Researchers and clinicians from the Quadram Institute, the Earlham Institute, the Norfolk and Norwich University Hospital, and University of East Anglia, with collaborators in Cambridge, London, and Leuven, have found that patients with Inflammatory bowel disease (IBD) develop the condition due to distinct and different mechanisms, determined by their genetics.
The team described the use of a novel systems genomics approach and workflow that identified which of several possible pathways to disease a patient has. They expect their findings 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.
“We describe a novel precision medicine workflow, the integrated single nucleotide polymorphism network platform (iSNP), designed to determine the mechanisms by which SNPs affect cellular regulatory networks, and how SNP co-occurrences contribute to disease pathogenesis in ulcerative colitis (UC),” write the investigators.
“Using SNP profiles of 377 UC patients we mapped the regulatory effects of the SNPs to a human signaling network containing protein-protein, miRNA-mRNA. and transcription factor binding interactions. Unsupervised clustering algorithms grouped these patient-specific networks into four distinct clusters driven by PRKCB, HLA, SNAI1/CEBPB/PTPN1 and VEGFA/XPO5/POLH hubs. Pathway analysis identified calcium homeostasis, wound healing, and cell motility as key processes in UC pathogenesis.
“Using transcriptomic data from an independent patient cohort, we validated the regulatory impact of non-coding SNPs. iSNP identified regulatory effects for disease-associated non-coding SNPs, and by predicting the patient-specific pathogenic processes, proposes a systems-level way to stratify patients.”
“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,” said co-lead study author Tamas Korcsmaros, PhD, from the Earlham Institute and the Quadram Institute. “To develop precision therapies based on patient specific genetics opens up the possibility of much needed personalized medicine approaches to tackle these complex and poorly understood conditions.”
Inflammatory Bowel Disease affects around 500,000 people in the U.K., causing a range of painful and debilitating symptoms linked to inflammation of the gut. The causes of IBD are not 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, the research team 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 single nucleotide polymorphisms (SNPs) can be mapped to the human genome.
If a 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% of the identified SNPs were in genes. Instead, over 90% of SNPs were in non-coding regions of the genome. This is not surprising, as most of the human genome is made up of this non-coding DNA, with genes comprising just 1%. The other 99% was once thought to just be junk DNA, but we now know it has important roles in controlling and regulating gene activity.
Additionally, some SNPs may only have subtle effects, but in combination lead to disease progression. Given the complex nature of IBD, it was likely this was the case for this condition. The immune system functions by taking a wide range of different inputs that trigger different signaling 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.
The study appears in Nature Communications.