Genetic Risk of Inflammatory Bowel Disease Is Associated With Disease Course Severity

Background & Aims Genetic susceptibility to inflammatory bowel disease (IBD) has been widely studied, whereas the genetic contribution to disease progression remains relatively underinvestigated. In a Danish nationwide cohort, we aimed to explore if genetic susceptibility to IBD associated with disease severity. Methods We estimated IBD polygenic scores (PGS) for 3732 patients with Crohn's disease (CD) and 4535 patients with ulcerative colitis (UC), 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 3 years after diagnosis. Lastly, we evaluated disease extent as a possible mediator. Results Increased PGS was associated with higher fecal calprotectin and C-reactive protein levels, and decreased hemoglobin levels. When comparing the highest vs lowest PGS quintile, we observed a hazard ratio for major surgery of 2.74 ( P = 7.19 × 10 −18 ) in patients with CD and of 2.04 ( P = 4.36 × 10 −7 ) in UC. Patients with severe disease had higher PGS than patients with less severe disease (CD, odds ratio=1.25; P = 3.36 × 10 −9 ; UC, odds ratio=1.33; P = 1.40 × 10 −15 per standard deviation 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. Conclusions Patients 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.