P1290 Gene set polygenic risk scores identifies genetic subgroups in inflammatory bowel disease patients
Authors: Jans D , Smeulders E , Veyt N , Ferrante M , Verstockt B , Sabino J , Vermeire S , Cleynen I 
Published: January 2025

Abstract

Background
Inflammatory bowel disease (IBD) patients exhibit varied disease presentation and therapy response. Its pathogenesis involves diverse biological pathways, which may contribute differently across individuals. Here, we explore whether stratifying patients using polygenic risk scores (PRS) based on groups of genes involved in particular biological processes, rather than all disease-related genes, can aid in patient subgrouping and as such may help in personalized treatment approaches.

Methods
We defined eight gene sets related to small molecule and biological treatments1 for IBD and twelve to IBD pathogenesis (Table 1). Selection was based on a literature review and gene selection on the GSEA-MSigDB. Gene set PRS were computed for 3,847 individuals (1,937 CD, 1,108 UC) using PRSet and weights from de Lange et al (2017)1. Resulting gene-set PRS were compared across clinical subphenotypes, and used for hierarchical clustering on IBD patients combined, and separately for CD and UC patients.

Results
Several gene set PRS showed a gradient increase from UC (lowest) to colonic CD, ileocolonic CD, and ileal CD (highest), particularly the TNF (p=1.26e-21) and NLR PRS (p=1.52e-22)(Fig1A). Of note, PRS did not differ between UC and colonic CD or between ileocolonic and ileal CD. No significant associations were found between gene set PRS and disease behavior in CD or disease extent in UC.
Clustering using therapy-related gene sets (Fig1B) revealed two distinct IBD patient clusters, one with generally higher PRS across gene sets, and two CD clusters, driven mainly by TNF PRS. These clusters were associated with disease location (IBD: p=1e-4; CD: p=0.01), with one IBD cluster enriched for ileal and ileocolonic CD and fewer UC patients, while CD clusters featured either ileal or colonic cases. UC patients formed two clusters, one with higher PRS across gene sets, without an association with disease extent.
Clustering based on pathogenesis pathways (Fig1B) identified two IBD patient clusters, one with higher PRS for cytokine, ER stress, innate immunity, and NLR gene sets. Similar results were seen for CD patients. Again, these clusters correlated with disease location (IBD: p=2.7e-12; CD: p=3.9e-3). UC patients showed two clusters, one with higher PRS for all gene sets, but without any association to disease extent.

Conclusion
Gene set PRS can identify genetic subgroups of IBD primarily associated with disease location, aligning with the proposed continuum and reclassification into UC, colonic CD, ileocolonic CD and ileal CD as per Cleynen et al (2016)2. Clustering driven by the TNF pathway in CD suggests that gene set PRS could potentially be valuable for guiding treatment strategies, though further studies are needed to confirm this possibility.

References
1.de Lange KM, Moutsianas L, Lee JC, et al. Genome-wide association study implicates immune activation of multiple integrin genes in inflammatory bowel disease. Nature genetics. 2017;49(2):256-261. doi:10.1038/NG.3760
2.Cleynen I, Boucher G, Jostins L, et al. Inherited determinants of Crohn’s disease and ulcerative colitis phenotypes: a genetic association study. Lancet (London, England). 2016;387(10014):156-167. doi:10.1016/S0140-6736(15)00465-1