A proteomic polygenic score to identify IL-18 driven inflammatory bowel disease

Abstract

High levels of IL-18 have been causally implicated in IBD risk and may represent a unique mechanism driving IBD yet to be therapeutically targeted. To identify individuals predisposed to increased levels of IL-18, we implemented a polygenic approach to predict IL-18 plasma protein levels. Using a dataset with over 50,000 individuals with both genetic and plasma protein levels from Olink, we developed a 27 SNP polygenic score that predicts IL-18 levels and IBD risk. Further, we identified a threshold to classify patients as IL-18 High using a data-driven approach that optimized prediction of both IL-18 and IBD risk. We show that [~]30% of the overall IBD patient population is IL-18 High, meaning a genetic predisposition towards higher protein levels. The IL-18 PGS and corresponding threshold have the potential to identify IBD patients with IL-18-driven IBD that may respond more effectively to a therapy targeting this mechanism.