http://www.eurekalert.org/pub_releases/2008-06/mgh-iti062608.php
International team identifies 21 new genetic risk factors for Crohn's
disease
Study combines efforts of 3 research groups, brings total risk sites
to 32
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,
sup****ting earlier evidence that disruptions in a process called
autophagy may lead to the disorder's characteristic immune system
overactivity. The re****t 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 re****t'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 =96 a North American-based team,
involving Daly and colleagues at six other institutions and clinical
sites; a U.K. team sup****ted by the Wellcome Trust; and a group of
French and Belgian investigators =96 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 pro****tion 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.
--
Luke
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