Study identifies four previously unknown genetic risk locations for primary sclerosing cholangitis

A study of unprecedented scale has led researchers to identify four previously unknown genetic risk locations for primary sclerosing cholangitis, a liver disease that lacks effective medical therapy. A Dec. 19 article in Nature Genetics highlights the undertaking, which is the largest genome-wide association study of primary sclerosing cholangitis to date and a step toward providing breakthrough treatments for the unmet needs of primary sclerosing cholangitis patients.

The study was led by Mayo Clinic's Konstantinos Lazaridis, M.D., and Carl Anderson, Ph.D., of the Wellcome Trust Sanger Institute, along with collaborators from six other U.S. medical centers and co-investigators from the U.K., Germany and Norway and collaborators from other European countries.

Primary sclerosing cholangitis affects 1 in 10,000 individuals, with about 75 percent developing inflammatory bowel disease (IBD), most often in the form of ulcerative colitis. However, only 5 to 7 percent of those affected by pre-existing IBD alone later develop primary sclerosing cholangitis.

Researchers compared the genetic information of 4,796 primary sclerosing cholangitis patients against a control population of nearly 20,000 individuals, the specimens of which were provided by patients from the U.S. and Europe, including healthy controls from Mayo Clinic Biobank.

"Considering the rarity of those affected by primary sclerosing cholangitis, the contribution of specimens by multiple centers across the globe allowed us to view the genetic comparisons of this disease in a much bigger picture," says Dr. Lazaridis. "This is a testament of trust from the primary sclerosing cholangitis patients to this investigative team to whom we are grateful. We feel a strong spirit of collaboration among the medical centers involved."

Using these data, researchers identified four new markers of primary sclerosing cholangitis risk on the human genome, bringing the total number of known predisposing locations to 20. One of the four new reported loci is expected to lower the protein expression of UBASH3A, a molecule that regulates T-cell signaling and correlates with lowering the risk of primary sclerosing cholangitis. Dr. Lazaridis says this molecule therefore should be further examined as a target of therapy for the disease.

The study also allowed for clearer estimations as to how primary sclerosing cholangitis and IBD may share genetic risk factors.

"The immense scale of this genetic study allowed us to analyze for the first time the complex genetic relationship between primary sclerosing cholangitis and IBD," says Lazaridis. "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."

Dr. Lazaridis says such knowledge will be important in facilitating the development of medical therapies for primary sclerosing cholangitis — an urgent need for patients.