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New insights into the causes of chronic bile duct inflammation


In an international research project, scientists from the Cluster of Excellence “Inflammation at Interfaces” have identified variants in four genetic regions, which significantly increase the risk of primary sclerosing cholangitis (PSC). This provides new insights into the causes of the chronic progressive inflammation, which obstructs the bile ducts inside and outside of the liver. Patients with PSC often also have a chronic inflammatory bowel disease, primarily ulcerative colitis. Previous studies also involving the Cluster of Excellence have already identified 16 genetic risk regions for PSC. “We have found four new loci, and for one of these four regions we already have an idea of what could be biologically responsible,” said Professor David Ellinghaus from the Institute of Clinical Molecular Biology at the Faculty of Medicine at Kiel University (CAU). “And, for the first time, we can make a quantitative statement on how similar chronic inflammatory bowel disease (IBD) is to the bile duct inflammatory disease PSC, on a genetic level.” The results of the world-wide largest genetic study on PSC to date have been published in the renowned scientific journal Nature Genetics. It compared DNA samples of around 4,800 patients with a control population of nearly 20,000 healthy individuals.

The underlying cause of primary sclerosing cholangitis (PSC), and what triggers it, remains a mystery. This chronic inflammatory disease attacks the bile ducts and thus impedes the flow of bile. In the long term, this can lead to cirrhosis of the liver. It is estimated that 1 in 10,000 Europeans are affected, often people of middle age (30 to 50 years old). Approximately three-quarters of the patients also have a chronic inflammatory bowel disease, in most cases ulcerative colitis. There is no specific pharmacological treatment; in cases with severe liver damage, a liver transplant is the only option. For many years, Kiel working groups from the Cluster of Excellence “Inflammation at Interfaces” have been participating in the International PSC Study Group and the German PSC Study Group, investigating the genetic causes. “We know that there is a genetic component. If we can learn more about this genetic basis, we will discover new approaches for further biological analyses, and potential areas of attack for treatments,” explained bioinformatics scientist David Ellinghaus, from the working group led by Professor Andre Franke at the Institute of Clinical Molecular Biology at the CAU.

In the largest genome-wide association study of PSC, now published in Nature Genetics, scientists in an international consortium compared DNA samples from around 4,800 patients with samples from nearly 20,000 healthy individuals from Europe, America and Canada. They analysed the samples using a DNA microarray, a chip with several millions of known genetic variants, and found four gene regions in our genotype which are related to bile duct inflammation. One of them was able to be characterised in more detail.

In addition, the enormous database made it possible to quantify the genetic similarities between PSC and chronic inflammatory bowel diseases. It was determined that “There are genetic factors which play a role in both. But with the current results, one can only partly explain the comorbidity between PSC and chronic bowel disease,” said Ellinghaus. The results of the genome-wide comparison mirrored the clinical observation that there is a greater genetic correlation with ulcerative colitis than with Crohn's disease.

Original publication:
Ji et al.: Genome-wide association study of primary sclerosing cholangitis identifies new risk loci and quantifies the genetic relationship with inflammatory bowel disease. Nature Genetics 2016, published online December 19, 2016. doi:10.1038/ng.3745

Picture: Jürgen Haacks/ CAU

Prof. Dr. David Ellinghaus
Institute of Clinical Molecular Biology at Kiel University
Tel.: +49 (0)431 500 15131

Prof. Dr. Andre Franke
Institute of Clinical Molecular Biology at Kiel University
Tel.: +49 (0)431 500 15110

Cluster of Excellence "Inflammation at Interfaces"
Scientific Office, Head: Dr. habil. Susanne Holstein
Press and Communications, Dr. Tebke Böschen
Postal address: Christian-Albrechts-Platz 4, 24118 Kiel, Germany
Tel.: +49 (0)431 880-4682, Fax: +49 (0)431 880-4894

The Cluster of Excellence "Inflammation at Interfaces" has been funded since 2007 by the Excellence Initiative of the German Government and the federal states with a total budget of 68 million Euros. It is currently in its second phase of funding. Around 300 cluster members are spread across the four locations: Kiel (Kiel University, University Medical Center Schleswig-Holstein (UKSH)), Lübeck (University of Lübeck, UKSH), Plön (Max Planck Institute for Evolutionary Biology) and Borstel (Research Center Borstel (FZB) – Center for Medicine and Biosciences) and are researching an innovative, systematic approach to the phenomenon of inflammation, which can affect all barrier organs such as the intestines, lungs and skin.

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