Interpreting coronary artery disease risk through gene-environment interactions in gene regulation

Abstract

GWAS and eQTL studies identified thousands of genetic variants associated with complex traits and gene expression. Despite the important role of environmental exposures in complex traits, only a limited number of environmental factors are measured in these studies. Measuring molecular phenotypes in tightly controlled cellular environments provides a more tractable setting to study geneenvironment interactions in the absence of other confounding variables.We performed RNA-seq and ATAC-seq in endothelial cells exposed to retinoic acid, dexamethasone, caffeine, and selenium to model genetic and environmental effects on gene regulation in the vascular endothelium, a common site of pathology in cardiovascular disease. We found that genes near regions of differentially accessible chromatin were more likely to be differentially expressed (OR = [3.41, 6.52], p < 10 −16 ). Furthermore, we confirmed that environment-specific changes in transcription factor binding are a key mechanism for cellular response to environmental stimuli. SNPs in these transcription response factor footprints for dexamethasone, caffeine, and retinoic acid were enriched in GTEx eQTLs from artery tissues indicating that these environmental conditions are latently present in GTEx samples. Additionally, SNPs in footprints for response factors in caffeine are enriched in colocalized eQTLs for coronary artery disease (CAD), suggesting a role for caffeine in CAD risk.

Dynamic effects of genetic variation on gene expression revealed following hypoxic stress in cardiomyocytes

“…This could reflect cell type specificity in response to stress, or the specificity of the cellular response to different stressors. Indeed, despite large gene expression changes in response to various stimulants in endothelial cells, there are a relatively small number of differentially accessible regions (Findley et al, 2019). We speculate that the transcriptional response to oxygen stress could result in the induction of transcription factors, which bind already accessible regions of open chromatin, and that cells are primed for a quick response to this universal cellular stress.…”

Transcription factor regulation of eQTL activity across individuals and tissues

“…While GxE interactions on human phenotype have been difficult to assess, GxE interactions in relation to gene expression have been studied under various contexts [8,[12][13][14][15][63][64][65]. Overlapping these effects with TF-eQTLs as in our analysis, or even performing TF-eQTL analysis in the environmental exposure datasets themselves, provides mechanistic hypotheses of how environmental effects impact genetic control of gene expression and phenotype.…”