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 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 have more IBD gene activity, including many that are involved in the body’s first line of 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 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.”
Luke Jostins, Stephan Ripke, Rinse K Weersma, et al (2012). ‘Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease’. Published in Nature online 01 November 2012. DOI: 10.1038/nature11582
A full list of funding can be found on the paper
Wellcome Trust Sanger Institute