TOPLINE

An HLA-DRB1 allele, HLA-DRB1*01:03, carried by 4.6% of patients with inflammatory bowel disease (IBD), was associated with multiple severe outcomes, including a higher risk for colectomy in patients with ulcerative colitis, a higher risk for colonic surgery in patients with Crohn’s disease, a higher risk for perianal disease in both patients with Crohn’s disease and those with ulcerative colitis or IBD unclassified, and earlier initiation of advanced therapies.

METHODOLOGY

• Although the HLA-DRB1*01:03 allele has been linked to IBD susceptibility, disease extent, colectomy, and some extraintestinal manifestations, these associations were largely reported by studies that did not adequately account for clinical or genetic confounding; as a result, the contribution of this allele across the full spectrum of IBD phenotypes and outcomes had not been systematically examined.
• Researchers conducted a genotype-phenotype association study to evaluate the relationship between HLA-DRB1*01:03 carriage and various IBD phenotypes, including multiple disease-related adverse outcomes.
• They analyzed data from 43,762 patients with IBD (21,839 with Crohn’s disease and 21,923 with ulcerative colitis or IBD unclassified) from two existing IBD biobanks in the UK between 2005 and 2025.
• Clinical phenotype and demographic data were abstracted from medical records at study entry in both cohorts; a subset of patients also completed a health and lifestyle questionnaire.
• HLA variants, including HLA-DRB1*01:03, were imputed from genotyping array data. Patients were classified as carriers if they had at least one copy of the HLA-DRB1*01:03 allele and as noncarriers if they had none.

TAKEAWAY

• The HLA-DRB1*01:03 allele was found in 4.6% of patients with IBD. After adjustment for clinical and genetic factors, the allele was associated with higher odds of colonic resection in patients with Crohn’s disease (odds ratio [OR], 1.35), colectomy in patients with ulcerative colitis or IBD unclassified (OR, 1.99), perianal disease in both patients with Crohn’s disease (OR, 1.65) and those with ulcerative colitis or IBD unclassified (OR, 1.70), and the need for advanced therapy in patients with Crohn’s disease (OR, 1.33) and those with ulcerative colitis or IBD unclassified (OR, 2.17; P < .05 for all).
• Patients with Crohn’s disease who carried the HLA-DRB1*01:03 allele had a higher risk for early development of perianal disease (hazard ratio [HR], 1.61) and an earlier need for colonic surgery (HR, 1.43), whereas among patients with ulcerative colitis or IBD unclassified, carriers had a higher risk of undergoing colectomy earlier than noncarriers (HR, 1.69).
• HLA-DRB1*01:03 carriage was associated with a higher risk for early initiation of advanced therapy in patients with Crohn’s disease (HR, 1.37) and those with ulcerative colitis or IBD unclassified (HR, 1.82). Carriers also had a higher risk for advanced therapy failure across IBD phenotypes (HR, 1.23); this association was particularly evident with anti-TNF and JAK inhibitors.
• The association between the HLA-DRB1*01:03 allele and age at diagnosis differed by disease subtype, with carriers developing ulcerative colitis or IBD unclassified at a younger age and Crohn’s disease at an older age.

IN PRACTICE

“Our findings suggest that HLA-DRB1*01:03 exerts independent effects on both IBD susceptibility and disease severity and further support a role for genetics in shaping the clinical course of IBD,” the authors of the study wrote.

“In clinical practice, HLA-DRB1*01:03 carriers could receive personalized education regarding perianal disease risk and the importance of early symptom reporting to allow proactive treatment escalation,” they added.

SOURCE

The study was led by Qian Zhang, PhD, Wellcome Sanger Institute, Hinxton, England. It was published online in The Lancet Gastroenterology & Hepatology.

LIMITATIONS

The analysis was limited to patients with IBD of European ancestry, which may have reduced the generalizability of the findings to other populations. HLA alleles were inferred from genotyping data rather than directly typed. The relatively small JAK inhibitor cohort limited statistical power, warranting cautious interpretation of the findings.

DISCLOSURES

The study was funded by the Wellcome Trust, the National Institute for Health and Care Research, the Medical Research Council, and other organizations. Several authors declared receiving consulting fees, research funding, honoraria, or travel support from; participating on advisory boards of; or holding leadership or committee roles in gastroenterology organizations. They also declared having other relationships with pharmaceutical, biotechnology, and nonprofit organizations. One author held stock options in two pharmaceutical companies, and two authors declared holding patents.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.