the Time Has Come for NOD2/CARD15 Testing for Families With Crohnʼs Disease. Pro

In only 8 years since the first genome-wide screen for inflammatory bowel disease (IBD) susceptibility loci was reported,1 vast progress has been made in the field of IBD genetics. At that time, the technique of positional cloning and linkage analysis was coming into its own with respect to its potential to identify susceptibility genes for complex disorders such as IBD. There was some controversy over the validity of the IBD1 locus on chromosome 16, and if in fact, it would even be possible to identify a susceptibility gene from within the region.2,3 However, after much hard work on the part of both the International IBD Genetics Consortium and individual investigators, allelic variants of the NOD2/CARD15 gene were identified as associated with Crohn's disease (CD) in 2001.4,–6 Since that time, much study has been devoted to understanding the role this gene plays in its predisposition toward CD and what impact it may have on disease course. Two additional genes have recently been identified as possible IBD susceptibility genes, making the understanding of the role of all of these genes even more complex.7,8 In addition to these susceptibility genes, numerous “candidate” genes have also been tested and have shown an association to IBD and other disease-related outcomes. Complete dissection of the genetic pathways affecting disease onset and course are yet to be elucidated, but much information is already available. There are 2 principle populations to consider when evaluating the role of genetic testing in IBD-the “presymptomatic” individuals and those with established disease. Let us first consider the situation for those with established disease because there is more data concerning this population. In this group, the value of genetic testing may lie in the influence on disease course or disease phenotype. Examples of such phenotypes include disease location, disease severity, disease behavior, extraintestinal manifestations, complications of disease, and pharmacogenomics. There are now well-established associations between alleles of NOD2/CARD15 and ileal CD as well as between HLA alleles and colonic CD, which have been replicated in several different populations.9,–11 Classification of IBD based on disease behavior and severity is somewhat controversial and imperfect, however, when applying the criteria for fibrostenotic and penetrating disease based on the Vienna classification; some but not all studies suggest an association of CARD15 alleles to these phenotypes of CD.12,–14 Numerous studies have also shown increased severity and extent of ulcerative colitis (UC) with particular HLA alleles as well as with the interleukin (IL)-1 receptor antagonist and with the IκB-like gene.15,–18 Some of the more serious complications of IBD such as colorectal cancer and primary sclerosing cholangitis are difficult to screen for and difficult to treat. Predicting an “at-risk” population where special efforts may be made to identify early disease may be useful, although early intervention does not necessarily correlate with improved outcome. Although it is known that defects in particular tumor suppressor genes and oncogenes are involved in the pathogenesis of IBD-associated colorectal cancer, genetic markers to identify individuals at increased risk of colorectal cancer in the setting of IBD have yet to be identified.19 Genetic markers associated with primary sclerosing cholangitis have been proposed, although they have not been proven to be reliable to correlate with increased risk of PSC.20 Other manifestations and complications of IBD where association with genetic markers have been described include low bone mineral density, vascular thrombosis, arthritis, erythema nodosum, uveitis, and pouchitis. While still in its infancy and not widely used, a particularly good illustration of how genetic testing may be useful for IBD-affected individuals is in the area of pharmacogenomics. TPMT genotyping, for example, has a shown role in predicting adverse effects of azathioprine/6-MP.21 Although there are some data on genetic markers as predictors of response to other therapies for IBD, such as corticosteroids and infliximab, more work is needed before recommending such markers for routine use. With the plethora of novel biologic agents about to become available, their specific modes of action herald the possibility that genetic markers will 1 day be used to select patients more likely to have efficacy with a decreased risk of toxicity. Examples of the use of pharmacogenomics abound in other complex diseases, and it is a matter of time before the benefits of this technology are realized for IBD.22 More studies are required to further define how testing with genetic markers such as CARD15 can be used prospectively to manage patients. In fact, large scale efforts are currently underway by international consortia to further define the associations described above. However, with the data already available, there is sufficient rationale to advocate testing patients at least for CARD15. One can imagine numerous examples where this information might be useful, but 1 scenario might be a patient where one might consider postponing or eliminating the need for a small bowel enema or capsule endoscopy for patients with CARD15 “negative” (and HLA “positive"?) genetic test results and typical Crohn's colitis at the time of endoscopy. Another example might be found in the individual with newly diagnosed terminal ileal disease who has been tested and found to carry 1 of the suspect CARD15 variants. One may have the opportunity to try and change the natural history of this patient and the propensity to stenosis and obstruction with the subsequent requirement for surgery by earlier intervention with more aggressive therapy, such as with immunosuppressives, infliximab, or other biologic therapies. While it may be premature to recommend testing patients with UC for the markers that are associated with extensive and severe colectomy, we may not be far away from having a “UC panel” of markers that may give useful information for those in whom steroids may not be effective or in whom earlier more aggressive therapy is required to obviate the need for colectomy.23 Another clinical question where genetic testing will likely be very helpful in the future includes differentiating patients with UC and those with Crohn's colitis or indeterminate colitis preoperatively to reduce the likelihood of postoperative fistula formation, pouchitis, or recurrent ileal inflammation. Genetic marker panels in combination with serological markers may give us a great deal of information toward helping classify patients by their disease behavior tendencies; however, more study and novel genetic and serological markers await discovery before the fruits of this approach can be fully realized. Approaching the case for genetic testing of individuals before developing gastrointestinal symptoms is fraught with many difficult questions. Those interested in such testing may be the asymptomatic relatives of IBD-affected individuals or even those from the general population belonging to a higher risk group, such as Ashkenazi Jews. There are a number of variables to consider when deciding on applying this type of “screening” test. Certainly, IBD is common enough and serious enough by most standards to be considered a good candidate for a presymptomatic screening test. However, at this time, we do not have enough information about the absolute risk and penetrance for CD in carriers of a CARD15 mutation. Prospective, population-based studies may be required to answer these questions. Even if such a risk could be quantified, the next question would be what could be done about the result. Currently, we do not know what potential environmental covariates trigger the onset of CD in those who carry a CARD15 variant, and those individuals could perhaps only be counseled to avoid smoking and nonsteroidal anti-inflammatory drug use. In addition to the difficulties intervening on the behavioral side, intervening on the genetics side is also still a distant dream, with even gene therapy for simple genetic disorders being relatively ineffective at this time.24 Not only does there seem to be limited positive benefits achievable by carrying out genetic testing in this population, but there may be substantial negative outcomes. Such adverse effects are likely to be psychologic or economic rather than physical but are still very important. For example, knowing that you or your healthy child is at risk based on a genetic test result may have serious repercussions on your choices in life, including those for employment and marriage, and result in perceived or real discrimination from insurance companies, peers, employers, and others. Clearly, we must get closer to answering the “ultimate” questions of why CARD15 carriers have an increased risk for developing CD and how to prevent it before it occurs before considering genetic testing for asymptomatic individuals. Are individuals from the IBD population even interested in undergoing genetic testing for themselves or their healthy relatives? A survey conducted at the Mount Sinai Hospital IBD Center in Toronto revealed that more than 85% of individuals affected by IBD were interested in pursuing genetic testing for themselves.25 Somewhat surprisingly, a similar proportion were also interested in genetic testing for their young children while they were presymptomatic. This high rate of interest was present even with the knowledge that a single genetic test may only provide a low likelihood of development of disease and may not make an immediate impact on their health. This seems to reflect the strong desire of individuals to gain a measure of autonomy over their health, even when medical science cannot answer all the questions they may have. Currently, genetic testing for IBD-related genes is mainly available only on a research basis; however, in North America, there is a commercially available test that can be ordered by any physician on any individual (PRO-Genologix; Prometheus Laboratories, Calif.). Once cannot necessarily debate whether genetic testing should be made available to patients with CD and their families because genetic testing already is available to those individuals and physicians that feel strongly about having the test performed. The question now is how this testing should be applied. There is enough justification to consider NOD2/CARD15 testing for those already affected by CD at presentation because it may add information helpful in finalizing a diagnosis and provide insight into potential disease complications on the horizon such as a fibrostenotic obstruction requiring surgery. At this time, genetic testing for presymptomatic individuals should be discouraged. There is insufficient data to help these people to manage such a risk, and the potential harm in most cases outweighs the potential benefit. In either case, given the current availability of these tests and the desires of the population, IBD centers must now move forward to prepare genetic testing and counseling services to their patients, similar to the type provided to those with familial colon cancer syndromes. Clearly, for both populations, large-scale genetic studies such as those being undertaken by the International and North American research communities will be required to provide more definitive answers to these compelling questions.

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