Allele May Heighten Risk of Severe Ulcerative Colitis

The presence of the single nucleotide variation HLA-DRB1*01:03 was associated with severe ulcerative colitis, according to a Danish genome-wide association study.

After testing more than 9.5 million single nucleotide variations, the researchers found that one chromosome 6 locus in the human leukocyte antigen (HLA) region — HLA-DRB1*01:03 — was significantly associated with severe versus less severe ulcerative colitis (OR 2.23, 95% CI 1.96-2.50, P=4.22 × 10^-9), reported Marie Vibeke Vestergaard, MSc, of the Center for Molecular Prediction of Inflammatory Bowel Disease (PREDICT) at Aalborg University in Copenhagen, Denmark, and colleagues in JAMA.

The HLA-DRB1*01:03 allele explained this association overall (OR 3.32, 95% CI 2.25-4.89, P=1.45 × 10^-9) and in the two cohorts used in the study: the PREDICT neonatal blood spot cohort (OR 3.29, 95% CI 2.22-4.89) and the North Denmark Biobank (OR 3.98, 95% CI 0.54-29.23). After conditioning on DRB1*01:03, no other allele had a P value below the genome-wide significance threshold.

The association between the HLA-DRB1*01:03 allele and ulcerative colitis has been noted previously, but there is a clinical need for biomarkers that could identify which patients are more likely to progress to severe disease, Vestergaard and team noted. Early genetic testing for HLA-DRB1*01:03 could show which patients with ulcerative colitis need more intense monitoring and earlier treatment to avoid repeated surgery or hospitalizations.

The association with HLA-DRB1*01:03 in carriers compared with noncarriers had an OR of 6.38 (95% CI 3.89-10.46, P<0.001) for major operations, 5.24 (95% CI 3.49-7.86, P<0.001) for at least two hospitalizations, and 2.30 (95% CI 1.42-3.71, P=0.001) for treatment with at least 5,000 mg of systemic corticosteroids.

Time-to-event analyses showed that the association with severity extended beyond 3 years after diagnosis. The analysis found a hazard ratio of 2.22 (95% CI 1.79-2.74, P<0.001) for time to hospitalization, 5.13 (95% CI 3.86-6.81, P<0.001) for time to major operation, and 1.69 (95% CI 1.38-2.07, P<0.001) for time to first treatment (500 mg) with systemic corticosteroids in carriers versus noncarriers.

Vestergaard told MedPage Today that she and her team found that 42% of patients carrying the allele had a major related surgery within the first 3 years after the date of diagnosis compared with 9% of noncarriers.

“Once the allele is validated in an external cohort, we hope that in the future it will be used by clinicians to identify patients at high risk of severe disease course with ulcerative colitis,” she said. “Based on this, clinical trials should be initiated to investigate a top-down treatment approach in the subgroup of patients carrying the allele. This could show whether a more intensive early treatment could improve the following disease course.”

Lea Ann Chen, MD, director of inflammatory bowel disease translational research at Rutgers Robert Wood Johnson Medical School in New Brunswick, New Jersey, and a spokesperson for the American Gastroenterological Association, told MedPage Today that “although genetic biomarkers hold high promise for improving clinical management of inflammatory bowel disease, they are currently not widely used.”

“Part of the challenge is that the biomarkers may not provide added information to guide clinical decisions,” she said. “For example, in this study, the carrier and noncarriers of the HLA-DRB1*01:03 allele have disease courses that separate very early after diagnosis. Patients who require high doses of steroids, hospitalization, and surgery in such a short time frame after diagnosis are already demonstrating a need for more aggressive management.”

However, she noted that the study and similar genetic studies are incredibly important to advancing the understanding of inflammatory bowel disease.

This genome-wide association study used two nationwide source populations in Denmark: the PREDICT neonatal blood spot cohort, which includes individuals born in Denmark who were diagnosed with ulcerative colitis from 1981 to 2022, and the North Denmark Biobank study, a population-based cohort of patients who had inflammatory bowel disease from 1978 to 2020. DNA was extracted from either dried blood spots or full blood using standard protocols.

The researchers divided the patients into two groups by the severity of their disease. Severe ulcerative colitis was defined as requiring at least one surgery, at least two hospitalizations longer than 2 days, and/or treatment with at least 5,000 mg of systemic corticosteroids within 3 years of diagnosis. Patients not meeting these criteria were considered to have less severe disease and were included as the comparison group. Patients with at least 3 years of follow-up were included.

The study included 4,491 patients (4,153 from PREDICT and 338 from the North Denmark Biobank). Mean age at diagnosis was 23.3, 53% were women, and 27% had severe disease.

Limitations to this study included that findings were based on Danish patients of European genetic ancestry, and validation in diverse patient cohorts is needed.

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