Editor's evaluation: Characterization of caffeine response regulatory variants in vascular endothelial cells
Year: 2023
Type: peer-review
Abstract: Genetic variants in gene regulatory sequences can modify gene expression andmediate the molecular response to environmental stimuli.In addition, genotype-environment interactions (GxE) contribute to complex traits such as cardiovascular disease.Caffeine is the most widely consumed stimulant and is known to produce a vascular response.To investigate GxE for caffeine, we treated vascular endothelial cells with caffeine and used a massively parallel reporter assay to measure allelic effects on gene regulation for over 43,000 genetic variants.We identified 665 variants with allelic effects on gene regulation and 6 variants that regulate the gene expression response to caffeine (GxE, false discovery rate [FDR] < 5%).When overlapping our GxE results with expression quantitative trait loci colocalized with coronary artery disease and hypertension, we dissected their regulatory mechanisms and showed a modulatory role for caffeine.Our results demonstrate that massively parallel reporter assay is a powerful approach to identify and molecularly characterize GxE in the specific context of caffeine consumption. Editor's evaluationThis important study identifies context-specific regulatory variants by an MPRA screen in vascular endothelial cells exposed to caffeine.The authors use a compelling and creative approach to pinpoint potential molecular mechanisms of gene-by-environment effects on gene regulation.The variants they identify are likely linked to complex disease risk.
Author: Stephen CJ Parker
Institution: University of Michigan
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: gold
Award: G2067920560
OpenAlex ID: W4392257216