HLA-DRB1*01:03 in patients with inflammatory bowel disease: a genotype–phenotype association study
18 affiliations
- 1Genomics of Inflammation and Immunity Group, Human Genetics Programme, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK
- 2Department of Metabolism, Digestion and Reproduction, Imperial College London, Hammersmith Hospital Campus, London, UK; St Mark's Hospital and Academic Institute, Central Middlesex, London, UK
- 3Department of Gastroenterology, Cambridge University Hospital NHS Foundation Trust, Cambridge, UK; Department of Medicine, University of Cambridge, Cambridge, UK
- 4St Mark's Hospital and Academic Institute, Central Middlesex, London, UK; Department of Surgery and Cancer, Imperial College, London, UK; IBD Centre, Guy's and St Thomas' NHS Foundation Trust, London, UK
- 5Department of Gastroenterology, Royal Devon University Healthcare NHS Foundation Trust, Exeter, UK; Exeter IBD and Pharmacogenetics Research Group, University of Exeter, Exeter, UK
- 6Immunity and Inflammation Theme, Newcastle University Translational and Clinical Research Institute, Newcastle, UK; Department of Gastroenterology, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle, UK
- 7Department of Gastroenterology, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle, UK
- 8East and North Hertfordshire NHS Trust, Stevenage, UK
- 9Nottingham University Hospitals NHS Trust, Nottingham, UK
- 10Liverpool University Hospitals NHS Foundation Trust, Liverpool, UK
- 11Dorset County Hospital NHS Foundation Trust, Dorchester, UK
- 12Northern Care Alliance NHS Foundation Trust, Salford, UK
- 13Kettering General Hospital NHS Foundation Trust, Kettering, UK
- 14Exeter IBD and Pharmacogenetics Research Group, University of Exeter, Exeter, UK; Torbay and South Devon NHS Foundation Trust, Torquay, UK
- 15Leeds Teaching Hospitals NHS Trust, Leeds, UK
- 16University Hospitals of Leicester NHS Trust, Leicester, UK
- 17West Hertfordshire Hospitals NHS Trust, Watford, UK
- 18Western Sussex Hospitals NHS Foundation Trust, Worthing, UK
Abstract
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.
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BibTeX
@article{zhang2026hladrb10103,
title = {{HLA-DRB1*01:03 in patients with inflammatory bowel disease: a genotype–phenotype association study}},
author = {Qian Zhang and Eathar Shakweh and Mohmmed Tauseef Sharip and Benjamin Zaré and Christopher Roberts and Nicola J Wyatt and Jennifer Clough and Claire Bewshea and Omar El Garwany and Robert D. Lees and Saima Mukhtar and Hameed Rehman and Hollie Thistle and Robert J Mulligan and Melanie Taylor and Parizade Raymode and Benjamin Hamilton and Nurulamin M Noor and Francesco Mordà and Madeleine Taylor and Mina Gyanwali and Ogwa Tobi and Stefanos Kateroglou and Sean Von Hagt and Jennifer Hollis and Gordon William Moran and Craig Mowat and Natalie J. Prescott and Mohammed Allah-Ditta and James Ashton and Bijay Baburajan and Michelle Baker-Moffatt and Tyara Banerjee and Ian Beales and John B. Beckly and James Berrill and Roisin Bevan and Monica Bose and John R. Bradley and Carolyn Brechin and Biljana Brezina and Jeffrey R. Butterworth and Melanie Caswell and Thean Soon Chew and Katie Clark and Laura Cocking and Rachel Cooney and Nicholas Michael Croft and Albert Davies and Juan De La Revilla Negro and Aminda De Silva and Rofaida Desoki and Anjan Dhar and Stephen Foley and Marco Gasparetto and Anton Gunasekera and Laura Hancock and Thomas Hartley and Virginia Hay and David I. Hobday},
journal = {The Lancet. Gastroenterology \& hepatology},
year = {2026},
month = jun,
doi = {10.1016/s2468-1253(26)00113-5},
url = {https://doi.org/10.1016/s2468-1253(26)00113-5},
note = {CC BY},
}
RIS
TY - JOUR
TI - HLA-DRB1*01:03 in patients with inflammatory bowel disease: a genotype–phenotype association study
AU - Qian Zhang
AU - Eathar Shakweh
AU - Mohmmed Tauseef Sharip
AU - Benjamin Zaré
AU - Christopher Roberts
AU - Nicola J Wyatt
AU - Jennifer Clough
AU - Claire Bewshea
AU - Omar El Garwany
AU - Robert D. Lees
AU - Saima Mukhtar
AU - Hameed Rehman
AU - Hollie Thistle
AU - Robert J Mulligan
AU - Melanie Taylor
AU - Parizade Raymode
AU - Benjamin Hamilton
AU - Nurulamin M Noor
AU - Francesco Mordà
AU - Madeleine Taylor
AU - Mina Gyanwali
AU - Ogwa Tobi
AU - Stefanos Kateroglou
AU - Sean Von Hagt
AU - Jennifer Hollis
AU - Gordon William Moran
AU - Craig Mowat
AU - Natalie J. Prescott
AU - Mohammed Allah-Ditta
AU - James Ashton
AU - Bijay Baburajan
AU - Michelle Baker-Moffatt
AU - Tyara Banerjee
AU - Ian Beales
AU - John B. Beckly
AU - James Berrill
AU - Roisin Bevan
AU - Monica Bose
AU - John R. Bradley
AU - Carolyn Brechin
AU - Biljana Brezina
AU - Jeffrey R. Butterworth
AU - Melanie Caswell
AU - Thean Soon Chew
AU - Katie Clark
AU - Laura Cocking
AU - Rachel Cooney
AU - Nicholas Michael Croft
AU - Albert Davies
AU - Juan De La Revilla Negro
AU - Aminda De Silva
AU - Rofaida Desoki
AU - Anjan Dhar
AU - Stephen Foley
AU - Marco Gasparetto
AU - Anton Gunasekera
AU - Laura Hancock
AU - Thomas Hartley
AU - Virginia Hay
AU - David I. Hobday
PY - 2026
DA - 2026/06/15
JO - The Lancet. Gastroenterology & hepatology
DO - 10.1016/s2468-1253(26)00113-5
UR - https://doi.org/10.1016/s2468-1253(26)00113-5
AB - 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.
SN - 2468-1156
SN - 2468-1253
ER -