Genetic variants in gene regulatory sequences can modify gene expression and mediate 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.
Excerpts citing our work:
"We also observed that the motif for SREBF2, also called SREBP2, is enriched for being within downregulated targets. In hepatocytes, caffeine is known to suppress SREBF2 activity, which reduces PCSK9 expression, and thus increases LDLR expression, which could be protective against CVD"
"Another study aimed to uncover mechanisms relevant to CVD upon caffeine exposure and found that caffeine inhibits the transcription factor SREBP2, which causes an overall protective effect against CVD. These results coincide with our findings."