Genetic risk of inflammatory bowel disease is associated with disease course severity

Background and aimsGenetic susceptibility to inflammatory bowel disease (IBD) has been widely studied, whereas the genetic contribution to disease progression over time remains relatively under-investigated. In a Danish nationwide cohort, we aimed to explore if genetic susceptibility to IBD is associated with disease severity. MethodsWe estimated polygenic scores (PGS) for IBD susceptibility for 3,732 patients with Crohns disease (CD), 4,535 patients with ulcerative colitis (UC), and 9,469 controls, and investigated their association with disease outcomes, including inflammatory markers, hospitalizations, major surgeries, and medication use. A composite severity outcome was defined based on the first three years following diagnosis. Lastly, we evaluated disease extent as a possible mediator of the association. ResultsIncreased susceptibility PGS was associated with higher fecal calprotectin and C-reactive protein levels, and decreased hemoglobin levels. When comparing the highest versus lowest PGS quintile, we observed a hazard ratio (HR) for major surgery of 2.74 (P=7.19x10-18) in patients with CD and of 2.04 (P=4.36x10-7) in UC. Patients with severe disease had higher susceptibility PGS than patients with less severe disease (CD: OR=1.25, P=3.36x10-9; UC: OR=1.33, P=1.40x10-15 per SD increase in PGS). Additionally, PGS was associated with a higher need for corticosteroids, immunomodulators, and biologic therapies. Adjusting for disease extent reduced the estimated associations for CD but had little impact on observed associations for UC. ConclusionPatients with higher genetic burden for developing IBD also experience a more severe disease course. For patients with CD this link was largely mediated by disease extent, however, this was not the case for UC, which suggests a shared genetic architecture between disease susceptibility and severity.