PSC may increase ulcerative colitis risk, but not Crohn’s disease

Researchers used Mendelian randomization to better understand association

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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Genetic variations that predispose people toward developing primary sclerosing cholangitis (PSC) are significantly associated with a higher risk of ulcerative colitis, a primary type of inflammatory bowel disease (IBD), a study shows.

The two conditions also share some genetic risk factors, but genetically determined PSC wasn’t linked to an increased risk of Crohn’s disease, the other main IBD type. Still, the mechanisms behind these observations about PSC and IBD aren’t fully understood.

“More animal experiments and clinical observational studies are required to further clarify the underlying mechanisms of PSC and IBD,” the researchers wrote in “Investigating the shared genetic architecture between primary sclerosing cholangitis and inflammatory bowel diseases: a Mendelian randomization study,” which was published in BMC Gastroenterology.

PSC is a chronic disease where inflammation and scarring, or fibrosis, in the tubes that carry the digestive fluid bile from the liver to the intestines cause progressive damage to the liver, which can become life-threatening. PSC predominantly affects men and is believed to be autoimmune in origin, with the immune system attacking healthy tissue. It’s commonly linked to IBD, an umbrella term for diseases marked by chronic inflammation of the gastrointestinal tract, including Crohn’s disease and ulcerative colitis. As with PSC, abnormal immune responses are implicated in IBD.

Studies have found that most PSC patients have some type of IBD. Likewise, PSC or other liver conditions are sometimes seen as extra-intestinal manifestations of IBD, although they occur less often.

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Exploring association between PSC, IBD

The underlying cause of either PSC or IBD is incompletely understood and it’s not known if there’s a causal relationship between them or a shared genetic underpinning. Moreover, “a lack of effective treatment methods” remain for either disease, meaning finding a possible link could help in developing new therapeutic approaches.

Here, scientists in China used a technique called Mendelian randomization (MR) to better understand the association between PSC and IBD. This type of analysis looks for relationships between a risk factor and an outcome. In this case, the risk factor is the genetic predisposition to PSC and the outcome is IBD.

MR analysis was based on data from genome-wide association studies (GWAS), large studies that collect genetic and clinical information from thousands of people to establish genetic changes linked to the risk of a certain clinical feature, such as a disease.

Across these studies, data were available from 14,890 PSC patients, 463,010 ulcerative colitis patients, and 212,356 Crohn’s disease patients. Five MR methods were used to understand the relationships between PSC and either ulcerative colitis or Crohn’s disease.

Four of these types of MR analysis showed that genetically predicted PSC was significantly associated with an increased risk of ulcerative colitis, but no method showed a significant link between PSC and Crohn’s disease.

The researchers also identified five single-nucleotide polymorphisms (SNPs) associated with an increased risk of PSC and ulcerative colitis. SNPs are changes in a single nucleotide, that is, a building block of DNA. Some of these SNPs have been linked to autoimmune disease and immune function, but their exact role in PSC and IBD hasn’t been fully investigated.

The findings “corroborated a causal association between genetically predicted PSC and [ulcerative colitis],” wrote the researchers, who acknowledged their study had several limitations, including that IBD GWAS data came from a European population, but PSC GWAS data was from a mixed population. “In the future, more populations should be included,” they wrote. “Our results may inspire possible mechanism analyses and the relationship between PSC and IBD in the future.”

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