An international consortium of Crohn's disease researchers has combined data from three independent studies to identify 21 new genetic variants associated with the inflammatory bowel disorder, bringing the total number of risk factors to 32. Several of these are involved with the immune system's inital response to pathogens, supporting earlier evidence that disruptions in a process called autophagy may lead to the disorder's characteristic immune system overactivity. The report will appear in the journal Nature Genetics and is receiving early online release.
"This greatly increases our knowledge of the genetic architecture of Crohn's and gives us more detailed insight into the biological underpinnings of the disease," says Mark Daly, PhD, of the Massachusetts General Hospital (MGH) Center for Human Genetic Research and the Broad Institute of MIT and Harvard, the report's senior author. "Better understanding of the precise functions of these genes and the molecular effects of Crohn's-associated variants should lead us to novel strategies for therapies and, someday, prevention."
In 2007 three separate research teams – a North American-based team, involving Daly and colleagues at six other institutions and clinical sites; a U.K. team supported by the Wellcome Trust; and a group of French and Belgian investigators – each published genome-wide association studies (GWAS) of Crohn's disease that, combined with earlier studies, brought the total number of Crohn's-associated gene sites to 11. Those explained only a small proportion of the heritability of Crohn's, which affects nearly half a million people in the U.S.
Since the power of any GWAS is limited by the number of samples available for screening, the three teams combined their data through a process called meta-analysis, allowing the comparison of data from more than 3,200 Crohn's patients with more than 4,800 controls. That was supplemented by an analysis of new data from an additional 3,700 patients and matching controls.
Both of those analyses strongly confirmed the 11 previously-identified sites and found an additional 21 areas associated with susceptibility to Crohn's. While the newly identified sites are not as strong as those found in earlier studies, they continue to build a picture of factors leading to the inappropriate immune-system activation that characterizes the disorder.
"It's amazing that all of the genes indentified in GWAS studies of Crohn's so far align with the pathways that we know are disrupted, systems that sense the presence of microbes and effectively clear them from the body." says 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, a co-author of the Nature Genetics study. "Mapping the internal circuitry of these systems and identifying the molecular switches that control those circuits should lead to better targeted drugs for Crohn's and other inflammatory bowel diseases." Daly is an assistant professor of Medicine at Harvard Medical School and Xavier is an associate professor.
Lead author Jeffrey Barrett of the University of Oxford led the extensive meta-analysis in conjuntion with Daly and investigators at the University of Liege, Belgium, and the University of Chicago. In total, the effort constituted a collaboration between clinical genetic researchers from 25 institutions across North America – including Yale University, University of Pittsburgh, University of Montreal, University of Toronto, Johns Hopkins University, and Cedars-Sinai Medical Center in Los Angeles – the United Kingdom, Belgium and France. The team is committed to further advancing these results in collaboration with investigators from additional countries. Support for the study came from several organizations, including the National Institute of Diabetes and Digestive and Kidney Diseases, through the Inflammatory Bowel Disease Genetic Consortium.
Massachusetts General Hospital (www.massgeneral.org), established in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of more than $500 million and major research centers in AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, human genetics, medical imaging, neurodegenerative disorders, regenerative medicine, systems biology, transplantation biology and photomedicine.
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