Interleukin(IL)-1 signaling is of major importance in human innate cytokine responses. Common variants in related 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. We identified strong associations for rare genetic variants in NCF4 (adjP=7.2E-05) and CASP1 (adjP=3.0E-05) with IL-6 production in response to PHA and LPS stimulation, respectively. In addition, common variants in IL36A and IL38 were associated to both C. albicans -induced IL-1β ( IL36A adjP=0.0442; IL38 adjP=0.0092) and IL-6 production ( IL36A adjP=0.0037; IL38 adjP=0.0082), an effect that was stronger at the subpathway level both for IL-1β (adjP=0.0017) and IL-6 (adjP=1.8E-04). The common variant signature for the IL-1β and IL-6 response to C. albicans was confirmed by an association with all anti-inflammatory genes (adjP=1.87E-03 and adjP=5.75E-04), and we validated this finding for non-coding common variants. Lastly, we identified a burden of rare variants in pro-inflammatory genes and LPS-induced IL-6 production (adjP=2.42E-04), and a new role for anti-inflammatory rare variants on S. aureus -stimulated IL-6 production (adjP=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 variant involvement in a wide variety of inflammatory and immunological mechanisms and diseases. ### Competing Interest Statement LABJ reports to be Scientific Advisory Board member of Olatec Therapeutics LLC. CAD serves as chair of SAB of Olatec Therapeutics LLC. All other authors declare that they have no conflict of interest.

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