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Varicose Vein GWAS Points to Vascular Risk Loci, Potential Treatment Targets

NEW YORK – The genetic contributors to varicose vein risk include factors shared with other vascular conditions, according to new research by a University of Pennsylvania-led team.

"In the largest and most diverse GWAS of varicose veins to date, we identify genetic risk loci for varicose veins, highlight shared risk factors with other vascular diseases, connect genetic variants to biological pathways with multiomic network analysis, and identify potential therapeutic targets and drug-repurposing opportunities," senior and corresponding author Scott Damrauer, a researcher at the Corporal Michael J. Crescenz VA Medical Center and the University of Pennsylvania Perelman School of Medicine, and his colleagues wrote.

The findings appeared in Nature Cardiovascular Research on Monday.

After performing an ancestry-specific genome-wide association study using genotyping data and electronic health record profiles for 18,977 varicose vein cases and 561,203 controls from the Veterans Affairs' Million Veteran Program (MVP), the researchers brought in data from several other large biobanks for multi-ancestry GWAS meta-analyses encompassing 49,765 individuals with varicose veins and more than 1.3 million unaffected control individuals of African, East Asian, European, or Hispanic ancestry.

In particular, the team's search uncovered more than 8,300 variants at 139 genome-wide significant, varicose vein-associated loci and validated 30 of the three dozen loci linked to varicose veins in the past.

Such variants appeared to be overrepresented in a range of vascular, reproductive, breast, and other tissues based on analyses of GWAS summary statistics in combination with RNA sequencing profiles available through version 8 of the Genotype-Tissue Expression project, the researchers noted.

They saw further overlap with vascular traits and conditions by mapping polygenic and gene-based features found for varicose vein risk — overlap that they explored in more detail with a phenome-wide association analysis focused on thousands of diagnosis/treatment, trait measurements, or circulating metabolite or protein profiles documented in the UK Biobank or the Medical Research Council Integrative Epidemiology Unit OpenGWAS project.

Together, the authors reported, results of the analyses "suggest that genetic risk variants for varicose veins are shared with anthropometric traits and vascular proteins, providing support for primary and secondary causes of varicose veins, and identifying potential molecular mediators of disease pathogenesis."

Meanwhile, by combining gene-set enrichment clues, gene function data, tissue-specific epigenetic profiles, and other features, the researchers got a look at some of the biological processes at play during varicose vein development. Their systems-based analyses suggested an over-representation of genes from pathways involved in inflammation and T-cell activation, leukocyte adhesion/invasion, blood pressure and endothelial shear stress, extracellular matrix and vascular wall remodeling, new blood vessel formation, and wound healing pathways.

The team also searched for potential therapeutic targets and drug repurposing opportunities by incorporating insights from genetic variant-based Mendelian randomization and proteome-wide Mendelian randomization analyses that looked at expression patterns and circulating proteins that appeared to have causal ties to the condition.

From dozens of potential targets, the authors flagged a handful of genes coding for potentially targetable proteins, including a phosphodiesterase enzyme, integrin beta 3, and thrombin, for example.

"Varicose veins represent a common cause of cardiovascular morbidity, with limited available medical therapies," the authors wrote, suggesting that results from the study "may facilitate future efforts to develop nonsurgical therapies for varicose veins."