Precision medicine discovers hidden genetic connections behind IBD

Published by  News archive

On 28th Apr 2022

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Patients with Inflammatory Bowel Disease (IBD) develop the condition due to distinct and different mechanisms determined by their genetics, according to new research involving the University of East Anglia.


Researchers from UEA’s Norwich Medical School worked in collaboration with colleagues at the Quadram Institute to discover the hidden genetic connections behind IBD.

They hope their work, published today in Nature Communications, could improve personalised medicine.

All humans carry genetic variations in their DNA, called Single Nucleotide Polymorphisms (SNPs) that can underlie susceptibility to diseases such as diabetes and cancer.

For IBD many disease-associated SNPs have been identified but exploiting these clinically has proven challenging, mostly due to the unknown effects of the SNPs.

A multi-disciplinary group of systems biologists, clinicians, immunologists and microbiologists developed and tested a systems medicine workflow that identifies the hidden genetic connections that form patient-specific patterns, which could guide better therapy selections.

The discovery was made by researchers and clinicians from the Quadram Institute, the Earlham Institute, the Norfolk and Norwich University Hospital (NNUH) and UEA with collaborators in Cambridge, London and Leuven (Belgium).

Using a novel and powerful systems genomics approach identifying which of several possible pathways to disease a patient has will lead to more effective diagnosis and treatments and provide a much better understanding of this complicated condition, which can also be applied to other perplexing disease studies to help more patients.

Prof Simon Carding, from UEA’s Norwich Medical School and the Quadram Institute, said: “For complex diseases, such as cancer, IBD, and other autoimmune diseases, there are always multiple answers.

“Until now there were only a few tools that could carry out a complex analysis on a patient-specific way and provide various molecular maps of the same disease.”

IBD affects around 500,000 people in the UK, causing a range of painful and debilitating symptoms linked to inflammation of the gut. The causes of IBD aren’t understood but are linked to dysfunction of the immune system and how it reacts to food and the gut microbiome. There is also a strong genetic link to IBD susceptibility.

To unpick how these complex factors interact in the development of IBD, gastroenterologists from the NNUH and the Addenbrooke's Hospital in Cambridge, microbiologists and immunologists from the Quadram Institute, genome biologists and network scientists from the Earlham Institute and cheminformaticians from University of Cambridge came together to link the genetic component of IBD susceptibility to its effects on patients.

Previous studies have linked the disease to specific alterations in the genetic code, finding minor changes of just one letter in the genetic code that associate with IBD. These so-called ‘Single Nucleotide Polymorphisms,’ or SNPs can be mapped to the human genome.

If an SNP linked to IBD maps to a gene, it identifies that gene and its genetic code as being important in the disease. For some conditions this has led to improved therapies.

However, for IBD, less than 10 per cent of the identified SNPs were in genes. Instead, more than 90 per cent of SNPs were in non-coding regions of the genome. This isn’t surprising, as most of the human genome is made up of this non-coding DNA, with genes comprising just 1 per cent. The other 99 per cent was once thought to just be junk DNA, but we now know it has important roles in controlling and regulating the activity of the genes.

Additionally, some SNPs may only have very subtle effects, but in combination lead to disease progression. Given the complex nature of IBD, it was very likely this was the case for this condition. The immune system functions by taking a wide range of different inputs that trigger different signalling networks within the cell, integrating these to produce a balanced, appropriate response.

Understanding how all of the IBD associated SNPs in non-coding regions of the genome combine to influence these intricately interlinked signals in the development of IBD would fill in major gaps in our knowledge.

Prof Carding said: “With iSNP, it is now a reality to screen large cohorts, understand better the individual pathogenesis stories, and find the best treatment for the right patient.”

The team built a computer simulation of interactions between the human genome and the cellular signalling pathways and networks the products of these genes influence, using databases of known and predicted interactions between proteins in the network.

With the workflow in place, the team then worked with the UK IBD Genetic Consortium to compare 377 patients with ulcerative colitis to see how their individual genomes affected the network. They found that the patients clustered into four distinct groups, based on their ‘network footprint’. 

This finding means that although their symptoms may be the same, the underlying drivers of ulcerative colitis may vary.

More work needs to be done with larger groups of patients to validate the pathways identified here, but if successful it could lead to a more stratified, or even personalised approach to treatment of the condition, based on the patients’ genomics.

Co-lead study author Dr Tamas Korcsmaros from the Earlham Institute and the Quadram Institute, said: “The workflow’s ability to identify cohorts of disease associated mutations and pathways isn’t limited to IBD - it has the potential for use in other complex disease including mental health, heart disease and autoimmune conditions.

 “To develop precision therapies based on patient specific genetics opens up the possibility of much needed personalised medicine approaches to tackle these complex and poorly understood conditions.”

The systems genomics workflow, called the integrated SNP Network Pipeline (iSNP), has now been published in the journal Nature Communications and is the subject of a patent filing.

The project was funded by the Biotechnology and Biological Sciences Research Council, part of UKRI (UK Research and Innovation), the European Research Council and the Norwich Research Park Translational Fund.

‘A systems genomics approach to uncover patient-specific pathogenic pathways and proteins in ulcerative colitis’ is published in the journal Nature Communications, on April 28, 2022.  

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