Inter-ethnic differences in lymphocyte sensitivity to glucocorticoids reflect variation in transcriptional response

Glucocorticoids (GCs) are steroid hormones widely used as pharmaceutical interventions, which act mainly by regulating gene expression levels. A large fraction of patients (∼30%), especially those of African descent, show a weak response to treatment. To interrogate the contribution of variable transcriptional response to inter-ethnic differences, we measured in vitro lymphocyte GC sensitivity (LGS) and transcriptome-wide response to GCs in peripheral blood mononuclear cells from African-American (AA) and European-American (EA) healthy donors. We found that transcriptional response after 8 h treatment was significantly correlated with variation in LGS within and between populations. We found that NFKB1, a gene previously found to predict LGS within populations, was more strongly downregulated in EAs on average. NFKB1 could not completely explain population differences, however, and we found an additional 177 genes with population differences in the average log2 fold change (false discovery rate<0.05), most of which also showed a weaker transcriptional response in AAs. These results suggest that inter-ethnic differences in GC sensitivity reflect variation in transcriptional response at many genes, including regulators with large effects (for example, NFKB1) and numerous other genes with smaller effects.