A study finds that 3% of ulcerative colitis patients carry a specific genetic variant, 40% of which require major surgery within three years, compared to 9% without the variant.
Study: HLA-DRB1*01:03 and Severe Ulcerative Colitis. Image Credit: Piyaset/Shutterstock.com
In a recent study published in the JAMA, a group of researchers identified biomarkers of severe ulcerative colitis through a Danish genome-wide association study (GWAS).
Background
Ulcerative colitis is a chronic, immune-mediated disease with rising incidence, creating a critical need to identify biomarkers that can help pinpoint subgroups requiring intensified monitoring and treatment to prevent recurrent hospitalizations and surgeries.
Further research is essential to refine these biomarkers for better risk assessment and targeted interventions in diverse patient populations.
About the study
Two source populations were used for the present study. The Center for Molecular Prediction of Inflammatory Bowel Disease (PREDICT) neonatal blood spot cohort (NBS) included individuals born in Denmark and diagnosed with ulcerative colitis from 1981 to 2022. The North Denmark Biobank study (NorDIBD) was a population-based cohort from Northern Denmark, comprising patients diagnosed with inflammatory bowel disease between 1978 and 2020.
To avoid duplicate data, one genotyped sample was randomly excluded for individuals present in both cohorts. Deoxyribonucleic Acid (DNA) was extracted from dried blood spots in NBS and full blood in NorDIBD using standard protocols. These cohorts were linked to Danish healthcare registers to capture both inpatient and outpatient data, including medication use, until September 2022.
The study received approval from the research ethics committees of the Capital of Denmark and North Denmark Region, with written and oral consent obtained where necessary. Patients classified as having severe ulcerative colitis had undergone at least one major ulcerative colitis-related surgery, had two or more hospitalizations exceeding two days or had received 5000 mg or more of systemic corticosteroids within three years of diagnosis.
Those not meeting these criteria were classified as having less severe disease and served as the comparison group. Only patients with a minimum of three years of follow-up were included.
Genotyping and analysis were performed using Regenie, version 3.4, adjusting for sex, year, and age at diagnosis. The two cohorts were analyzed separately to account for differences in recruitment and genotyping materials, and results were combined in a meta-analysis using Plink, version 1.90b6.18. Post hoc analyses included a GWAS to determine whether associations identified at chromosome 6 were linked to the Human Leukocyte Antigen - DR Beta 1*01:03 (HLA-DRB1*01:03) allele.
Additional analyses were performed on the individual components of the severity criteria. Long-term effects were explored using time-to-event analyses with the Cox proportional hazards model, including all available long-term data from the Danish health registers. The significance thresholds were set at 5 × 10−8 for GWAS and .05 for time-to-event analyses.
Study results
The combined cohort for the study consisted of 4491 patients, with 4153 from the PREDICT NBS and 338 from the NorDIBD. The mean age at diagnosis for the patients was 23.3 years, with a standard deviation of 8.4 years. Of the total patient population, 53% were female, and 27% were classified as having severe ulcerative colitis. This division between severe and less severe cases enabled a detailed investigation into the genetic markers associated with disease severity.
From a total of 9,508,878 single-nucleotide variations tested, a specific locus on chromosome 6, located within the HLA region, was found to be significantly associated with severe ulcerative colitis. The odds ratio (OR) for this association was 2.23 (95% confidence interval [CI], 1.96 to 2.50; P = 4.22 × 10−9), highlighting a robust link between this locus and disease severity.
Further analysis of imputed HLA alleles revealed that the HLA-DRB1*01:03 allele was the primary driver of this association, with an overall OR of 3.32 (95% CI, 2.25 to 4.89; P = 1.45 × 10−9). Specifically, the OR for the NBS cohort was 3.29 (95% CI, 2.22 to 4.89), while the NorDIBD cohort showed an odds ratio of 3.98 (95% CI, 0.54 to 29.23).
The frequency of the HLA-DRB1*01:03 allele in the combined cohorts was 2.8%. After conditioning on the presence of this allele, no other genetic variant reached genome-wide significance, underscoring the key role of HLA-DRB1*01:03 in severe ulcerative colitis.
The HLA-DRB1*01:03 allele was associated with significantly higher risks of severe disease outcomes. For carriers, the OR for undergoing a major operation was 6.38 (95% CI, 3.89 to 10.46; P < 0.001), for having at least two hospitalizations was 5.24 (95% CI, 3.49 to 7.86; P < 0.001), and for using at least 5000 mg of systemic corticosteroids within three years of diagnosis was 2.30 (95% CI, 1.42 to 3.71; P = 0.001), compared to noncarriers.
Time-to-event analyses confirmed that the association between HLA-DRB1*01:03 and disease severity persisted beyond three years after diagnosis. Carriers of the allele had a hazard ratio of 2.22 (95% CI, 1.79 to 2.74; P < 0.001) for time to hospitalization, 5.13 (95% CI, 3.86 to 6.81; P < 0.001) for time to major operation, and 1.69 (95% CI, 1.38 to 2.07; P < 0.001) for time to the first use of systemic corticosteroids, compared to noncarriers.
Conclusions
To summarize, HLA-DRB1*01:03 is associated with severe ulcerative colitis, increasing the likelihood of major operations, hospitalizations, and systemic corticosteroid use compared to less severe cases. Previous studies have linked this allele to ulcerative colitis incidence, and this research further supports its connection to both total and severe disease. Despite its low frequency, HLA-DRB1*01:03 could serve as a cost-effective tool for assessing the risk of severe disease in ulcerative colitis patients
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