HLA-DRB1*01:03 linked to adverse outcomes across IBD subtypes, analysis finds

Evidence before this study

We searched MEDLINE, Embase, and Google Scholar for studies published between Jan 1, 1990, and Nov 30, 2025, with no language restrictions, using the following search constraints: (“HLA-DRB1*01:03” OR “HLA-DRB1*01:03” OR “HLA DRB1 01:03” OR “DRB1*01:03” OR “HLA-DRB1”) AND (“inflammatory bowel disease” OR “IBD” OR “ulcerative colitis” OR “Crohn's disease” OR “Crohn's disease”) AND (“surgery” OR “surgical” OR “colectomy” OR “biologic therapy” OR “biologic*” OR “advanced therapy” OR “therapy” OR “treatment” OR “response” OR “outcome*” OR “perianal” OR “extraintestinal manifestation*” OR “arthritis” OR “uveitis” OR “erythema nodosum” OR “primary sclerosing cholangitis” OR “PSC” OR “orofacial granulomatosis”). This search returned 75 papers. Previous studies have identified HLA-DRB1*01:03 as a susceptibility factor for both ulcerative colitis and Crohn's disease. Beyond disease susceptibility, several associations have been reported between this HLA allele and some subphenotypes of inflammatory bowel disease (IBD), including disease extent, colectomy in patients with ulcerative colitis, and some extraintestinal manifestations. However, many of these studies were underpowered and none of them adequately addressed potential confounding factors (either genetic or clinical). For example, it remains unclear whether the reported association with colectomy in patients with ulcerative colitis is a true effect or driven by more extensive disease. Likewise, a confounding effect of linkage disequilibrium with other HLA alleles has never been systematically examined. Interest in this allele and its links to IBD have been rekindled with the recent discovery of a strong association between HLA-DRB1*01:03 and development of neutralising auto-antibodies against the immunomodulatory cytokine IL-10. There is therefore urgent need of a comprehensive evaluation of how HLA-DRB1*01:03 contributes across the full spectrum of IBD phenotypes and disease outcomes.

Added value of this study

We did a comprehensive analysis of the association between HLA-DRB1*01:03 and a large panel of IBD subphenotypes in two large and deeply phenotyped UK cohorts (collectively comprising more than 43 000 patients). These cohorts—assembled by the National Institute for Health and Care Research IBD BioResource and the UK IBD Genetics Consortium—reflect a UK-wide collaboration involving over 100 hospitals over 20 years, providing a unique opportunity to assess the role of HLA-DRB1*01:03 in IBD. Using the power of these cohorts, we not only identify novel associations with clinically relevant disease phenotypes, including perianal complications, surgery in patients with Crohn's disease, and the burden and onset of independent severe clinical outcomes, but also refute some previously reported associations, showing that they result from confounding factors (eg, the apparent association with enteropathic arthritis is actually driven by HLA-B27). These results clarify the true phenotypic associations of HLA-DRB1*01:03 and extend the spectrum of associated clinical phenotypes, highlighting the potential of this allele to identify a subset of patients with a greater chance of developing clinically significant complications.

Implications of all the available evidence

We identify HLA-DRB1*01:03 as the first comprehensive severity allele that is associated with adverse outcomes across the spectrum of IBD subtypes. In patients with IBD, carriage of this allele identifies a subgroup who could be considered for more intensive monitoring and perhaps earlier use of advanced therapies, aiming to modify the disease course to which they are genetically predisposed.

Source: The Lancet Gastroenterology & Hepatology