An international research team -- including investigators from Massachusetts General Hospital (MGH) and the Broad Institute of Harvard University and Massachusetts Institute of Technology -- has identified several novel genetic variations associated with the risk of Crohn's disease. One of the identified genes establishes a role for autophagy, a previously unsuspected biological pathway, in Crohn's disease pathology; and the report documents functional studies which establish that this gene is integral to immune responses to intestinal bacteria. The report will appear in the journal Nature Genetics and is receiving early online release.
"Our discovery of several new genetic risk factors for Crohn's should improve understanding of the true causes of this disease and reveal new causal pathways that can be targeted therapeutically," says Mark Daly, PhD, of the MGH Center for Human Genetics Research and the Broad Institute, co-senior author of the Nature Genetics paper. "The study takes advantage of new knowledge of genetic variation patterns and new technology for assessing genetic variation that have only recently become available."
A chronic inflammatory bowel disease for which no single causative factor has been identified, Crohn's usually affects the small intestine, causing abdominal pain and chronic diarrhea. Serious symptoms can include ulceration, bleeding, the development of fistulas -- openings from affected areas into other organs -- or intestinal blockage. About half a million people in the U.S.are affected by Crohn's, and another half-million have a related condition called ulcerative colitis. Since Crohn's can run in families and is more common in some ethnic populations, it is likely to have genetic components. Previous studies have identified two genetic variations as increasing the risk for Crohn's, but those factors only account for a small percentage of inherited cases.
One of the known risk genes was identified in 2001 at the Broad Institute by Daly and John Rioux, PhD, first author of the current study. That study was instrumental to identifying the structure of human genetic variation, leading to the HapMap project to catalog common variation patterns as a tool for accelerating medical genetic research. The recent completion of HapMap, an effort on which Daly and Broad Institute colleagues played a significant role, has paved the way for the current generation of genome-wide association studies, of which this is an early success story.
In an effort to identify additional genetic risk factors, the research team scanned the entire genome of approximately 1,000 Crohn's patients and 1,000 healthy controls. They tested more than 300,000 genetic variations -- also called single nucleotide polymorphisms or SNPs -- and identified several that were strongly associated with Crohn's. Those findings were tested in two additional sets of patients and controls, and the results confirmed strong associations with variations in two genes -- one of which was identified in a preliminary study this group published in 2006 -- and one gene-free segment of the genome. They also found likely risk factors may be associated with three other genes.
One of the newly identified genes, called ATG16L1, has been thought to be required for autophagy, a process that leads to programmed cell death and is involved in the process of inflammation. When the research team used RNA interference to suppress the gene's activity in bacterially infected cells, decreased molecular action associated with autophagy confirmed that the process depends on ATG16L1 activity.
"We have shown that ATG16L1 is essential for the normal autophagic process used to degrade worn-out cellular components and help eliminate some pathogenic bacteria," says co-author Ramnik Xavier, MD, of the Center for the Study of Inflammatory Bowel Disease in the MGH Gastroenterology Unit and the MGH Center for Computational and Integrative Biology. "We propose that variation in the ATG16L1 gene alters how the body uses autophagy and may result in increased persistence of both cellular and bacterial components, leading to inappropriate immune activation and increased risk of Crohn's disease." Xavier is an assistant professor of Medicine at Harvard Medical School, as is Daly.
Among the other potential genetic risk factors identified are a gene called PHOX2B, which may relate to the activity of neuroendocrine cells in the intestinal lining, and one called NCF4, which like ATG16L1 plays a role in the immune system's response to bacteria. Additional risk factors may exist in areas of the genome not associated with specific genes but possibly regulating the activity of other genes. Further understanding of how these variations contribute to the development of Crohn's should identify new targets for drug development, the authors write.
Rioux, the report's lead author, initiated the study while at the Broad Institute and is now at the University of Montreal. The co-senior author is Steven Brant, MD, of Johns Hopkins University. Additional co-authors are from MGH Gastroenterology; the Broad Institute; Cedars Sinai Medical Center, Los Angeles; University of Montreal; Mt. Sinai Hospital, Toronto; University of Pittsburgh; Johns Hopkins University; the Hospital for Sick Children, Toronto; the University of Chicago; the University of Pittsburgh and Yale University. The study was supported by the National Institute of Diabetes and Digestive and Kidney Diseases, through the Inflammatory Bowel Disease Genetic Consortium.
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