Genetic risk of inflammatory bowel disease is associated with disease course severity
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Background
Genetic susceptibility to inflammatory bowel disease (IBD) has been widely studied, whereas the genetic contribution to disease progression over time remains largely unknown. In a unique population-based cohort, we explored if genetic susceptibility to IBD associated with disease course severity.
Methods
In a Danish nationwide cohort of 3688 patients with Crohn’s disease (CD), 4491 patients with ulcerative colitis (UC), and 9469 controls, we estimated polygenic scores (PGS) for IBD susceptibility. We then investigated the association between susceptibility PGS and severe versus less severe disease courses. Patients were categorized as having a severe disease course if needing I) at least two IBD-related hospitalizations exceeding two days, II) at least two IBD-related major surgeries, III) one hospitalization and one major surgery not overlapping in time, or IV) total use of minimum 5000 mg systemic corticosteroids within the first three years of diagnosis. Secondary analyses explored the association with other severity measures including inflammatory markers, exposure to biologics and immunomodulators, and time to hospitalization and major IBD-related surgery. Statistical analyses included logistic, linear, and Cox proportional hazards regression, and predictive modeling using random forest.
Findings
Patients with severe disease courses had higher susceptibility PGS than patients with less severe disease courses (CD: OR=1·27, P =7·73×10 −10 , UC: OR=1·35, P =7·29×10 −17 per SD increase in susceptibility PGS). When comparing the highest versus lowest PGS quintile, we observed a hazard ratio (HR) for major surgery of 2·74 ( P =7·19×10 −18 ) in patients with CD and 2·04 ( P =4·36×10 −7 ) in patients with UC. A higher susceptibility PGS was also associated with longer and more frequent hospitalizations, higher levels of C-reactive protein, decreased hemoglobin, and a higher need for corticosteroids, immunomodulators, and biologic therapies.
Interpretation
Patients with a higher genetic burden for developing IBD also experience a more severe disease course, suggesting a shared genetic architecture between disease susceptibility and severity.
Funding
Danish National Research Foundation, DNRF148, Lundbeck Foundation, R313-2019-857, Novo Nordisk Foundation, NNF23OC0087616, Danish Colitis Crohn Association.
