Genetics of IBD The DNA double helix - the sequencing of DNA is now automated and the identification of genes associated with IBD has become much easierThis shows the multitude of genes likely to be involved in IBD. It also shows the genetic overlap between Crohn's disease and ulcerative colitisThe role of genetics in inflammatory bowel disease A genetic susceptibility for inflammatory bowel disease (IBD) has been known for many years. There are three main lines of evidence. IBD is more or less common in some ethnic groups. For example, in New Zealand, IBD is very uncommon in Maori or Pacific Islanders. There is clustering of disease within families. About 25% of individuals with IBD know of another family member with IBD. The lifetime risk for a first-degree relative (siblings or parent-child) developing IBD is 10%. The most compelling evidence comes from identical twin studies. These studies show there is a 1/3rd chance of a twin developing Crohn's disease if the first affected twin has Crohn’s disease. For ulcerative colitis the chance of the second twin having colitis is 7%. This is called concordance (both twins having inflammatory bowel disease). Mostly the type of IBD is the same – i.e both ulcerative colitis or both Crohn’s disease. Some families have both types of IBD. This suggests that there is some genetic overlap. For example, it may be that genes A, B, C and D = susceptibility to Crohn’s disease and genes C, D, E and F = susceptibility to ulcerative colitis. In reality in seems that the distinction between the two types of IBD will involve much higher numbers of gene - i.e much more complex than initial estimates It has been observed that IBD is more likely to occur at an early age if there is a strong family history of IBD. This could be termed “genetic loading” - inheriting 30 important variations in genes rather than involving just 10 genes may impact on the nature of the condition. The magnitude of the genetic effect can be seen when comparing non-identical and identical twins. Only 4% of non-identical twins develop IBD (where the first affected twin had Crohn’s disease) compared to 30% for identical twins - ie. genetics is much more important than environment - being raised in the same home. The genetic susceptibility in IBD is clearly not a simple inheritance pattern caused by a single gene. There are mutations (variations) in many genes (recent studies have identified over 150 genes that play a role) This sort of multi-gene susceptibility pattern is also present in other conditions like hypertension and diabetes. IBD is one of the “multi-gene” conditions with the strongest “genetic susceptibility”. The genetic risk appears to be most obvious in Crohn’s disease (compared with ulcerative colitis). It also seems that genetic background explains more than just the diagnosis; the pattern of disease is probably genetically determined The knowledge of the genetic risk has been known for a long time but the technology has only recently been available to search for these genes The problem has been solved using genome-wide scans using automated techniques that pick-up “hot spots” of interest. Several large DNA banks have been created in Europe and USA and also in Australia and New Zealand The Nutragenomics study group in Auckland has also been involved in these studies. The Human Genome project has been a big help because a researcher can “look up” the genes that are within an area of interest to try and “guess” which genes might have something to do with causing the disease. The NOD 2 gene (the first of many genes shown to be involved in Crohn's diseae) Research into Crohn’s disease suggests that it is not the result of a particular infection or bacteria but is the result of an abnormal response of the body’s immune system to normal bacteria. It seems that with a particular set of genes the immune system is unable to adequately “switch off” the inflammatory response. The NOD2 gene and many other gene mutation recently discovered relate to the way the immune system responses to “normal” bacteria in the bowel. This initial insight is exciting and may lead to new treatments. People who have NOD2 mutations tend to have disease in the ileum (small bowel) and are more likely to require an operation to remove this section of bowel. The exact way changes in this gene and other genes yet to be discovered affect response to bacteria will be crucial information and will hopefully led to significant advances in our knowledge of the cause of the disease. This is the field of interest for a study at the Department of Molecular Medicine, School of Medicine, University of Auckland Genetic reserach has helped to identify new targets for treatments. These are specific molecules that could be inhibited by monoclonal antibodies Ultimately the increased understanding of the genetic susceptibility will have several “spin-offs”. Firstly, an improved understanding of the disease will lead to new types of treatment. We have already seen how research into mechanisms of inflammation can lead to treatment. The central role of a molecule called TNF (tumour necrosis factor) lead to the development of a blocking antibody (Remicaide or Humira) – the first genuine new treatment for Crohn’s disease for many years. Secondly, it may lead to new diagnostic tests. Often the distinction between Crohn’s disease and ulcerative colitis is difficult and sometimes making the correct diagnosis is very important. It may be that genetic tests will further define different groups. Genetic testing could be led to a better choice of treatments. Knowing who will response better to different treatments. Perhaps also knowing who will have more aggressive disease and require more intensive treatment at an earlier stage.