11/11/2022
The results of the international study with the participation of the PMI Cluster of Excellence also point to a previously unknown path of origin of the chronic inflammatory bowel disease.
© Andrea Danti – Fotolia.com
What is special about the study is its size on the one hand and the methodological approach on the other. About abnormalities in the genome of patients with Crohn’s disease An international consortium compared DNA samples from about 30,000 people with Crohn’s disease and 80,000 controls without the disease. The aim was to find gene variants that make people susceptible to inflammatory bowel disease (IBD). The investigation method was the so-called exome sequencing. Here, all genomic regions that code for proteins are sequenced. So far, abnormalities in the genome of patients have been searched for in particular in genome-wide association studies. “In the new study, we identified genetic variants in ten genes that increase susceptibility to Crohn’s disease. Changes in six genes were identified in regions that had not previously been associated with Crohn’s disease,” explains Professor Andre Franke from the Cluster of Excellence “Precision Medicine in Chronic Inflammation” (PMI), who was involved in the study with his working group. The results have been published in the renowned specialist journal “Nature Genetics” and provide new starting points for further research into the causes of the disease. “With the discovery of new risk genes, Professor Franke’s group helped us enormously in the clinic. These genes, which have not yet been noticed in previous genome studies, will result in new approaches for therapy methods,” says PMI spokesman Professor Stefan Schreiber, Director of the Clinic for Internal Medicine I at the University Hospital Schleswig-Holstein (UKSH), Campus Kiel and Director at the Institute for Clinical Molecular Biology (IKMB) at the Christian-Albrechts-University in Kiel (CAU) and the UKSH, Campus Kiel.
Genetic studies are used to search for the causes of diseases
Crohn’s disease is a disease that restricts the quality of life and is characterized by relapsing, chronic inflammation of the gastrointestinal tract. The causes of the disease have not been adequately researched. It is believed to be triggered by an overactive immune response in genetically susceptible individuals. While there are medications that can help relieve symptoms in many sufferers, there is no cure and severe flare-ups are common.
Previous genome-wide association studies (GWAS) have identified more than 200 regions of the genome associated with Crohn’s disease. However, these studies are limited to looking for specific, previously known variants. “Moreover, these studies usually reveal changes that are not in a protein-coding region. This makes it more difficult to identify the genes that are affected,” explains co-author Dr. Britt-Sabina Loescher, postdoc in Franke’s working group at the IKMB. The large-scale exome sequencing study led by working groups from the Broad Institute at the Massachusetts Institute of Technology, Harvard University, and the Wellcome Sanger Institute, Cambridge, was therefore carried out to supplement GWAS, to better define biological targets and to identify rare variants. UNITED STATES. The study included samples from more than 35 centers worldwide, including those from the IBD cohort of the Cluster of Excellence PMI. This resulted in a total of samples from around 30,000 patients and 80,000 controls. Only with these large numbers of samples is it possible to identify rare variants that drive the disease.
“The newly discovered risk variants for Crohn’s disease not only underscore the central role of innate and adaptive immune cells and autophagy (the cell’s ‘recycling program’) in disease development, but also reveal the role of mesenchymal cells in intestinal inflammation. In doing so, they help to explore the genetic roots of inflammatory bowel disease and provide new starting points for the development of new therapies,” emphasizes co-author Professor Stefan Schreiber. Mesenchymal cells are a type of stem cell found in the gut. They play a role in maturation, migration and recruitment of immune cells. Apparently, a disruption in these cells contributes to triggering and maintaining intestinal inflammation.
Methods for genome analysis
Next-generation sequencing, NGS for short, is a technology for high-throughput analysis of DNA, which is often used in modern genetic diagnostics to clarify genetic diseases. In this method, all genes of the human genome can be sequenced in parallel in order to identify the smallest changes, such as mutations. A blood or tissue sample from which the DNA can be obtained is sufficient for the examination. NGS can be used to examine the genome – either the entire genome or, for example, only the protein-coding region (exome).
Genome-wide association studies (GWAS) look for risk factors for disease. In such studies, the researchers look for typical changes in the entire genome and see whether these changes occur more frequently in people with certain diseases. For this purpose, several hundred thousand to several million positions of the genome are analyzed with so-called biochips (SNP arrays). Here, only specific positions in the genome are searched for that are known to be variable. The altered gene regions do not necessarily have to be causally related to the disease. However, they are associated with the disease, i.e. connected to it in a known or unknown way.
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(Frederike Buhse, Press and Public Relations, Cluster of Excellence Precision Medicine for Chronic Inflammatory Diseases)
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Sources: idw-online.de, Cluster of Excellence Precision Medicine for Chronic Inflammatory Diseases, Nature Genetics