The impact of rare and common genetic variation in the Interleukin-1 pathway for human cytokine responses

Interleukin(IL)-1 signaling is of major importance in human innate cytokine responses. Common variants in underlying genes have been linked to various inflammation-mediated diseases and stimulation induced cytokine responses, but the role of rare variants remains to be elucidated. In this study, we characterize the role of rare and common genetic variation, as identified by molecular inversion probe-based sequencing, in 48 genes related to the IL-1 pathway. We examined the inter-individual variability in in vitro stimulation-specific human cytokine responses from 463 healthy individuals of the Human Functional Genomics Project and assessed the role of rare and common genetic variants, separately and combined, by means of the Sequence Kernel Association Test with various variant grouping strategies. We identified strong NCF4 and CASP1 rare genetic variant associations with IL-6 cytokine production in response to PHA (P=7.2E-05) and LPS (P=3.0E-05) stimulation. In addition, common variants in IL36A and IL38 were associated to both C. albicans induced IL-1β and IL-6 (IL36A P=0.0442 and 0.0037; IL38 P=0.0092 and 0.0082), an effect that was magnified on the respective IL-30 subpathway level (IL-1β P=0.0017; IL-6 P=1.8E-04). The inflammatory-phenotype level analysis confirmed the common variant signature for the immunological response to C. albicans by an association with the anti-inflammatory group (IL-1β P=1.87E-03; IL-6 P=5.75E-04), and we validated this finding for non-coding common variants. Lastly, we identified a rare variant signature for LPS-induced IL-6 production with the pro-inflammatory group (P=2.42E-04), and we detected a new role for anti-inflammatory rare variants on S. aureus stimulated IL-6 cytokine (P=6.71E-03). In conclusion, we show that both common and rare genetic variation in genes of the IL-1 pathway, separately and combined, differentially influence in vitro cytokine responses to various stimuli in healthy individuals. This study therefore provides insight into potential mechanisms that are translatable into new hypothesis-driven characterization of common and rare genetic variant involvement in a wide variety of inflammatory and immunological mechanisms and diseases.