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Update on the genetics of PSC

Update on the Genetics of PSC

New discoveries from an international PSC genetic study open the door to new potential drug targets and trials

Update on genetics of PSC

Primary sclerosing cholangitis (PSC) is a disease that affects the bile ducts – the tubes that deliver bile from the liver to the small bowel. They become inflamed and scarred, meaning bile cannot drain properly and it builds up in the liver. This can lead to infection and liver damage with prolonged exposure.

PSC is complex and we don’t know what causes it, but current evidence suggests PSC is caused by a combination of genetic changes making you prone to immune attack and equally important, some collection of environmental triggers. People with a particular genetic make-up may be susceptible to particular toxic or infectious agents, which triggers their immune system to effectively ‘attack’ the bile ducts.

What has interested researchers for a long time is that around 75 per cent of people with PSC also have inflammatory bowel disease (IBD), but until now, the genetic relationship between the two diseases has not been fully understood. There have been clues that the colitis in a PSC patient is not always quite the same as classic colitis.

In order to understand more about what causes PSC, and the genetic relationship to IBD, researchers led by Dr Carl Andersonfrom the UK and Kostas Lazaridis from the USA under the auspices of the International PSC Study Group looked at the DNA of 4,796 PSCers and compared them with those of 19,955 healthy people. PSCers from all over the world have contributed DNA samples since 2009, including those of us in the UK-PSC Study funded by PSC Support and NIHR Rare Disease Translational Research Collaboration. Researchers also used data from the International IBD Genetics Consortium for 20,550 Crohn’s Disease cases, 17,647 ulcerative colitis cases and 48,485 controls of European ancestry.

This was a huge undertaking. Their landmark paper, representing six years of work, provides a substantial advance in our understanding of the genetics of PSC.

What did the study find?

The researchers reported the identification of four regions of our DNA newly-associated with risk of developing PSC, bringing the number of regions on our DNA associated with PSC to twenty-three

They also found that one of these new regions increases the level of a protein called UBASH3A, suggesting that decreased levels of UBASH3A may be associated with a lower risk of PSC. In a tantalising way, this provides hope that genetic studies can bridge from why we get PSC to how we might treat it. This is however something we need to understand more before getting too excited!

The research team found many regions of our DNA associated with both PSC and IBD risk, but they also found others that were only associated with risk of PSC. This is critical, because it shows that there are unique genetic aspects to PSC-IBD, which are different to those only with IBD.  This makes sense, as we know the colitis of PSC behaves very differently to that of classical ulcerative colitis. Therefore PSC-IBD is genetically slightly different to IBD, and the classical concept of PSC being a complication of colitis is not accurate: it is more that PSC-IBD is a distinct disease with some distinct risk factors, even if some risk factors are shared and some clinical aspects look the same.

There is no doubt that this important work is of major importance in furthering our knowledge of PSC. However, we should remember that PSC is a rare disease. One of the acknowledged limitations of this study was that despite nearly 5,000 international PSC samples (many from the UK-PSC), there were not enough to do a detailed analysis on the interaction of the risk-genes and different kinds of PSC.

Gideon Hirschfield from Birmingham commented, "We are all really pleased that this study has come to fruition, and that the collection that Simon Rushbrook was able to drive in the UK with the help of our patients over the last ten years, has proved so helpful and informative.  However we must keep working at it because this study tells us a small part of the puzzle as to why someone gets PSC-IBD; the reality is that for our patients we still don't know how to track from why the disease starts, to how it behaves and affects them.  It is reassuring to see however that for a rare disease, collaboration can work, and that's why UK-PSC continues to try and secure a long term approach to studying and treating PSC."

What’s next?

Simon Rushbrook from Norwich told PSC Support, "This work will now obviously lead us to start to look at how these genetic changes affect different cells of the immune system in terms of their expression of the proteins made by these genetic regions. Through a better understanding of this, we hope that we can start to develop a clear understanding of which parts of the immune system are altered in PSC, and how we can target these for new therapies. This work, currently being done by Dr Elizabeth Goode and Dr Carl Anderson, will be a fundamental next step.”

Carl Anderson, from the Wellcome Trust Sanger Institute in Cambridgeshire told us, “This study gives us key insights into the regions of our DNA that affect risk of PSC. But the next major challenge is to work out how these genetic changes perturb normal physiology in a way that leads to the disease. Cracking this puzzle has the potential to uncover new drug targets for PSC. Our discovery that PSC has biological components independent of those seen in IBD indicates that these important downstream experiments need to be conducted in PSC-IBD if they are to be successful. The continued enthusiasm of PSCers to contribute to research is thus vitally important. None of this would be possible without this involvement”.

Step by step, researchers and scientists are systematically breaking down the PSC puzzle and building a fundamental understanding of the factors at play in our condition.  We need to go from why the bile ducts are attacked, to how the bile ducts respond to being attacked, through to why and how to change that process.

These newly announced findings are a compelling example of the importance of patient engagement. PSC Support has been a long-term financial, advocacy and governing partner for the UK-PSC study, but more importantly, it is the PSC patient community that has played a fundamental role by providing a significant set of research samples for this study.

And this research is on-going. Genetics only partly explains the mechanism and cause of PSC, so it’s also important to build up a picture of personal medical history and long-term experience of people with PSC. That’s why the UK-PSC study broadened its scope in terms of samples taken and age of contributors (ALL ages are welcome to provide samples).

What can you do to help further?

The response from you has been phenomenal, with around 2,000 UK-PSC patients registered to date, but more PSC samples are needed to continue to move our understanding forward.

If you’ve already provided a blood or saliva sample to the UK-PSC Study, then watch out for a “re-consenting” request and consider returning it as soon as possible. If your contact details have changed or you have not heard anything, or if you have not yet contributed to the UK-PSC Study, and you want to, then please e-mail the UK-PSC Project Manager for details.

PSC patients in the UK of all ages are eligible to take part.

Ji S-G. 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. 2017;49:269–73.
Chung BK, Hirschfield GM. Immunogenetics in primary sclerosing cholangitis. Current Opinion in Gastroenterology. 2017 Jan:1.

Reviewed by Professor Gideon Hirschfield, Dr Simon Rushbrook and Dr Carl Anderson, 10 March 2017