CIRCULATIONAHA.121.058389 (2).pdf (3.14 MB)
Download file

Effects of Coronary Artery Disease-Associated Variants on Vascular Smooth Muscle Cells

Download (3.14 MB)
journal contribution
posted on 02.08.2022, 16:33 authored by Charles U Solomon, David G McVey, Catherine Andreadi, Peng Gong, Lenka Turner, Paulina J Stanczyk, Sonja Khemiri, Julie C Chamberlain, Wei Yang, Tom R Webb, Christopher P Nelson, Nilesh J Samani, Shu Ye

Background

Genome-wide association studies have identified many genetic loci that are robustly associated with coronary artery disease (CAD). However, the underlying biological mechanisms are still unknown for most of these loci, hindering the progress to medical translation. Evidence suggests that the genetic influence on CAD susceptibility may act partly through vascular smooth muscle cells (VSMCs).

Methods

We undertook genotyping, RNA sequencing, and cell behavior assays on a large bank of VSMCs (n>1499). Expression quantitative trait locus and splicing quantitative trait locus analyses were performed to identify genes with an expression that was influenced by CAD-associated variants. To identify candidate causal genes for CAD, we ascertained colocalizations of VSMC expression quantitative trait locus signals with CAD association signals by performing causal variants identification in associated regions analysis and the summary data-based mendelian randomization test. Druggability analysis was then performed on the candidate causal genes. CAD risk variants were tested for associations with VSMC proliferation, migration, and apoptosis. Collective effects of multiple CAD-associated variants on VSMC behavior were estimated by polygenic scores.

Results

Approximately 60% of the known CAD-associated variants showed statistically significant expression quantitative trait locus or splicing quantitative trait locus effects in VSMCs. Colocalization analyses identified 84 genes with expression quantitative trait locus signals that significantly colocalized with CAD association signals, identifying them as candidate causal genes. Druggability analysis indicated that 38 of the candidate causal genes were druggable, and 13 had evidence of drug-gene interactions. Of the CAD-associated variants tested, 139 showed suggestive associations with VSMC proliferation, migration, or apoptosis. A polygenic score model explained up to 5.94% of variation in several VSMC behavior parameters, consistent with polygenic influences on VSMC behavior.

Conclusions

This comprehensive analysis shows that a large percentage of CAD loci can modulate gene expression in VSMCs and influence VSMC behavior. Several candidate causal genes identified are likely to be druggable and thus represent potential therapeutic targets.

History

Author affiliation

Department of Cardiovascular Sciences, University of Leicester

Version

VoR (Version of Record)

Published in

Circulation

Publisher

Lippincott, Williams & Wilkins for American Heart Association

issn

0009-7322

eissn

1524-4539

Copyright date

2022

Available date

02/08/2022

Spatial coverage

United States

Language

eng