Lazarenko Victor, Churilin Mikhail, Azarova Iuliia, Klyosova Elena, Bykanova Marina, Ob'edkova Natalia, Churnosov Mikhail, Bushueva Olga, Mal Galina, Povetkin Sergey, Kononov Stanislav, Luneva Yulia, Zhabin Sergey, Polonikova Anna, Gavrilenko Alina, Saraev Igor, Solodilova Maria, Polonikov Alexey
Department of Surgical Diseases, Institute of Continuing Education, Kursk State Medical University, 3 Karl Marx Street, 305041 Kursk, Russia.
Department of Infectious Diseases and Epidemiology, Kursk State Medical University, 3 Karl Marx Street, 305041 Kursk, Russia.
Biomedicines. 2022 Jan 25;10(2):259. doi: 10.3390/biomedicines10020259.
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 ( = 0.009), rs55730499 of ( = 0.0007), rs3136441 of ( < 0.0001), and rs6065906 of ( = 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.
本研究旨在通过全面的统计和生物信息学分析，评估全基因组关联研究（GWAS）鉴定出的脂质相关基因座参与冠状动脉疾病（CAD）分子发病机制的潜在机制。对来自俄罗斯中部的1700名斯拉夫裔无关个体进行了检查，其中包括991名CAD患者和709名健康对照。从欧洲研究中选择了16个脂质相关的GWAS基因座，并使用MassArray-4系统进行基因分型。这些多态性与血浆脂质如总胆固醇（rs12328675、rs4846914、rs55730499和rs838880）、低密度脂蛋白胆固醇（rs3764261、rs55730499、rs1689800和rs838880）、高密度脂蛋白胆固醇（rs3764261）以及颈动脉内膜中层厚度/CIMT（rs12328675、rs11220463和rs1689800）相关。诸如rs4420638（P = 0.009）、rs55730499（P = 0.0007）、rs3136441（P < 0.0001）和rs6065906（P = 0.002）等多态性与CAD风险显示出显著关联，无论性别、年龄和体重指数如何。大多数观察到的关联在大型独立队列中成功得到复制。生物信息学分析有助于确定：（1）对所有研究的心血管表型有贡献的表型特异性和共享的上位基因-基因以及基因与吸烟的相互作用；（2）脂质相关的GWAS基因座可能是来自控制动脉粥样硬化多方面分子机制的基因调控网络的转录因子的等位基因特异性结合位点。
