A consortium of Canadian and American researchers report in Nature Genetics the results from a search of the entire human genome for genetic risk factors leading to the development of Crohn's disease. Specifically, using a novel approach, the authors identified that the PHOX2B, NCF4 and ATG16L1 genes constitute genetic risk factors for Crohn's disease. In addition, their study identified two regions of the genome where genetic risk factors are located but no known genes were implicated – further work will be necessary to identify the causal genes in these regions.
More than 150,000 Canadians suffer from Crohn's disease and ulcerative colitis, known collectively as inflammatory bowel disease (IBD). The study's authors represent the NIDDK IBD Genetics Consortium, which is funded by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health in the United States. The Consortium's member institutions include the University of Toronto, the Université de Montréal, the Cedars-Sinai Medical Center in Los Angeles, the University of Chicago, the Johns Hopkins University, the University of Pittsburgh, and Yale University.
Since IBD tends to run in families and is more frequent in certain ethnic populations, especially Ashkenazi Jews, scientists have long suspected a significant genetic component. Although previous genetic studies found a link between Crohn's disease and mutations in a gene known as CARD15, those mutations alone are not considered to account for the entire genetic component of disease. To identify additional genes that are associated with IBD, the international team of researchers scanned the genome—all of 22,000 or so genes— by testing more than 300,000 single nucleotide polymorphisms, or SNPs, in people with Crohn's disease and in healthy controls. The comparison of these SNPs (common genetic variants) between patient and control groups identified multiple SNPs that were strongly associated with Crohn's disease. These findings were then tested in two additional sets of patients and healthy controls in order to confirm their results.
According to the study co-author, Dr. Mark Silverberg, Assistant Professor of Medicine and Surgery at the University of Toronto and Staff Gastroenterologist at Mount Sinai Hospital in Toronto, the findings highlight numerous biological pathways not previously thought to play a role in Crohn's disease. "The identification of the PHOX2B gene in this study, for example, may implicate a role for neuroendocrine cells of the intestinal epithelium as having a role to play in Crohn's disease. In addition, the identification of the NCF4 gene indicates that altered reactive oxygen species (ROS) production, important in the generation of an effective anti-microbial response, may lead to increased risk to developing Crohn's disease."
The fact that the authors also found strong association of the ATG16L1 gene provides further evidence that an individual's response to microbes has an influence on susceptibility to Crohn's disease. Specifically, in addition to demonstrating its association to disease, these authors have shown that ATG16L1 is essential for the normal autophagic process used to degrade worn-out cellular components and help eliminate some pathogenic bacteria.
"We propose that genetic variation in the ATG16L1 gene leads to alterations in how the body uses autophagy and therefore may result in increased persistence of both cellular and bacterial components, leading to inappropriate immune activation and increased risk of Crohn's disease," says co-author Dr. Hillary Steinhart, Head of the Combined Division of Gastroenterology at Mount Sinai Hospital / University Health Network.
The findings reported in this study are expected to not only improve on the biological understanding of disease but should also have a long-term impact on clinical practice.
According to Dr. Steven Brant, senior co-author and gastroenterologist at Johns Hopkins University, "the multiple genetic risk factors we've identified provide important targets for current functional studies aimed at understanding the disease and important targets for drug development to improve therapy of Crohn's disease in the future."
Dr. Stephen P. James, M.D., director of the Division of Digestive Diseases and Nutrition at the National Institutes of Health's NIDDK continued by saying that "these important discoveries not only offer new hope for better therapies for patients with Crohn's disease, they also highlight the promise of the human genome project and subsequent investments by the NIH in large scale, collaborative research projects to unravel the causes of, and hopefully better treatments for complex, enigmatic diseases."
Jodi Salem | EurekAlert!
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