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New Candidate Genes for Heart Valve Condition Uncovered in Integrative Genomic Study

NEW YORK – With a combination of genomic association and sequencing approaches, researchers have identified new genetic risk loci, candidate genes, and pathways contributing to a heart valve condition called calcific aortic valve stenosis (CAVS), which is marked by progressive calcification that narrows the aortic valve, restricting the volume of blood that can move through it and increasing pressure on the heart.

"We highlight the potential contribution of endothelial-mesenchymal transition, circulating lipoproteins, blood pressure, vascular remodeling, and inflammation in the disease process," first and corresponding author Sébastien Thériault, a researcher affiliated with Laval University and the University Institute of Cardiology and Pneumology of Quebec-ULaval, and his colleagues wrote in Nature Communications on Monday, noting that the results "pave the way for the identification of novel therapeutic targets for CAVS."

For their study, researchers at Laval, the University of Tartu, the University of Cambridge, and other centers started with a genome-wide association study and GWAS meta-analysis involving 14,819 participants of European ancestry with CAVS and 941,863 without, focusing in on 32 new or previously described CAVS-related loci.

By bringing in RNA sequencing profiles for 500 human aortic valve samples, together with expression quantitative trait locus (eQTL) results, the team found that the CAVS risk loci tended to turn up in parts of the genome that are linked to expression regulation. Digging into these expression regulatory sites, in turn, led to suspected causal genes as well as pathways that appear to be altered in affected tissues.

"We report several significant eQTL at [CAVS-associated] genomic loci, many of which are specific to the aortic valve, implicating tissue-specific regulatory mechanisms," the authors reported. "We also show robust evidence of [a] genetic relationship between CAVS and several traits, including circulating lipids, blood pressure, atherosclerotic cardiovascular diseases, and inflammation."

Using combined colocalization, Mendelian randomization, and transcriptome-wide association study analyses, meanwhile, the investigators flagged eight genes — PRRX1, ATP13A3, TWIST1, BCL10, RAD9A, NRBP1, FES, and AFAP1 — with apparent ties to CAVS.

The team noted that two of the genes, PRRX1 and TWIST1, code for epithelial-mesenchymal transition-related transcription factors with ties to transcriptional regulatory networks related to fibroblast activation.

Moreover, the investigators explained, a CAVS-linked locus near TWIST1 appeared to have pronounced effects on gene expression profiles found in the aortic valve, particularly when two copies of a CAVS-associated variant turned up at this locus. Likewise, they highlighted a tissue-specific eQTL neighboring PRRX1, which is itself expressed at high levels in human aortic valve tissue.

The team also conducted additional cross-phenotype analyses and a phenome-wide association study of genes or loci found by GWAS or TWAS that was done using data on dozens of cardiovascular traits profiled in UK Biobank participants. Those results pointed to blood pressure, inflammation, and circulating lipoprotein pathways as potential players in CAVS development and disease biology.

The authors noted that several CAVS-associated loci overlapped with sites linked to blood lipid levels or blood pressure traits, while their genetic correlation findings "showed consistent relationships between CAVS and pulse pressure as well as aortic calcification, further supporting shared genetic mechanisms with vascular remodeling."