A non-coding ABO regulatory variant associatedwith VWF levels, thrombosis risk, and COVID-19 severity is topologically linked to ADAMTS13 in endothelial cells

TL;DR

This study finds that non-coding ABO gene variants are linked to blood clot risk, VWF levels, and severe COVID-19 by regulating ADAMTS13 in blood vessel cells.

Contribution

The study identifies a non-coding ABO variant that regulates ADAMTS13 through chromatin interactions, linking it to thrombosis and COVID-19 severity.

Findings

Non-coding ABO variants are spatially linked to ADAMTS13 in endothelial cells.

CRISPRa activation of a non-coding ABO variant increases ADAMTS13 transcription.

The rs505922-C allele reduces transcriptional activity in endothelial cells.

Abstract

Venous thromboembolism (VTE) is a major cause of mortality, influenced by genetic and environmental factors. von Willebrand factor (VWF) mediates hemostasis by promoting platelet adhesion, and its plasma levels are associated with thrombotic risk. Although many non-coding variants in ABO are associated with VWF levels, VTE risk, and COVID-19 severity, the mechanisms underlying these associations remain unclear. In this study, we identified the ABO locus as the genomic region with the highest concentration of variants associated with VWF levels. Chromatin conformation analyses in endothelial cells revealed non-coding ABO variants (rs657152, rs9411377, rs660340, and rs505922) associated with VWF levels, VTE risk, and COVID-19 severity, located in spatial proximity to ADAMTS13. ADAMTS13 is a key regulator of VWF activity, and both ADAMTS13 and VWF play crucial roles in coagulation and thrombosis. Chromatin activation (CRISPRa) of the region near the non-coding ABO variant rs657152 increased ADAMTS13 transcription in endothelial cells, suggesting that this variant resides in a regulatory region with the potential to modulate long-range transcriptional control of ADAMTS13. Luciferase assay revealed reduced transcriptional activity driven by the rs505922-C allele in endothelial cells. These findings provide insights into the spatial organization of the ABO locus and its potential role in ADAMTS13 regulation.

Non-coding ABO variants associated with thrombosis, von Willebrand factor levels, and COVID-19 severity reveal topological proximity to ADAMTS13 in endothelial cells. Chromatin interaction data, CRISPRa assays, and enhancer activity analyses support a regulatory role for these variants in ADAMTS13 expression, revealing a potential cis-regulatory mechanism contributing to coagulation phenotypes.

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