Genetic Regulatory Mechanisms of Smooth Muscle Cells Map to Coronary Artery Disease Risk Loci

Abstract

Coronary artery disease (CAD) is the leading cause of death globally. Genome-wide association studies (GWASs) have identified more than 95 independent loci that influence CAD risk, most of which reside in non-coding regions of the genome. To interpret these loci, we generated transcriptome and whole-genome datasets using human coronary artery smooth muscle cells (HCASMCs) from 52 unrelated donors, as well as epigenomic datasets using ATAC-seq on a subset of 8 donors. Through systematic comparison with publicly available datasets from GTEx and ENCODE projects, we identified transcriptomic, epigenetic, and genetic regulatory mechanisms specific to HCASMCs. We assessed the relevance of HCASMCs to CAD risk using transcriptomic and epigenomic level analyses. By jointly modeling eQTL and GWAS datasets, we identified five genes (SIPA1, TCF21, SMAD3, FES, and PDGFRA) that may modulate CAD risk through HCASMCs, all of which have relevant functional roles in vascular remodeling. Comparison with GTEx data suggests that SIPA1 and PDGFRA influence CAD risk predominantly through HCASMCs, while other annotated genes may have multiple cell and tissue targets. Together, these results provide tissue-specific and mechanistic insights into the regulation of a critical vascular cell type associated with CAD in human populations.

Coronary artery disease genes SMAD3 and TCF21 promote opposing interactive genetic programs that regulate smooth muscle cell differentiation and disease risk

“…We have extended these studies to investigate the causality and directionality of the SMAD3 gene in CAD with three additional strategies. First, we assessed gene expression at the putative causal variant rs17293632 with disease relevant eQTL data from human coronary artery smooth muscle cells [ 59 ], and found that the risk C allele increases expression of SMAD3 ( p <0.05), indicating SMAD3 is a CAD promoting transcription factor and suggesting that this gene is active in this cell type in vivo ( Fig 5A ).…”

“…Having recently established the likely causality of SMAD3 for CAD [ 11 ], the overall goal of the work reported here was to determine the mechanism and direction of effect for this gene, and thus integrate it into a causal framework that regulates disease pathophysiology. We have demonstrated with various genetic and genomic approaches that a significant portion of the genetic risk for CAD resides in the smooth muscle cell lineage and that the TGFβ pathway in particular regulates genomic features in disease loci, and have thus focused here on HCASMC [ 11 , 59 ]. These studies confirm previous work in other SMC models that SMAD3 promotes a differentiation program in these cells, as evidenced by upregulation of lineage markers [ 22 , 61 , 62 ].…”

“…The putative SMAD3-TCF21 interactions are consistent with data from various types of experiments presented here which indicate that TCF21 has an inhibitory role toward SMAD3 regulation of gene expression. While directionality of disease effect is in general difficult to establish, compelling data from HCASMC and vascular eQTL data presented here suggest that expression of SMAD3 is directly correlated to disease risk, and importantly these findings are opposite to those indicating that expression of TCF21 has a protective role [ 33 , 59 ]. Further, given that expression of SMAD3 appears to promote disease risk along with HCASMC differentiation, and TCF21 promotes de-differentiation of this cell type and inhibits disease risk, these findings together argue that the process of phenotypic modulation is protective toward disease risk [ 33 , 34 , 74 ].…”

The rs1892818 polymorphism of ADRB3 is associated with coronary artery disease in a Han population

“…Xiao et al performed a meta-analysis and found that the leptin rs7799039 variant might affect individual susceptibility to CAD [4]. Liu et al identified five genes (encoding signal-induced proliferation-associated 1, transcription factor 21, SMAD family member 3, FES proto-oncogene, and platelet-derived growth factor receptor alpha) that might modulate CAD risk through human coronary artery smooth muscle cells, with all genes having relevant functional roles in vascular remodeling [5]. Furthermore, Li et al provided additional evidence that a genetic variation in the platelet endothelial cell adhesion molecule 1-encoding gene, namely rs1867624, and hypoxia-inducible factor 1 subunit alpha gene, namely rs2057482, can modulate lipid levels in myocardial infarction patients [6].…”

Cell-type–specific eQTL of primary melanocytes facilitates identification of melanoma susceptibility genes

“…Moreover, the collection and sampling process of tissue samples from organs does not allow precise control over cell representation, adding a major source of biological variability in addition to other technical variation (McCall et al 2016). However, other than for immune cells (Kim-Hellmuth et al 2017), induced Pluripotent Stem Cells (iPSC) (Kilpinen et al 2017), or smooth muscle cells (Liu et al 2018), eQTL data sets representing single primary cell types and direct comparison of these to the tissue type of origin have been lacking.…”