In a genome-wide association study, Danish researchers found strong links between an allele on the human leukocyte antigen gene and more severe ulcerative colitis.

The allele in question, HLA-DRB1×01:03, is rare; 2.8% of study participants carried it. Even so, researchers recommend genotyping everyone with UC to identify carriers. That is a modest up-front cost to spot patients who may need closer monitoring, the researchers noted.

“Earlier, more intensive treatment in these patients could improve their disease course,” said investigator Marie Vibeke Vestergaard, MSc, a bioinformatician and doctoral student at the Center for Molecular Prediction of Inflammatory Bowel Disease at Aalborg University, in Copenhagen, Denmark.

The study included 4,491 people with UC in Denmark; 53% were female, and the mean age at diagnosis was 24 years (JAMA 2024 Oct 15. doi:10.1001/jama.2024.20429).

Ms. Vestergaard and her co-investigators genotyped everyone in the cohort, which they divided into people with severe or less severe UC based on at least three years of follow-up. They defined severe UC as disease requiring one major UC-related operation, at least two hospital stays of more than two days and/or the use of at least 5,000 mg of systemic corticosteroids within three years of diagnosis.

They used DNA from dried blood spots or blood samples to conduct a genome-wide association study that analyzed 9,508,878 single-nucleotide variations. Variations at chromosome 6 within the HLA region had strong associations with the development of more severe UC (odds ratio [OR], 2.23; 95% CI, 1.96-2.50; P=4.22×10^-9).

This same allele was linked to a greater risk for major surgeries (OR, 6.38; 95% CI, 3.89-10.46; P<0.001), multiple hospitalizations (OR, 5.24; 95% CI, 3.49-7.86; P<0.001) and use of at least 5,000 mg of corticosteroids (OR, 2.30; 95% CI, 1.42-3.71; P=0.001).

Future studies with more diverse samples are needed to validate the findings, although Ms. Vestergaard noted that the same HLA allele has long been associated with worse outcomes in UC, such as the need for colectomy (Tissue Antigens 2003;62[6]:527-535).

“So, it makes sense that this allele would be linked with increased disease severity too. I trust the findings, but it’s always nice to have external validation,” Ms. Vestergaard said.

Mechanistic studies that isolate why this allele carries such risk for people with UC also are needed to inform new targeted treatments, she added. Currently, someone with this allele would receive the same UC treatments as anyone else, but it’s possible that more targeted treatments would be more beneficial. “The ultimate goal in the future is to tailor treatments to different subtypes of patients,” Ms. Vestergaard said.

Some of the earlier studies that identified links between the HLA gene and severe UC are from academic medical centers, noted Dermot McGovern, MD, PhD, a gastroenterologist and the director of Precision Health Medicine at Cedars-Sinai, in Los Angeles. Those study populations are not representative of an entire country, Dr. McGovern said, unlike the Denmark study.

A Population-Based Study

“What’s nice about the study—not only is it population-based, but when you look at each of the parts of the end point, all of them are associated with the HLA variant,” added Dr. McGovern, who was not involved in the study. The link between the variant and surgeries, hospitalizations, and steroid use strengthens the findings, he said.

“If you think about how much it costs to run a genome, that’s roughly $400,” Dr. McGovern said, noting that it is significantly less than the cost of lab tests clinicians routinely order when treating UC. Given this, Dr. McGovern said he supports the idea of genotyping upon UC diagnosis to help stratify patients at the highest risk for severe disease. “This pulls the small number of people who carry this variant into our awareness, so we can monitor them more closely and be more aggressive with our treatments,” he said.

In addition to developing targeted treatments that inhibit the impact of this allele, Dr. McGovern said, researchers should explore combination therapies that best reduce disease burden.

—Marcus A. Banks

Dr. McGovern and Ms. Vestergaard reported no relevant financial disclosures.