Center for Molecular Medicine and Genetics, Wayne State University, Detroit, United States.
Department of Biostatistics, University of Michigan, Ann Arbor, United States.
Elife. 2024 Feb 9;13:e85235. doi: 10.7554/eLife.85235.
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.
基因调控序列中的遗传变异可以改变基因表达，并介导对环境刺激的分子反应。此外，基因型-环境相互作用（GxE）有助于心血管疾病等复杂特征。咖啡因是最广泛消费的兴奋剂，已知会产生血管反应。为了研究咖啡因的 GxE，我们用咖啡因处理血管内皮细胞，并使用大规模平行报告基因检测来测量超过 43000 个遗传变异对基因调控的等位基因效应。我们确定了 665 个具有基因调控等位基因效应的变体和 6 个调节咖啡因基因表达反应的变体（GxE，错误发现率 [FDR] < 5%）。当我们将 GxE 结果与与冠状动脉疾病和高血压共定位的表达数量性状基因座重叠时，我们剖析了它们的调节机制，并显示咖啡因具有调节作用。我们的结果表明，大规模平行报告基因检测是一种强大的方法，可以在咖啡因消费的特定背景下识别和分子特征化 GxE。
