Leveraging genetic data to investigate the effects of interleukin-6 receptor signalling on levels of 40 circulating cytokines.

Interleukin 6 (IL-6) is a circulating cytokine implicated in inflammatory processes. However, the broad effects of IL-6 receptor (IL-6R) signalling on other circulating cytokines is not known. Using summary-level data from genome-wide association studies, we leveraged genetic variants that proxy IL-6R signalling in two-sample Mendelian randomization analyses to investigate effects on levels of 40 circulating cytokines. Increased genetically proxied IL-6R signalling was associated with reduced levels of 10 circulating interleukins, chemokines and growth factors. The significant results include IL-10 (Mendelian randomization estimate -0.306, standard error [SE] 0.093), IL-4 (estimate -0.393, SE 0.1007), eotaxin (estimate -0.510, SE 0.1213) and Fibroblast growth factor (estimate -0.334, SE 0.1005). The findings from this study support the feedback effects of IL-6R signalling on reducing levels of some circulating cytokines and identify compensatory mechanisms that maybe modulating its inflammatory effects. These results provide insight into the mechanisms by which IL-6R signalling may be contributing to inflammatory and autoimmune diseases.