Background: Drug-mediated disruption of IL17A, IL17F, and IL17RA proteins is effective in psoriasis. However, disruption of the IL17 pathway by functional mutations has so far only been shown to affect risk in IL23R and TRAF3IP2. It is unclear if this is due to rarity of disruptive mutations.
Objective: (i) to delineate the prevalence of mutations in key IL17-pathway genes; (ii) to identify candidate regulatory sites acting on IL23R, IL17A, IL17RA, TRAF3IP2 from a distance.
Methods: Extraction of mutation frequencies from ExAc data, evolutionary sequence alignment; mapping of long-range-interacting (LRI) enhancers; genetic association testing in a novel psoriasis cohort.
Results: the prevalence of disruptive mutations in genes such as IL17RA is sufficient to have been detectable by existing datasets. Therefore, lack of their association with psoriasis indicates that genetic risk primarily resides in variants acting from a distance. We identify two LRI enhancer sites, regulating IL17RA and TRAF3IP2, respectively. The TRAF3IP2 regulator localises to the TRAF3IP2-antisense promoter, suggesting feedback-regulation. Both LRI sites are associated with psoriasis in a novel Scottish psoriasis cohort and the TRAF3IP2-LRI at rs71562294 replicates in the WTCCC cohort.
Conclusion: Genetic risk for psoriasis may be encoded at LRI sites regulating IL17 pathway genes from a distance.