The results of an international study with the participation of the PMI Cluster of Excellence also point to a hitherto unknown pathway for the development of chronic inflammatory bowel disease.
What is special about the study is its size on the one hand and its methodological approach on the other. To detect abnormalities in the genome of patients with Crohn’s disease, an international consortium compared DNA samples from approximately 30,000 people with Crohn’s disease and 80,000 controls without the disease. The goal 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. Abnormalities in the genome of patients have so far been mainly searched for in genome-wide association studies. “In a new study, we identified genetic variants in ten genes that increase susceptibility to Crohn’s disease. Changes in six genes were identified in areas not previously associated with Crohn’s disease,” explains Professor Andre Franke from the Cluster of Excellence “Precision Medicine in Chronic Inflammation” (PMI), who participated in the study with his working group. The results were published in the renowned specialist journal “Nature Genetics” and provide new starting points for further research into the causes of the disease. “Professor Franke’s group helped us immensely in the clinic with the discovery of new risk genes. These genes, which have not yet been recorded in previous genome studies, will lead to new approaches to therapeutic methods,” says PMI spokesperson Professor Stefan Schreiber, director of the Department of Internal Medicine I at the Schleswig-Holstein University Hospital (UKSH). Campus Kiel and Director of the Institute for Clinical Molecular Biology (IKMB) at the Christian-Albrechts-University in Kiel (CAU) and UKSH, Campus Kiel.
Genetic studies are used to find the causes of diseases
Crohn’s disease is a disease that limits the quality of life and is characterized by recurrent chronic inflammation of the gastrointestinal tract. The causes of the disease have not been sufficiently investigated. It is thought to be triggered by an overactive immune response in genetically susceptible individuals. Although there are medications that can help relieve symptoms in many patients, 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 the search for specific, previously known variants. “Additionally, these studies usually detect changes that are not in the protein-coding region. This makes it difficult to identify the genes that are affected,” explains co-author Dr. Britt-Sabina Loescher, postdoc in Franke’s working group at IKMB. A 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 undertaken to complement GWAS, better define biological targets, and identify rare variants. UNITED STATES OF AMERICA. The study included samples from more than 35 centers worldwide, including those from PMI’s Cluster of Excellence IBD cohort. This resulted in a total of samples from approximately 30,000 patients and 80,000 controls. Only with this large number of samples is it possible to identify rare disease-causing variants.
“The newly discovered risk variants of Crohn’s disease not only underscore the central role of innate and adaptive immune cells and autophagy (the cellular ‘recycling program’) in the development of the disease, but also reveal the role of mesenchymal cells in intestinal inflammation.” At the same time, they help to investigate 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 the maturation, migration and recruitment of immune cells. Apparently, disruption of these cells contributes to the initiation and maintenance of intestinal inflammation.
Methods for genome analysis
Next Generation Sequencing, or NGS for short, is a technology for high-throughput DNA analysis that is often used in modern genetic diagnostics to elucidate genetic diseases. In this method, all the genes of the human genome can be sequenced in parallel to identify the smallest changes, such as mutations. A blood or tissue sample from which 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 disease risk factors. In such studies, scientists look for typical changes throughout the genome and see if these changes occur more often in people with certain diseases. For this purpose, several hundred thousand to several million genome positions are analyzed using so-called biochips (SNP arrays). Here, only specific positions in the genome that are known to be variable are searched. Altered gene regions are not necessarily related to disease. However, they are associated with the disease, i.e. they are associated with it in a known or unknown way.
(Frederike Buhse, Press and Public Relations, Cluster of Excellence Precision Medicine for Chronic Inflammatory Diseases)
Sources: idw-online.de, Cluster of Excellence Precision Medicine for Chronic Inflammatory Diseases, Nature Genetics