Scientists Find Major Susceptibility Genes for Crohn's Disease - Discoveries reveal new genetic risk factors for the millions of people with inflammatory bowel diseases

    MONTREAL, April 16 /CNW Telbec/ - A consortium of Canadian and American
researchers led by Dr. John D. Rioux, PhD, Associate Professor of Medicine at
the Montreal Heart Institute and the Université de Montréal, report in the
April 15 online edition of 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 1 million Americans and some 170,000 Canadians have Crohn's or
colitis, known collectively as inflammatory bowel disease (IBD). The study's
authors represent the 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 addition to the Montreal Heart Institute and
Université de Montréal, the Consortium's member institutions include the
Cedars-Sinai Medical Center in Los Angeles, the University of Chicago, the
Johns Hopkins University, the University of Pittsburgh, the University of
Toronto, and Yale University.
    Because 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 corresponding author John D. Rioux, 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" adds
Dr. Rioux.
    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. Edmond-Jean Bernard, co-author
and gastroenterologist at the Hotel Dieu Hospital in Montreal and the
Université de Montréal "the multiple genetic risk factors we've identified
provide important molecular 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".


    About Dr. John D. Rioux

    Dr. Rioux, PhD, is an Associate Professor of Medicine at the Université
de Montréal and at the Montreal Heart Institute where he works as a researcher
and director of the Laboratory in Genetics and Genomic Medicine of
Inflammation (, as well as visiting scientist at the Broad
Institute of MIT and Harvard, and holder of the Canada Research Chair in
Genetics and Genomic Medicine of Inflammation.

    About the Montreal Heart Institute

    Founded in 1954, the Montreal Heart Institute is Canada's largest and
oldest institution dedicated to research, education and clinical care of
cardiovascular diseases. It is affiliated with the Université de Montréal and
constantly aims for the highest standards of excellence through its leadership
in prevention, ultra-specialized care, professional training, clinical and
basic research, and development of new innovative treatments. The MHI Research
Centre officially came into existence in 1976 and has made enormous strides
since its creation. Today, there are approximately 500 employees, students and
researchers at the MHI Research Centre. The MHI's outstanding feature is the
balance it achieves between basic research, clinical research and clinical
care. Its prime focus areas of research are vascular diseases, myocardial
function and electrophysiology. Genomics (including pharmacogenomics),
biomarkers and preventive cardiology are other areas of focus. To learn more
about the Institute, please visit our website at

    About the Université de Montréal

    Deeply rooted in Montreal and dedicated to its international mission, the
Université de Montréal is one of the top universities in the French-speaking
world. Founded in 1878, the Université de Montréal today has 13 faculties and
together with its two affiliated schools, HEC Montréal and Ecole
Polytechnique, constitutes the largest centre of higher education and research
in Québec, the second largest in Canada, and one of the major centres in North
America. It brings together 2,500 professors and researchers, accommodates
more than 55,000 students, offers some 650 programs at all academic levels,
and awards about 3,000 masters and doctorate diplomas each year.

For further information:

For further information: Doris Prince, Head, Communications and Public
Relations, Montreal Heart Institute, (514) 376-3330, ext. 3074,; Valérie Gonzalo, (514) 626-6976,

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