HLA-DRB1*01:03 in patients with inflammatory bowel disease: a genotype-phenotype association study

Background: The association between HLA-DRB1*01:03 and severe ulcerative colitis has long been recognised. However, the recent discovery of an association with neutralising auto-antibodies against IL-10 raises new questions about whether this haplotype contributes to other subphenotypes of inflammatory bowel disease (IBD). We sought to systematically reappraise the contribution of HLA-DRB1*01:03 across the full spectrum of IBD subphenotypes, including multiple disease-related adverse outcomes. Methods: In this genotype–phenotype association study, we used data from patients with IBD of inferred European ancestry from more than 100 UK hospitals who were recruited into the National Institute for Health and Care Research IBD BioResource or the UK IBD Genetics Consortium cohorts between 2005 and 2025. Associations between HLA-DRB1*01:03 and IBD phenotypes were examined using logistic or linear regression, and adjusted for sex, smoking, diagnosis, follow-up, genetic principal components, six co-inherited HLA alleles, and other significant associations. Time-to-event analyses were performed using Cox regression models. Findings: 43 762 patients with IBD (21 839 with Crohn's disease and 21 923 with ulcerative colitis or IBD unclassified) were included in our analysis. HLA-DRB1*01:03 carriage was observed in 2009 (4·6%) patients with IBD and associated with multiple severe outcomes in the adjusted models, including colonic resection in patients with Crohn's disease (odds ratio 1·35 [95% CI 1·07–1·69]), colectomy in patients with ulcerative colitis or IBD unclassified (1·99 [1·63–2·43]), perianal disease in both patients with Crohn's disease (1·65 [1·42–1·92]) and patients with ulcerative colitis or IBD unclassified (1·70 [1·27–2·28]), and advanced therapy use in patients with Crohn's disease (1·33 [1·12–1·58]) and patients with ulcerative colitis or IBD unclassified (2·17 [1·86–2·52]). HLA-DRB1*01:03 was associated with younger-onset ulcerative colitis or IBD unclassified and older-onset Crohn's disease. HLA-DRB1*01:03 also associated with earlier development of perianal Crohn's disease (hazard ratio 1·61 [95% CI 1·24–2·07]), earlier need for colonic surgery in patients with Crohn's disease (1·43 [1·13–1·82]), and earlier colectomy in patients with ulcerative colitis or IBD unclassified (1·69 [1·33–2·14]). HLA-DRB1*01:03 carriers initiated advanced therapy earlier (HR 1·37 [95% CI 1·18–1·59] in patients with Crohn's disease and 1·82 [1·53–2·16] in patients with ulcerative colitis or IBD unclassified) and had a higher risk of advanced therapy failure across IBD phenotypes (HR 1·23 [95% CI 1·02–1·50]). Interpretation: HLA-DRB1*01:03 emerges as a genetic determinant of severe disease in both patients with Crohn's disease and patients with ulcerative colitis. Although further validation is needed, assessing HLA-DRB1*01:03 carriage might help identify patients who could benefit from more intensive monitoring or earlier use of advanced therapies, aiming to modify the disease course to which they are genetically predisposed. Funding: Wellcome Trust, the National Institute for Health and Care Research, the Medical Research Council, Open Targets, Crohn's & Colitis UK, the Helmsley Charitable Trust, Crohn's in Childhood Research Association, and AstraZeneca's Centre for Genomics Research.