RT Journal Article
SR Electronic
T1 Interpreting coronary artery disease risk through gene-environment interactions in gene regulation
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 475483
DO 10.1101/475483
A1 Anthony S Findley
A1 Allison L Richards
A1 Cristiano Petrini
A1 Adnan Alazizi
A1 Elizabeth Doman
A1 Alexander G Shanku
A1 Omar Davis
A1 Nancy Hauff
A1 Yoram Sorokin
A1 Xiaoquan Wen
A1 Roger Pique-Regi
A1 Francesca Luca
YR 2018
UL http://biorxiv.org/content/early/2018/11/23/475483.abstract
AB 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 gene-environment 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. Interestingly, each treatment may amplify or buffer genetic risk for CAD, depending on the particular SNP considered.