31 October 2012

Gut reaction: The evolution of IBD

Study finds immune response to bacterial infection may have shaped genetics of inflammatory bowel disease

Number of overlapping IBD associated genetic regions with other immunemediated diseases (IMD), leprosy, and Mendelian primary immunodeficiencies.

Number of overlapping IBD associated genetic regions with other immunemediated diseases (IMD), leprosy, and Mendelian primary immunodeficiencies. [10.1038/nature11582]

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In one of the largest studies of its kind, researchers have identified 71 genetic regions newly associated with inflammatory bowel disease (IBD), increasing the total number discovered to date to 163. This new information reveals that there is a vast amount of genetic overlap between Crohn’s disease and Ulcerative colitis (the two most common subtypes of IBD), suggesting that they share common biological pathways. In addition, analyzing these regions reveals that IBD may result from the body’s immune response over-reacting, the result of a long-term evolutionary balancing act between defense against bacterial infection and harmful excessive inflammation.

IBD is a group of inflammatory conditions of the colon and small intestine. About one person in every 250 people in the United Kingdom suffers from one of the major types of IBD. It is not yet known what causes this disease; an unknown factor, or a combination of factors seems to trigger the body’s immune system to produce an inflammatory reaction in the intestinal tract that continues without control. As a result of the inflammatory reaction, the intestinal wall is damaged leading to bloody diarrhoea and abdominal pain. IBD patients require lifelong treatment with dietary management and drug therapy, and often need surgery to repair the damage the disease causes.

"We have greatly expanded the map of genetic regions that are associated with IBD,” says Luke Jostins, joint first author from the Wellcome Trust Sanger Institute. "Each of these regions increases a person's chance of developing IBD by only a fraction of one per cent and even taken together they cannot tell us who will or will not develop the disease. But they each tell a small story about the biology of this disorder, and by combining them we find biological pathways that, if disrupted, can lead to IBD."

The team also studied the activity of genes in their IBD regions in hundreds of different types of cells involved in the immune system. They found that certain cells tended to produce more of these IBD genes, including many that are involved in the body’s first line defence against invasion. This illustrates that an immune response seems to be a major factor in IBD: when a bacterium is detected, these cells are not just activated, but become overactive.

" We have greatly expanded the map of genetic regions that are associated with IBD. "

Dr Luke Jostins

"We see a genetic balancing act between defending against bacterial infection and attacking the body's own cells. 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,” says Dr Jeffrey Barrett, co-lead author from the Wellcome Trust Sanger Institute. "Infectious organisms are known to evolve quickly in response to selective pressures - such as our bodies’ abilities to fight them off. So we wanted to investigate whether the regions in our own genomes that are associated with IBD are also evolving as the types of bacteria and how often we’re exposed to them changes. The answer, it appears, is yes, and that sometimes the response becomes too well developed and results in IBD.”

The team found that 70 per cent of the genetic regions associated with IBD are shared with other complex diseases, especially those also driven by abnormal inflammation, such as psoriasis and ankylosing spondylitis. They also observed a strong overlap between their IBD regions and genes underlying susceptibility to mycobacterial infections such as leprosy and tuberculosis, again highlighting the relationship between IBD risk and our immune response to bacteria.

"Up until this point we have been studying the two forms of the diseases, Crohn's disease and Ulcerative colitis, separately," says Dr Judy Cho, co-lead author from Yale University. "We created this study on the basis that there seems to be a vast amount of genetic overlap between the two disorders.

"Our research has highlighted the incredible power working together in a large consortium can have: this work has only been possible because the consortium shared funding, brought together such large numbers of DNA samples from patients with this condition, and shared expertise between the many groups. Collectively, our findings have begun to shed light on the biological mechanisms behind this disease.”

Notes to Editors

Publication details

  • Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease.

    Jostins L, Ripke S, Weersma RK, Duerr RH, McGovern DP, Hui KY, Lee JC, Schumm LP, Sharma Y, Anderson CA, Essers J, Mitrovic M, Ning K, Cleynen I, Theatre E, Spain SL, Raychaudhuri S, Goyette P, Wei Z, Abraham C, Achkar JP, Ahmad T, Amininejad L, Ananthakrishnan AN, Andersen V, Andrews JM, Baidoo L, Balschun T, Bampton PA, Bitton A, Boucher G, Brand S, Büning C, Cohain A, Cichon S, D'Amato M, De Jong D, Devaney KL, Dubinsky M, Edwards C, Ellinghaus D, Ferguson LR, Franchimont D, Fransen K, Gearry R, Georges M, Gieger C, Glas J, Haritunians T, Hart A, Hawkey C, Hedl M, Hu X, Karlsen TH, Kupcinskas L, Kugathasan S, Latiano A, Laukens D, Lawrance IC, Lees CW, Louis E, Mahy G, Mansfield J, Morgan AR, Mowat C, Newman W, Palmieri O, Ponsioen CY, Potocnik U, Prescott NJ, Regueiro M, Rotter JI, Russell RK, Sanderson JD, Sans M, Satsangi J, Schreiber S, Simms LA, Sventoraityte J, Targan SR, Taylor KD, Tremelling M, Verspaget HW, De Vos M, Wijmenga C, Wilson DC, Winkelmann J, Xavier RJ, Zeissig S, Zhang B, Zhang CK, Zhao H, International IBD Genetics Consortium (IIBDGC), Silverberg MS, Annese V, Hakonarson H, Brant SR, Radford-Smith G, Mathew CG, Rioux JD, Schadt EE, Daly MJ, Franke A, Parkes M, Vermeire S, Barrett JC and Cho JH

    Nature 2012;491;7422;119-24

Funding

A full list of funding can be found on the paper.

Participating Centres

A full list of participating centres can be found on the paper

The International IBD Genetics Consortium

The International IBD Genetics Consortium is a network of researchers working on the genetics of inflammatory bowel disease. We have undertaken a number of large-scale genome-wide association studies of both Crohn's disease and ulcerative colitis, which have identified dozens of genomic loci implicated in these diseases. We hope that this research can be translated into a more complete understanding of the biology of IBD that might lead to improved diagnoses and treatment.

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Crohn's and Colitis UK

Crohn's and Colitis UK (the working title for the National Association for Colitis and Crohn's Disease - NACC) provides a valuable support network and information resource for people and families affected by Colitis and Crohn's Disease as well as raising significant funds for research.Since 1984, its members and supporters have raised almost £6 million and more than 150 research awards have been made to hospitals and universities throughout the United Kingdom. Crohn's and Colitis UK also campaigns for better healthcare services and seeks to raise awareness of these lifelong illnesses and their impact on people's lives.The charity has 30,000 members and 70 Groups across the UK.

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Yale School of Medicine

Founded in 1810, Yale School of Medicine is a world-renowned center for biomedical research, education and advanced health care. Among its 28 departments are one of the nation's oldest schools of public health and the internationally recognized Child Study Center, founded in 1911. Its Yale Cancer Center is one of 41 comprehensive cancer centers designated by the National Cancer Institute.

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The school's unique curriculum, known as the Yale system of medical education, promotes teaching in small seminar, conference and tutorial settings, and requires student self-evaluation, independent thinking and investigation.

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The Wellcome Trust Sanger Institute

The Wellcome Trust Sanger Institute is one of the world's leading genome centres. Through its ability to conduct research at scale, it is able to engage in bold and long-term exploratory projects that are designed to influence and empower medical science globally. Institute research findings, generated through its own research programmes and through its leading role in international consortia, are being used to develop new diagnostics and treatments for human disease.

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The Wellcome Trust is a global charitable foundation dedicated to achieving extraordinary improvements in human and animal health. We support the brightest minds in biomedical research and the medical humanities. Our breadth of support includes public engagement, education and the application of research to improve health. We are independent of both political and commercial interests.

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