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

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.