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Researchers developed a polygenic score (PGS) consisting of 27 genetic variants capable of predicting plasma levels of the inflammatory protein IL-18 and individual susceptibility to inflammatory bowel disease (IBD). Using a dataset of over 50,000 individuals with matched genetic and proteomic data, they established a data-driven threshold to classify patients as "IL-18 High," identifying approximately 30% of IBD patients as genetically predisposed to elevated IL-18 levels. This suggests that a meaningful subset of IBD cases may be driven by an IL-18-specific biological mechanism that has not yet been therapeutically targeted.
Why it matters
This polygenic score could enable clinicians to stratify IBD patients by underlying molecular mechanism, potentially guiding the development and use of IL-18-targeted therapies in the subset of patients most likely to benefit from them.
⚠️ Preprint – Noch nicht peer-reviewed
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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.
Source: A proteomic polygenic score to identify IL-18 driven inflammatory bowel disease