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.