Human genetic diversity regulating the locus confers increased cytokines in response to .

Human genetic diversity can have profound effects on health outcomes upon exposure to infectious agents. For infections with (), the wide range of genital and ocular disease manifestations are likely influenced by human genetic differences that regulate interactions between and host cells. We leveraged this diversity in cellular responses to demonstrate the importance of variation at the Toll-like receptor 1 (), , and locus to cytokine production in response to . We determined that a single-nucleotide polymorphism (SNP) (rs1057807), located in a region that forms a loop with the promoter, is associated with increased expression of , and and secreted levels of ten induced cytokines. Production of these induced cytokines is primarily dependent on MyD88 and TLR6 based on experiments using inhibitors, blocking antibodies, RNAi, and protein overexpression. Population genetic analyses further demonstrated that the mean IL-6 response of cells from two European populations were higher than the mean response of cells from three African populations and that this difference was partially attributable to variation in rs1057807 allele frequency. In contrast, a SNP associated with a different pro-inflammatory cytokine (rs2869462 associated with the chemokine CXCL10) exhibited an opposite response, underscoring the complexity of how different genetic variants contribute to an individual's immune response. This multidisciplinary study has identified a long-range chromatin interaction and genetic variation that regulates to broaden our understanding of how human genetic variation affects the induced immune response.