Interactions between glucocorticoid treatment and cis-regulatory polymorphisms contribute to cellular response phenotypes

Glucocorticoids (GCs) are steroid hormones produced by the human body in response to environmental stressors. Despite their key role as physiological regulators and widely administered pharmaceuticals, little is known about the genetic basis of inter-individual and inter-ethnic variation in GC response. As GC action is mediated by the regulation of gene expression, we profiled transcript abundance and protein secretion in EBV-transformed B lymphocytes from a panel of 114 individuals, including those of both African and European ancestry. Combining these molecular traits with genome-wide genetic data, we found that genotype-treatment interactions at polymorphisms near genes affected GC-regulation of expression for 26 genes and of secretion for IL6. A novel statistical approach revealed that these interactions could be distinguished into distinct types, with some showing genotypic effects only in GC-treated samples and others showing genotypic effects only in control-treated samples, with differing phenotypic and molecular interpretations. The insights into the genetic basis of variation in GC response and the statistical tools for identifying gene-treatment interactions that we provide will aid future efforts to identify genetic predictors of response to this and other treatments.

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Maranville JC, Luca F, Richards AL, Wen X, Witonsky DB, Baxter S, Stephens M, Di Rienzo A