Scientists find new genes for Crohn's disease

[Guest guest]

Public release date: 15-Apr-2007

University

of Pittsburgh Schools of the Health Sciences

Scientists

find new genes for Crohn's disease

University of Pittsburgh researchers also help uncover potential

modes of action for debilitating inflammatory process

PITTSBURGH,

April 15 – Just a few months after their landmark article in Science

magazine reporting the discovery of strong links between variations in a gene

that codes for a cellular receptor involved in controlling inflammation and

Crohn's disease, a consortium of U.S. and Canadian researchers is reporting in

today's online issue of Nature Genetics that they have discovered several more

genetic variations that are strongly linked to an increased risk for the disease. The discovery of these Crohn's disease-associated genetic

variants has identified several key biological pathways that will be the focus

of further research to understand how the debilitating inflammatory process is

initiated and maintained in many cases of the disease.

" As

we collect more and more data from these genome-wide association studies, we

continue to discover susceptibility genes for Crohn's and other inflammatory

bowel diseases (IBDs). More

importantly, those genes are leading us to the biological pathways that relate

to IBD pathogenesis. By understanding these pathways,

we may be better able to develop more effective therapies for IBD, " said

consortium member H. Duerr, M.D., associate

professor of medicine and human genetics at the University

of Pittsburgh, co-director of the Inflammatory

Bowel Disease Center

and director of the IBD Genetics Program.

These

latest results are helping to fill in the gaps in knowledge about Crohn's and

other IBDs, which affect more than 1 million

Americans. Because IBDs

tends to run in families and are more frequent in certain ethnic populations,

especially Ashkenazi Jews, scientists have long suspected that they have a

significant genetic component.

Previous

genetic studies have found strong links between Crohn's disease and mutations

in two genes, one known as CARD15, and, more recently, a gene known as IL23R,

which codes for the immune cell receptor for interleukin-23, an important

biochemical mediator of inflammation in the body.

However,

mutations in these two genes alone cannot account for the entire genetic

component of the disease. To identify additional genes

that are associated with Crohn's, the researchers scanned more than 300,000

single nucleotide polymorphisms, or SNPs, in the

genomes—all of 22,000 or so genes—in people with Crohn's disease

and in healthy controls. SNPs

are subtle variations in the genetic code found in all genes.

Some variations can be harmful, while others may be helpful or have no

effect at all.

The

comparison of these SNPs between patients with

Crohn's disease and people without the disease identified multiple variations

in several genes that were strongly associated with Crohn's disease. These findings were then retested in two additional sets

of patients and healthy controls in order to confirm their significance. After all of the comparisons, the consortium identified

variations in three genes — PHOX2B, NCF4 and ATG16L1 — as

contributing significantly to the risk for Crohn's disease.

According

to corresponding author D. Rioux, Ph.D.,

associate professor of medicine at the Montreal Heart Institute and at the Université de Montréal, the identification of the PHOX2B

gene in this study suggests that neuroendocrine cells

of the intestinal epithelium have a key role to play in Crohn's. In addition, the identification of the NCF4 gene indicates

that the production of altered reactive oxygen species, which are important in

the generation of a protective response against microbes, may lead to an

increased risk of developing the condition.

Particularly

interesting to the authors was the association between Crohn's and variations

in the ATG16L1 gene, which they found is essential for the cell's normal

mechanism for degrading worn-out cellular components and helping to eliminate

some pathogenic bacteria—a pathway known as autophagy

(pronounced AU-TOF-A-GEE ).

Finding

ATG16L1's involvement in Crohn's disease provides confirmatory evidence for

what doctors have long suspected: that an individual's ability to respond

effectively to harmful microbes influences his or her susceptibility to the

disease.

" 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 [toxic] cellular and bacterial components. This may lead to an inappropriate immune activation and

increased risk of Crohn's disease, " says co-author Dr. Ramnik

Xavier, a gastroenterologist at the Massachusetts

General Hospital's

(MGH) Center for the Study of IBD and a researcher at the MGH

Center for Computational and

Integrative Biology.

This

study's findings are expected not only to improve on the biological

understanding of disease but also should have a long-term impact on clinical

practice, according to Dr. Brant, co-author and gastroenterologist at s

Hopkins University.

" The

multiple genetic risk factors we've identified provide important targets for

current functional studies aimed at understanding the disease.

These will be important targets for drug development to improve therapy

of Crohn's disease in the future, " he said.

P. , M.D., director of the division of digestive diseases and nutrition at

the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

agreed, saying that " these important discoveries not only offer new hope

for better therapies for patients with Crohn's disease, but 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 " .

In

addition to finding the additional Crohn's disease susceptibility genes, the

researchers got strong signals for genetic risk factors located in areas of the

genome where there are no known genes. " Further

work will be necessary to identify the causal genes in these regions, " the

authors said.

The

study's authors represent the IBD Genetics Consortium, which is funded by the

NIDDK of the National Institutes of Health. The

Consortium includes members from Cedars-Sinai

Medical Center

in Los Angeles, the University

of Chicago, the s Hopkins

University, Montreal Heart Institute, Université de

Montréal, the University of Pittsburgh,

the University of Toronto and Yale

University.

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