Genetic pathway score for IL-4/IL-13 signaling is associated with diseases that respond to Dupilumab

<bold>Background:</bold> Human genetics informs drug development by providing biology-agnostic evidence that natural perturbation of gene expression affects disease pathophysiology. We tested if human genetics can identify diseases that respond to drugs that inhibit IL-4/IL-13 signaling, such as Dupilumab. <bold>Methods:</bold> We developed a genetic pathway score (GPS) for IL-4/IL-13 signaling that includes variants in IL4, IL13, IL4R and STAT6, independently associated with asthma (p<5×10⁻⁸) in a GWAS performed in the UK Biobank (55,830 cases, 261,925 controls). This GPS was then tested for association with five diseases shown to respond to Dupilumab in phase 3 clinical trials, using data from seven additional cohorts (total N up to 214,395). <bold>Results:</bold> The IL-4/IL-13 GPS was associated with all five Dupilumab-responsive diseases: asthma (P=8x10⁻²⁷), eosinophilic esophagitis (EoE; P=2x10⁻⁶), chronic rhinosinusitis with nasal polyposis (CRwNP; P=8x10⁻⁶), atopic dermatitis (AD; P=6x10⁻⁴); and prurigo nodularis (PN; P=0.004). Individuals in the top 20% of the GPS – predicted to have greater IL-4/IL-13 signaling – had 1.28-fold greater risk of PN relative to the rest of the population (95% CI 1.11–1.48), followed by 1.21-fold for EoE (95% CI 1.05–1.39), 1.16-fold for CRwNP (95% CI 1.06–1.26), 1.11-fold for AD (95% CI 1.03–1.20) and 1.10-fold for asthma (95% CI 1.07–1.13). Three non-atopic diseases were not associated (rheumatoid arthritis and Crohn’s disease) or inversely associated (psoriasis) with the IL-4/IL-13 GPS. <bold>Conclusion:</bold> We developed a GPS that is associated with diseases that respond to Dupilumab, which can be used to identify potential new indications for drugs that inhibit IL-4/IL-13 signaling.