The functional insight into the genetics of cardiovascular disease: results from the post-GWAS study.

L O Bryzgalov,T I Merkulova,E E Korbolina,I S Damarov

doi:10.18699/vjgb-22-10

Abstract

Cardiovascular diseases (CVDs), the leading cause of death worldwide, generally refer to a range of pathological conditions with the involvement of the heart and the blood vessels. A sizable fraction of the susceptibility loci is known, but the underlying mechanisms have been established only for a small proportion. Therefore, there is an increasing need to explore the functional relevance of trait-associated variants and, moreover, to search for novel risk genetic variation. We have reported the bioinformatic approach allowing effective identif ication of functional non-coding variants by integrated analysis of genome-wide data. Here, the analysis of 1361 previously identif ied regulatory SNPs (rSNPs) was performed to provide new insights into cardiovascular risk. We found 773,471 coding co-segregating markers for input rSNPs using the 1000 Genomes Project. The intersection of GWAS-derived SNPs with a relevance to cardiovascular traits with these markers was analyzed within a window of 10 Kbp. The effects on the transcription factor (TF) binding sites were explored by DeFine models. Functional pathway enrichment and protein–protein interaction (PPI) network analyses were performed on the targets and the extended genes by STRING and DAVID. Eighteen rSNPs were functionally linked to cardiovascular risk. A signif icant impact on binding sites of thirteen TFs including those involved in blood cells formation, hematopoiesis, macrophage function, inf lammation, and vasoconstriction was found in K562 cells. 21 rSNP gene targets and 5 partners predicted by PPI were enriched for spliceosome and endocytosis KEGG pathways, endosome sorting complex and mRNA splicing REACTOME pathways. Related Gene Ontology terms included mRNA splicing and processing, endosome transport and protein catabolic processes. Together, the f indings provide further insight into the biological basis of CVDs and highlight the importance of the precise regulation of splicing and alternative splicing

Highlights

While the running data indicate that the prevalence of cardiovascular disease may vary among regions of the world, they remain one of the leading causes of death and health loss and a large proportion of their forms are shown to have a familial aggregation and high heritability (Smith J.G., Newton-Cheh, 2015; Roth et al, 2017; Wang Y., Wang J.-G., 2018)
One interesting result was that ten GWASderived SNPs including the ones for phenotypical associations with systolic and diastolic blood pressure, pulse pressure, retinal arteriolar microcirculation and one for coronary artery disease (CAD) entered the list of founded regulatory SNPs in the study
We considered the input regulatory SNPs (rSNPs) targets (Korbolina et al, 2018), and any gene targeted to these ten GWAS-SNPs to be a candidate for mediating the association

Summary

Introduction

While the running data indicate that the prevalence of cardiovascular disease may vary among regions of the world, they remain one of the leading causes of death and health loss and a large proportion of their forms are shown to have a familial aggregation and high heritability (Smith J.G., Newton-Cheh, 2015; Roth et al, 2017; Wang Y., Wang J.-G., 2018). The previous efforts led to the identification of candidate risk genes including the genes of renal homeostasis for Mendelian forms of abnormal blood pressure levels and several transcription fact ors (including NKX25, GATA4, TBX) for congenital sep tal (Kathiresan, Srivastava, 2012). With the recent technological advances, the whole-exome sequencing (Li A.H. et al, 2017; Seidelmann et al, 2017; Khera et al, 2019) and genome-wide association studies, GWASs (in particular (Erdmann et al, 2018; Schunkert et al, 2018)) have been shown to be a powerful tool for discovering the genetic variation associated with cardiovascular risk. The genes related to regulating blood pressure, the tone and elasticity of the vascular wall, the inflammation process, the proliferation of vascular smooth muscle cells and the levels of low density lipoprotein cholesterol (LDC-C) are ‘traditionally’ involved in cardiovascular risk. A considerable overlap has been shown between the risk genes for monogenic forms of CVDs and those generating an association signal in GWAS (Rau et al, 2015)

Methods

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Discussion

Conclusion