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Uncovering the Genetic Basis for Primary Sclerosing Cholangitis

In the largest study of its kind, an international group of researchers revealed several areas of the human genome that convey risk for developing primary sclerosing cholangitis (PSC), a disease that can lead to liver damage, also shedding light on this disease’s relationship to inflammatory bowel disease (IBD). In PSC, a network of tubes, called biliary ducts, become inflamed. These tubes carry bile from the liver, where it is made, to the small intestine, where it helps digest fats and certain vitamins. As the bile ducts become inflamed and then scarred, they eventually become blocked. Unable to exit the liver, the accumulating bile has devastating effects on the liver tissue, causing scarring, cirrhosis, and, ultimately, liver failure. The reasons underlying the bile duct inflammation are not completely understood, although genes appear to play a role, as people who have relatives with PSC are more prone to develop the disease themselves. But finding genes that could be involved has been difficult because PSC is relatively rare: it is diagnosed in about 1 in 100,000 people per year in the United States. Roughly three-quarters of the people with PSC also have a form of IBD, most often ulcerative colitis, raising the possibility that there are shared genetic factors between these two diseases.

Recently, a group of researchers studied the DNA of about 4,800 people with PSC and compared it to the DNA of almost 20,000 healthy individuals. PSC is more common in men than women, but women do develop the disease, so the researchers studied both sexes. They identified four areas of the genome with variants—changes in the DNA—that are more common in people with the disease. One of the variants causes higher levels of a protein called UBASH3A, suggesting that this protein may have a role in PSC and could be a therapeutic target. The scientists also partnered with the International IBD Genetics Consortium, of which the NIDDK’s IBD Genetics Consortium is a member, to compare the genomes of people with PSC to those who have IBD. The researchers found that genetic factors linked to PSC are more closely correlated with ulcerative colitis than Crohn’s disease, another form of IBD. This could explain why a larger percentage of people with PSC have the ulcerative colitis form of IBD, rather than Crohn’s disease. However, the genetic associations that they found were not enough to fully explain why so many people have both PSC and ulcerative colitis. This suggests that there may be other shared factors between these two diseases that have yet to be uncovered, such as environmental influences or rare genetic variants that are more difficult to detect. Further research could pinpoint the genes involved in PSC, resulting in potential therapeutic targets and improved screening methods to help diagnose and treat the disease.

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