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Researchers Discover 71 New Human Genes Associated With Bowel Diseases

Published: Tuesday, November 06, 2012
Last Updated: Monday, November 05, 2012
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Study brings the total number of known genes associated with IBD to 163.

Researchers have found 71 new human genes associated with Crohn's disease and ulcerative colitis, two chronic inflammatory bowel diseases (IBD) that affect the small and large (colon) intestines of nearly 2.5 million people worldwide.

The study was conducted by a consortium of researchers from the United States, Canada, and Europe.

It was funded in part by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) IBD Genetics Consortium, at the National Institutes of Health. The results were published in the Nov. 1 issue of the journal Nature.

The first phase of the genome-wide association studies involved combining 15 previously reported datasets of people with Crohn's disease, ulcerative colitis, and unaffected controls (people who did not have either disease). This analysis covered common genetic variants throughout the genome.

Researchers then analyzed the DNA samples using the Immunochip, which is a new technique to validate and confirm genes associated with diseases.

This analysis provided more complete coverage of variants in genes functioning in the immune system, and associated with other immune disorders.

The analysis scanned DNA samples of people from 15 countries who had been recruited from 11 research centers.

A total of 60,828 samples were genotyped from 20,076 people with Crohn's disease, 15,307 people with ulcerative colitis, and 25,445 people who did not have either disease.

As a result of these scans, 71 new genes strongly associated with IBD were identified, including many also associated with other inflammatory diseases such as ankylosing spondylitis (spine inflammation) and the skin disorder psoriasis.

It also appears that these IBD-variants have evolved in regions responsible for resisting mycobacterial infections, which are microbes that cause diseases such as tubercolosis and leprosy.

The exact cause of IBD is still unclear. Researchers believe an unknown factor or agent triggers an abnormal reaction by the body's immune system.

The most common signs of the diseases are diarrhea and abdominal pain. IBD tends to run in families and is more likely diagnosed in young adults. People of Jewish heritage, particularly Ashkenazi Jews who are of Eastern European descent, have an increased risk of developing the disease.

Further analysis revealed that of the 163 genes associated with IBD, 110 are associated with Crohn's disease and ulcerative colitis, 30 are specific to Crohn's, and 23 are specific to ulcerative colitis.

For 29 of these new and previously reported specific gene locations, the researchers observed genetic differences between people with IBD that predict changes to the protein structure.

Among the remaining 134 genes, genetic variants associated with the disease did not cause changes in the structure of the encoded proteins and many of these variants may change the levels of gene expression.

These clues will help investigators determine the specific genes, alleles and altered pathways responsible for increasing a person's disease risk.

"Performing the meta-analysis on these large datasets provides the statistical power and integrity to confirm the associations of these genes to IBD and identifies gene variants that until now, were only suspected to overlap with other inflammatory diseases," said Judy H. Cho, M.D., lead author and professor of medicine and genetics and director of the Inflammatory Bowel Disease Center at Yale School of Medicine. "The marked extent to which the findings make clear the overlap between IBD and mycobacterial infections was rather unexpected."

To find more genes, refine these results and explore how these genes interact to increase risk of IBD and other inflammatory diseases, researchers will need to use newer and more powerful methods of genetic analysis.

"These findings are only the beginning. We expect new approaches like systems biology will provide a more complete picture of the genetic pathways involved with IBD. In turn, the greater level of detail will help us develop better, more targeted treatments," said Robert W. Karp, Ph.D., project officer for NIDDK's IBD Genetics Consortium.


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