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Genomic study of bowel disorders is a global effort

Medicine@Yale, 2012 - Nov Dec


In one of the largest studies of its kind ever conducted, an international team of scientists has thrown new light on the genetic basis of inflammatory bowel disease (IBD), a group of chronic autoimmune digestive disorders affecting 2.5 million people worldwide.

The new study links variations in 163 regions of the human genome, 71 of which are newly discovered, to increased risk of contracting IBD. These regions showed a striking overlap with those implicated in other autoimmune diseases, and suggest that IBD results from overactive immune defense systems that evolved to fight off serious bacterial infections.

In the two most common forms of IBD, Crohn’s disease (CD) and ulcerative colitis, (UC) the immune system produces an ongoing inflammatory reaction in the intestinal tract that injures the intestinal wall, leading to diarrhea and abdominal pain. IBD patients typically need lifelong treatment with drugs, and often need surgery to repair tissue damage.

“Up until this point we have been studying Crohn’s disease and ulcerative colitis separately,” says Judy H. Cho, M.D., the Henry J. and Joan W. Binder Professor of Gastroenterology (see related story) and professor of genetics, a lead author of the study, which was published in the journal Nature on November 1. “We created this study on the basis that there seems to be a vast amount of genetic overlap between the two disorders.”

As a first step, the researchers conducted a “meta-analysis” of 15 previous genomic studies of either CD or UC, creating a large dataset that combined genetic information from some 34,000 individuals who took part in those studies. The results then formed part of a second meta-analysis that included data from new genome-wide scans of more than 41,000 DNA samples from CD or UC patients and healthy comparison subjects collected at 11 centers around the world by the International IBD Genetics Consortium.

In addition to confirming that 92 regions identified in previous studies confer a significant risk of CD, UC, or both, the study linked 71 additional stretches of the genome to IBD. The IBD-linked variants largely fall in genomic regions that regulate the expression of immune-system genes implicated in other autoimmune diseases, particularly the skin disease psoriasis and a joint disorder known as ankylosing spondylitis. Genes affected by these regulatory regions are also involved in the production of immune cells that fight infection by mycobacteria, a family of microbes that cause diseases such as leprosy and tuberculosis.

“We see a genetic balancing act between defending against bacterial infection and attacking the body’s own cells,” says Jeffrey C. Barrett, D.Phil., of the Wellcome Trust Sanger Institute in Cambridge, England, also a lead author of the study. “Many of the regions we found are involved in sending out signals and responses to defend against ‘bad’ bacteria. If these responses are over-activated, we found it can contribute to the inflammation that leads to IBD.”

Nearly 100 scientists in 15 countries contributed to the new work, which “highlights the incredible power that working together in a large team can have,” says Cho, director of Yale’s Inflammatory Bowel Disease Center in the Department of Internal Medicine’s Section of Digestive Diseases. “This would not have been possible without the thousands of DNA samples from patients with these conditions assembled by the International IBD Genetics Consortium. Collectively, our findings have begun to uncover the biological mechanisms behind this disease.”

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