Identification of genetic susceptibility to prurigo nodularis in the IL31 gene locus

Summary: Abstract Body: The IL31 cytokine is central to the pathogenesis of itch and inflammation in prurigo nodularis (PN). IL31 expression is up-regulated in the skin of individuals with PN and correlates with the intensity of itch. Overexpression of IL31 in animal models leads to skin inflammation and pruritus, and treatment with the IL31 receptor inhibitor nemolizumab has been found to be highly effective in PN. However, the etiology of PN remains unknown. Previous studies (ancestry differences and polygenic risk score) have suggested that genetic factors contribute to PN susceptibility. We therefore conducted the largest GWAS meta-analysis of PN to date (4,239 cases and 583,544 controls) to investigate the genetic mechanisms involved. Our study, combining data from the All of Us research program with the BioVU, FinnGen and Partners biobanks, identified a significant genetic signal (p=7.5x10-13, OR=1.17) associated with Prurigo Nodularis (PN) located at the IL31 locus on chromosome 12q24.31; we replicated this result using the Michigan Genomics Initiative (MGI) cohort. Notably, the risk allele frequency for the signal was different between population groups (10 times higher in European than African ancestries), and in linkage disequilibrium (LD) with GWAS signals for other diseases where pruritus is prominent (psoriasis and atopic dermatitis). The IL31 signal is located in a transcription factor binding hotspot, and our functional analyses demonstrate that it acts as an expression quantitative trait locus (eQTL), overlapping chromatin accessibility peaks in T-cells and keratinocytes. These findings represent an important step towards understanding the mechanisms underlying PN predisposition and suggests the PN risk allele could influence IL31 expression levels in relevant skin cells. Our results reinforce PN as a genetic disease, and expand upon the role of IL31 as a central mediator in PN pathogenesis, and its relationship with other pruritic inflammatory skin diseases. Matthew Patrick¹, Yuntian Wu¹, Xue Zhong², Qinmengge Li¹, Valérie Julia³, Bingshan Li², Johann E. Gudjonsson¹, Lam C. Tsoi¹ 1. University of Michigan, Ann Arbor, MI, United States. 2. Vanderbilt University, Nashville, TN, United States. 3. Galderma, Lausanne, Switzerland. Genetic Disease, Gene Regulation, Gene Therapy & Epigenetics