Immunochip to Survey Genome Regions

Researchers have newly identified three genetic regions associated with primary biliary cirrhosis (PBC), the most common autoimmune liver disease, increasing the number of known regions associated with the disorder to 25. The team used a DNA microchip, called Immunochip, to survey more thoroughly regions of the genome known to underlie other autoimmune diseases to discover if they play a role also in PBC susceptibility. By combining the results from this survey with details of gene activity from a database called ENCODE, they were able to identify which cells types are most likely to play a role in PBC.

PBC affects approximately one in every three thousand people in the UK, and one in a thousand women over the age of 40. Inflammation in the bile ducts blocks the flow of bile, damaging the liver cells and causing further inflammation and scarring, and in severe cases will result in the need for a liver transplant.

There is currently no cure for PBC, so treatment is focused on slowing down the progression of the disease and treating any symptoms or complications that may occur. The biological pathways underlying primary biliary cirrhosis are poorly understood, although autoimmunity, where the body attacks its own cells, is known to play a significant role.

"Previous genetic screens have identified 22 regions of the genome underlying PBC risk, and many of these are known to play a role in other autoimmune diseases, such as multiple sclerosis and type I diabetes," says Dr Carl Anderson, co-senior author from the Wellcome Trust Sanger Institute.

"Using the Immunochip we were able to perform a much more thorough screen of the genomic regions previously associated with other autoimmune diseases. This resulted in us identifying a further three regions involved in PBC risk and identifying additional independent signals within some of those we already knew about."

The advantage of Immunochip over genome-wide technologies is that it focuses only on regions of the genome known to be associated with an autoimmune disease and thus captures more of the genetic variation within these regions. Immunochip can therefore be used to more thoroughly test these key candidate genes for association to a whole-host of immune-related traits, and identify low frequency and rare genetic variants associated with disease that would likely be missed by a microarray that covers a broader range of genetic regions.

The researchers found five genomic regions with multiple independent signals associated with the disorder, with one small region on chromosome 3 harbouring four independent association signals. These findings suggest that densely genotyping or sequencing known disease regions will be a powerful approach for identifying additional genetic risk variants and for further elucidating the role of rare genetic variation in complex disease risk.

"This study has allowed us to better understand the genetic risk profile of PBC and, by comparing our results with similar studies of other autoimmune diseases, we hope to further characterise the genetic relationship between this group of clinically diverse but biologically related disorders" says Dr Richard Sandford, co-senior author from the University of Cambridge "Over the next few years we will be extending our studies to search for genetic variants that affect disease course and treatment response. We hope that our studies will have a clinical impact, either directly through a more personalized approach to treatment or indirectly by furthering our understanding of the biological pathways underlying PBC leading to new treatments."

The most associated genetic variant within the newly implicated TYK2 gene was a low-frequency variant previously associated with multiple sclerosis (MS) that changes the coding sequence of the gene. Previous studies in MS have shown that individuals that carry a single copy of this variant have significantly reduced TYK2 activity, suggesting that modulation of TYK2 activity might represent a new therapeutic approach for the treatment of PBC.

"This study is an example of how people with rare conditions like primary biliary cirrhosis can work together with scientists and physicians to find a path towards drug targets and treatments for these diseases," says Collette Thain, MBE, Chief Executive of the PBC Foundation. "Although this is just the beginning of a long road to finding the genetic basis of PBC, with each study we are moving closer and closer to finally understanding and tackling this disease."

Jimmy Z. Liu, Mohamed A. Almarri et al 'Dense fine-mapping study identifies novel disease loci and implicates coding and non-coding variation in primary biliary cirrhosis risk'

Published online in Nature Genetics on 9 September DOI: 10.1038/ng.2395

Most Popular Now

New AI Tool Predicts Protein-Protein Int…

Scientists from Cleveland Clinic and Cornell University have designed a publicly-available software and web database to break down barriers to identifying key protein-protein interactions to treat with medication. The computational tool...

AI for Real-Rime, Patient-Focused Insigh…

A picture may be worth a thousand words, but still... they both have a lot of work to do to catch up to BiomedGPT. Covered recently in the prestigious journal Nature...

New Research Shows Promise and Limitatio…

Published in JAMA Network Open, a collaborative team of researchers from the University of Minnesota Medical School, Stanford University, Beth Israel Deaconess Medical Center and the University of Virginia studied...

G-Cloud 14 Makes it Easier for NHS to Bu…

NHS organisations will be able to save valuable time and resource in the procurement of technologies that can make a significant difference to patient experience, in the latest iteration of...

Start-Ups will Once Again Have a Starrin…

11 - 14 November 2024, Düsseldorf, Germany. The finalists in the 16th Healthcare Innovation World Cup and the 13th MEDICA START-UP COMPETITION have advanced from around 550 candidates based in 62...

Hampshire Emergency Departments Digitise…

Emergency departments in three hospitals across Hampshire Hospitals NHS Foundation Trust have deployed Alcidion's Miya Emergency, digitising paper processes, saving clinical teams time, automating tasks, and providing trust-wide visibility of...

MEDICA HEALTH IT FORUM: Success in Maste…

11 - 14 November 2024, Düsseldorf, Germany. How can innovations help to master the great challenges and demands with which healthcare is confronted across international borders? This central question will be...

A "Chemical ChatGPT" for New M…

Researchers from the University of Bonn have trained an AI process to predict potential active ingredients with special properties. Therefore, they derived a chemical language model - a kind of...

Siemens Healthineers co-leads EU Project…

Siemens Healthineers is joining forces with more than 20 industry and public partners, including seven leading stroke hospitals, to improve stroke management for patients all over Europe. With a total...

MEDICA and COMPAMED 2024: Shining a Ligh…

11 - 14 November 2024, Düsseldorf, Germany. Christian Grosser, Director Health & Medical Technologies, is looking forward to events getting under way: "From next Monday to Thursday, we will once again...

In 10 Seconds, an AI Model Detects Cance…

Researchers have developed an AI powered model that - in 10 seconds - can determine during surgery if any part of a cancerous brain tumor that could be removed remains...

Does AI Improve Doctors' Diagnoses?

With hospitals already deploying artificial intelligence to improve patient care, a new study has found that using Chat GPT Plus does not significantly improve the accuracy of doctors' diagnoses when...