系统对SNP进行基因分型。SNP rs3025039，rs833061和rs3025000仅与男性的CAD风险相关（P = 0.05）。单体型H3（rs833061-T–rs833068-A–rs3025000-T–rs3025039-C）和H2（rs833061-T–rs833068-G–rs3025000-C–rs3025039-С）与男性CAD风险降低相关，P = 0.01和P分别为0.05。相反，在女性中，H4单倍型（rs833061-C–rs833068-G–rs3025000-C–rs3025039-T）与CAD风险增加相关（P = 0.01）。按性别分层的SNP之间的连锁不平衡（LD）分析显示，男性中rs833061-T等位基因与rs833068-G和rs3025000-C等位基因呈阴性LD，女性中呈阳性LD（P = 2.0×10 ^–16），而SNP rs3025039与男性的SNP rs3025039呈弱阳性LD。miRBase数据库可以识别rs3025039-T等位基因为miRNA hsa-mir-591创建一个结合位点，该位点可以抑制VEGFA的翻译基因通过阻断和降解其DNA转录物。GTEx门户数据的分析表明，与CAD相关的单倍型可能会影响VEGFA基因的表达。VEGFA的SNP之间的连锁不平衡及其与冠状动脉疾病的联系的性别特异性特征首次引起人们的关注，需要进一步研究。