6 February 2011

Research links 29 genome regions with common form of inflammatory bowel disease

Genome regions are signposts to the biology of ulcerative colitis

Histopathological image of the active stage of ulcerative colitis. Researchers have made new links between 29 regions of the genome and ulcerative colitis - a common form of inflammatory bowel disease.

Histopathological image of the active stage of ulcerative colitis. Researchers have made new links between 29 regions of the genome and ulcerative colitis - a common form of inflammatory bowel disease. [http://commons.wikimedia.org/wiki/...File:Ulcerative_colitis_(2)_active.jpg]

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An international team of researchers have made new links between 29 regions of the genome and ulcerative colitis - a common form of inflammatory bowel disease (IBD). The new findings increase the total number of genome regions known to be associated with inflammatory bowel disease to 99.

The results point to several biological processes, including the way that our bodies maintain the lining of the intestinal wall, which are likely to play an important role in the development of ulcerative colitis.

The causes of inflammatory bowel disease are not fully understood, although it is thought that patients with inflammatory bowel disease have an overactive immune response against typical gut contents. Together, ulcerative colitis and Crohn's disease - the two primary causes of inflammatory bowel disease - affect one in 250 people in Europe, North America and Australasia.

Unlike Crohn's disease, which can impair any part of the human digestive tract, ulcerative colitis is restricted to the large bowel. Up to 20 per cent of ulcerative colitis patients will require surgery to remove the entire large bowel.

"The outcomes and quality of life for patients with ulcerative colitis can be bleak," says Dr John Rioux, from the Université de Montréal and Montreal Heart Institute, senior author on the paper, and co-chair of the International IBD Genetics Consortium. "To understand the genetic causes of the disease, we carried out the largest study of the disease to date - taking a magnifying glass to over one million sites in the genomes of more than 26,000 people.

"Ultimately, we hope that unmasking the genetic processes that give rise to the disease will minimise the need for surgical outcomes, by opening the door for new therapies that can stop the disease in its tracks."

The team carried out a genome-wide scan to look for changes in the genetic code common to patients with ulcerative colitis. They did this by looking at genetic data from more than 32,000 apparently healthy people, and more than 16,000 people suffering from ulcerative colitis.

Using the technique, the team homed in on 29 regions that are associated with the disease - bringing the total number for ulcerative colitis to 47 and the total for inflammatory bowel disease to 99.

Like signposts, these regions pointed the researchers towards several genes that might play an important role in ulcerative colitis.

"The genomic regions we have identified give us an insight into the biology underlying ulcerative colitis," says Dr Carl Anderson, from the Wellcome Trust Sanger Institute and first author on the paper. "These important initial discoveries are the building blocks on which we can begin to derive better IBD treatments, though much further work is needed before these become a clinical reality.

" These important initial discoveries are the building blocks on which we can begin to derive better IBD treatments, though much further work is needed before these become a clinical reality. "

Dr Carl Anderson

"To give us a better understanding of IBD biology, we compared the results of this ulcerative colitis study to those of a similar study we recently completed looking at Crohn's disease, and the results were very informative."

The team found significant overlap between the genetic regions associated with each disease, with at least 19 of the total 47 ulcerative colitis regions also associated with Crohn's disease.

The researchers show that many of the overlapping regions include genes involved in expanding and maintaining a group of T-cells involved in our immune response. The finding supports the idea that the way our immune system responds to the natural bacteria found in the gut could be an important part of the disease profile of inflammatory bowel disease.

The researchers suggest that the candidate genes - including several key members of the 'IL23 pathway' - could provide good targets for researchers developing therapeutic interventions against the disease.

As well as finding genes that point towards a shared biology - the researchers also found evidence of genetic events that might be unique to ulcerative colitis.

"For many of our patients, ulcerative colitis means a lifetime of bloody diarrhoea and stomach pains," says Dr Charlie Lees, consultant gastroenterologist at the Western General Hospital in Edinburgh. "The disease can be very severe in some patients resulting in life-threatening inflammation of the large bowel, and there is an increased risk of developing bowel cancer. This is a really unpleasant and intrusive illness that typically affects young adults, and for which we presently have no known cure.

"We have some good medical therapies, but for many patients these are either not effective or poorly tolerated. We therefore have an urgent unmet therapeutic need and it is my great hope that we can translate our really exciting genetic findings into effective new therapies in the next five to ten years."

The new findings open the door for further research to explore the candidate genes identified and their possible role in the development of the ulcerative colitis and inflammatory bowel disease.

"This research will give renewed hope to the 160,000 people in the UK who face a lifetime coping with Ulcerative Colitis," says Richard Driscoll, Chief Executive of Crohn's and Colitis UK. "The illness tends to flare-up quite unpredictably and without apparent cause and at these times the symptoms of urgent diarrhoea, pain and fatigue can dominate everyday life and may eventually lead to major surgery. Knowing that researchers have identified specific new targets for research and that progress is being made will be seen as very good news."

Notes to Editors

About inflammatory Bowel Disease (IBD)

Inflammatory bowel disease is a term used to describe conditions that are characterised by inflammation of the gastrointestinal tract. The term IBD is used predominantly to describe two diseases: Crohn's disease and ulcerative colitis. In Crohn's disease, the inflammation can affect any part of the digestive tract. In ulcerative colitis, the inflammation affects only the colon. Together, ulcerative colitis and Crohn's disease affect one in 250 people in Europe, North America and Australasia.

Inflammatory bowel disease should not be mistaken for irritable bowel syndrome - a separate disease which can present some similar symptoms.

Publication details

  • Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47.

    Anderson CA, Boucher G, Lees CW, Franke A, D'Amato M, Taylor KD, Lee JC, Goyette P, Imielinski M, Latiano A, Lagacé C, Scott R, Amininejad L, Bumpstead S, Baidoo L, Baldassano RN, Barclay M, Bayless TM, Brand S, Büning C, Colombel JF, Denson LA, De Vos M, Dubinsky M, Edwards C, Ellinghaus D, Fehrmann RS, Floyd JA, Florin T, Franchimont D, Franke L, Georges M, Glas J, Glazer NL, Guthery SL, Haritunians T, Hayward NK, Hugot JP, Jobin G, Laukens D, Lawrance I, Lémann M, Levine A, Libioulle C, Louis E, McGovern DP, Milla M, Montgomery GW, Morley KI, Mowat C, Ng A, Newman W, Ophoff RA, Papi L, Palmieri O, Peyrin-Biroulet L, Panés J, Phillips A, Prescott NJ, Proctor DD, Roberts R, Russell R, Rutgeerts P, Sanderson J, Sans M, Schumm P, Seibold F, Sharma Y, Simms LA, Seielstad M, Steinhart AH, Targan SR, van den Berg LH, Vatn M, Verspaget H, Walters T, Wijmenga C, Wilson DC, Westra HJ, Xavier RJ, Zhao ZZ, Ponsioen CY, Andersen V, Torkvist L, Gazouli M, Anagnou NP, Karlsen TH, Kupcinskas L, Sventoraityte J, Mansfield JC, Kugathasan S, Silverberg MS, Halfvarson J, Rotter JI, Mathew CG, Griffiths AM, Gearry R, Ahmad T, Brant SR, Chamaillard M, Satsangi J, Cho JH, Schreiber S, Daly MJ, Barrett JC, Parkes M, Annese V, Hakonarson H, Radford-Smith G, Duerr RH, Vermeire S, Weersma RK and Rioux JD

    Nature genetics 2011;43;3;246-52

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Montreal Heart Institute

Founded in 1954 by Dr. Paul David, the Montreal Heart Institute constantly aims for the highest standards of excellence in the cardiovascular field through its leadership in prevention, ultra-specialized care, training of professionals, clinical and fundamental research, and assessment of new technologies. It is affiliated with the Université de Montréal and its clinical outcomes are among the best in the world.
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The Wellcome Trust Sanger Institute, which receives the majority of its funding from the Wellcome Trust, was founded in 1992. The Institute is responsible for the completion of the sequence of approximately one-third of the human genome as well as genomes of model organisms and more than 90 pathogen genomes. In October 2006, new funding was awarded by the Wellcome Trust to exploit the wealth of genome data now available to answer important questions about health and disease.

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