Researchers find new risk markers for sclerosing cholangitis

Last Updated: 2016-12-29

By David Douglas

NEW YORK (Reuters Health) - An international group of researchers have established four new primary sclerosing cholangitis (PSC) markers, one of which points to a possible therapeutic intervention in this currently untreatable liver disease.

As Dr. Carl Anderson told Reuters Health by email, "By identifying regions of the genome where PSC risk variants reside, we were able to gain key insights into the disease biology. We found that one of the significantly associated variants not only reduced risk of PSC, but also lowered expression of a gene called UBASH3A."

"The gene," he added, "plays a role in T cell signalling, a central process of the immune system. This suggests that it is possible to reduce risk of PSC by altering levels of UBASH3A, highlighting this protein as a potential therapeutic target for PSC."

In a paper online December 19 in Nature Genetics, Dr. Anderson of The Wellcome Trust Sanger Institute, Hinton, U.K., and colleagues note that PSC is characterized by chronic inflammation and stricturing fibrosis of the biliary tree and about 75% of patients go on to develop inflammatory bowel disease (IBD).

There is evidence to suggest that 19 regions of the genome are associated with PSC risk and the team sought to extend this knowledge. They examined genome-wide associations in nearly 4,800 PSC patients and 20,000 controls.

The team identified four new PSC risk loci and "now consider 23 regions of the genome to be associated with disease risk."

"One of our new associations," they write, "suggests that decreased UBASH3A is associated with a lower risk of PSC through a common nonstop-mediated mRNA decay variant."

They add that "by conducting genome-wide comparisons with Crohn's disease (CD) and ulcerative colitis (UC), we showed that the comorbid gastrointestinal inflammation seen in the majority of PSC patients cannot be fully explained by shared genetic risk."

Co-investigator Dr. Konstantinos Lazaridis of the Mayo Clinic in Rochester, Minnesota, said in a statement, "Additional scientific efforts for genome sequencing of primary sclerosing cholangitis patients will give us more opportunities to find the specific genetic underpinnings that contributing to the risk of primary sclerosing cholangitis and to explain what makes the correlation between primary sclerosing cholangitis and IBD."

As to the possible therapeutic target, Dr. Anderson concluded, "Developing a drug against UBASH3A will be tough, because it is difficult to target using current small molecule approaches."

SOURCE: http://bit.ly/2iHTL5Z

Nat Genet 2016.