Comprehensive Statistical and Bioinformatics Analysis in the Deciphering of Putative Mechanisms by Which Lipid-Associated GWAS Loci Contribute to Coronary Artery Disease
Victor Lazarenko,
Mikhail Churilin,
Iuliia Azarova,
Elena Klyosova,
Marina Bykanova,
Natalia Ob'edkova,
Mikhail Churnosov,
Olga Bushueva,
Galina Mal,
Sergey Povetkin,
Stanislav Kononov,
Yulia Luneva,
Sergey Zhabin,
Anna Polonikova,
Alina Gavrilenko,
Igor Saraev,
Maria Solodilova,
Alexey Polonikov
Affiliations
Victor Lazarenko
Department of Surgical Diseases, Institute of Continuing Education, Kursk State Medical University, 3 Karl Marx Street, 305041 Kursk, Russia
Mikhail Churilin
Department of Infectious Diseases and Epidemiology, Kursk State Medical University, 3 Karl Marx Street, 305041 Kursk, Russia
Iuliia Azarova
Department of Biological Chemistry, Kursk State Medical University, 3 Karl Marx Street, 305041 Kursk, Russia
Elena Klyosova
Laboratory of Biochemical Genetics and Metabolomics, Research Institute for Genetic and Molecular Epidemiology, Kursk State Medical University, 18 Yamskaya Street, 305041 Kursk, Russia
Marina Bykanova
Laboratory of Genomic Research, Research Institute for Genetic and Molecular Epidemiology, Kursk State Medical University, 18 Yamskaya Street, 305041 Kursk, Russia
Natalia Ob'edkova
Department of Polyclinical Therapy and General Medical Practice, Kursk State Medical University, 3 Karl Marx Street, 305041 Kursk, Russia
Mikhail Churnosov
Department of Medical Biological Disciplines, Belgorod State University, 85 Pobedy Street, 308015 Belgorod, Russia
Olga Bushueva
Laboratory of Genomic Research, Research Institute for Genetic and Molecular Epidemiology, Kursk State Medical University, 18 Yamskaya Street, 305041 Kursk, Russia
Galina Mal
Department of Pharmacology, Kursk State Medical University, 3 Karl Marx Street, 305041 Kursk, Russia
Sergey Povetkin
Department of Clinical Pharmacology, Kursk State Medical University, 3 Karl Marx Street, 305041 Kursk, Russia
Stanislav Kononov
Department of Internal Medicine No 2, Kursk State Medical University, 3 Karl Marx Street, 305041 Kursk, Russia
Yulia Luneva
Department of Clinical Pharmacology, Kursk State Medical University, 3 Karl Marx Street, 305041 Kursk, Russia
Sergey Zhabin
Department of Surgical Diseases No 1, Kursk State Medical University, 3 Karl Marx Street, 305041 Kursk, Russia
Anna Polonikova
Department of Biology, Medical Genetics and Ecology, Kursk State Medical University, 3 Karl Marx Street, 305041 Kursk, Russia
Alina Gavrilenko
Department of Infectious Diseases and Epidemiology, Kursk State Medical University, 3 Karl Marx Street, 305041 Kursk, Russia
Igor Saraev
Department of Internal Medicine No 2, Kursk State Medical University, 3 Karl Marx Street, 305041 Kursk, Russia
Maria Solodilova
Department of Biology, Medical Genetics and Ecology, Kursk State Medical University, 3 Karl Marx Street, 305041 Kursk, Russia
Alexey Polonikov
Department of Biology, Medical Genetics and Ecology, Kursk State Medical University, 3 Karl Marx Street, 305041 Kursk, Russia
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 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.
