Comprehensive Statistical and Bioinformatics Analysis in the Deciphering of Putative Mechanisms by Which Lipid-Associated GWAS Loci Contribute to Coronary Artery Disease.

Victor Lazarenko,Igor Saraev,Maria Solodilova,Mikhail Churnosov,Elena Klyosova,Olga Bushueva,Sergey Zhabin,Natalia Ob'Edkova,Marina Bykanova,Yulia Luneva,Alexey Polonikov,Alina Gavrilenko,Galina Mal,Sergey Povetkin,Stanislav Kononov,Mikhail Churilin,Iuliia Azarova,Anna Polonikova

doi:10.3390/biomedicines10020259

Victor Lazarenko, Igor Saraev + Show 16 more

Open Access

https://doi.org/10.3390/biomedicines10020259

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Abstract

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.

Highlights

Cardiovascular diseases (CVD) were defined by the World Health Organization as the leading cause of death worldwide with an estimated 17.5 million of these cases occurring in 2017, and 42.3% of them were attributed to coronary artery disease (CAD) [1].CAD is one of the most common cardiovascular disorders responsible for, in addition to high mortality rates, an increased disability as well as a decreased quality of life in the world [1,2]
We performed a comprehensive statistical and bioinformatics analysis including (a) the model-based multifactor dimensionality reduction method for stochastic modeling gene-gene and gene-environment interactions constituting the polygenic mechanisms of coronary artery disease and contributing to the intermediate cardiovascular phenotypes such as plasma lipids, lipoproteins, and carotid intima-media thickness, (b) functional SNP annotation for assessing their regulatory potential and impact on gene expression in a tissue specific manner, and (c) in silico prediction of allele-specific binding sites for transcription factors at the lipid-associated genome-wide association studies (GWAS) loci to identify pathways and gene regulatory networks controlling the molecular pathogenesis of CAD
Putative mechanisms by which lipid-associated GWAS loci contribute to CAD susceptibility involve well-recognized atherogenic changes in the plasma lipid profile, such as increased levels of total cholesterol and low-density lipoprotein cholesterol, as well as thickening of the arterial wall, as assessed through measuring Carotid intima-media thickness (CIMT)

Summary

Introduction

Cardiovascular diseases (CVD) were defined by the World Health Organization as the leading cause of death worldwide with an estimated 17.5 million of these cases occurring in 2017, and 42.3% of them were attributed to coronary artery disease (CAD) [1]. CAD is one of the most common cardiovascular disorders responsible for, in addition to high mortality rates, an increased disability as well as a decreased quality of life in the world [1,2]. Disorders of lipid metabolism are characterized by the deposition of cholesterol and atherogenic lipoproteins in the vascular wall, thereby contributing to the development of coronary atherosclerosis [3]. Carotid intima-media thickness (CIMT) along with atherogenic lipid metabolism disorders represents well-characterized diagnostic markers for assessing the initial stages of vascular wall modifications underlying atherosclerosis [6]

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