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PSC genome study finds four new risk loci, clarifies genetic link to IBD

The largest genome-wide association study of primary sclerosing cholangitis has led to the discovery of four previously unidentified genetic risk locations for the disease.

Results from the international study also further clarified the genetic relationship between PSC and inflammatory bowel disease, representing “a substantial advance in understanding of the genetics of PSC,” Konstantinos Lazaridis, MD, of the Mayo Clinic in Rochester, Minn., Carl Anderson, PhD, of the Wellcome Trust Sanger Institute, and colleagues wrote.

U.S. and European co-investigators compared the genomes of 4,796 PSC patients vs. 19,995 healthy controls; PSC specimens were provided by patients from multiple international centers, and control specimens were obtained from the Mayo Clinic Biobank.

Ultimately, they identified four new genomic regions that correlated with PSC risk, bringing the total number of known PSC risk locations to 20. One of these showed that PSC is associated with increased levels of the UBASH3A protein, which regulates T-cell signaling.

“We discovered that lower levels of the UBASH3A protein correlate with lower risk of PSC,” Anderson said in a press release. “A drug that could reduce the amount of UBASH3A may thus be helpful in treating people with PSC, so this gives pharmaceutical companies insight into biological systems to target.”

Further, the researchers compared their findings with those from previous genomic IBD studies, which clarified the genetic relationships and distinctions between the diseases. Specifically, PSC and ulcerative colitis shared greater genetic correlation than PSC and Crohn’s disease, while ulcerative colitis and Crohn’s disease were more genetically similar to each other than either was to PSC, the researchers wrote.

This suggests that although an estimated 75% of PSC patients also have IBD, usually ulcerative colitis, “there are unique aspects to the biology of PSC and … the disease is not simply caused by IBD,” per the press release.

“Looking at PSC and IBD patients, we saw both clinical and genetic differences between the two groups,” Lazaridis said in the press release. “If we want to understand bowel inflammation in PSC, we need to look at that specifically and compare it with a separate group of IBD patients without PSC, not merge the two groups and look at the average. Our study suggests PSC is a separate disease to IBD, despite the many genetic and clinical commonalities.” – by Adam Leitenberger

Disclosures: The researchers report no relevant financial disclosures.