The human genome project offers the promise of identifying every human gene. Once that job is complete, however, another hard job begins: identifying the function of these genes and their imperfections that result in human disease. Crohn's disease is a multigenic disorder with diverse clinical presentations. Recently, several groups have identified mutations in the CARD15/NOD2 gene in patients with Crohn's disease. 1–3 Both Jewish patients and non-Jewish patients with Crohn's disease carry the common mutations in the NOD2 gene, 4 but it seems that Jewish patients may have additional mutations that confer disease susceptibility. 5 Even within the Jewish population, history and geography play a role in their genetic tapestry. Thus, identification and clinical characterization of well-defined genetically homogenous ethnic groups provide a strong tool for the discovery of new Crohn's disease-associated genes and their relationship with the pathogenesis of disease.
In the current issue of the Journal, Fidder and colleagues 6 have provided us an in-depth description of the clinical characteristics of Israeli Jewish patients with Crohn's disease. These investigators were able to study Jewish patients of both Ashkenazi (eastern European) and Sephardic (Asian and African) descent. Northern American studies of patients with Crohn's disease have largely focused on Ashkenazi Jews. The prevalence of Crohn's disease in Ashkenazi Jews is thought to be higher than that in Sephardic Jews. 7 This difference in prevalence may be caused by environmental differences and/or genetic differences. Because this study was performed in Israel, the environmental influences should be similar for both groups. We are not told, however, whether the majority of patients were Israeli-born and how many generations were raised in Israel to understand the similarity in environmental exposures. In this study, the prevalence and familial relative risk in Ashkenazi and Sephardic Jews is similar for both groups. Because the authors do not know the demographics of patients at their hospital, they do not claim to know the true prevalence of Crohn's disease in these two groups. Although the frequency and type of susceptibility genes may be different for Ashkenazi and Sephardic Jews because of different evolutionary histories, the similarity in familial relative risk (Fig. 1) reflects the fact that once a family carries a high-risk gene, the index case is just as likely to have a first-degree relative with Crohn's disease, regardless of ethnic subgroup.
The principal findings of their study are a predominance of ileal-only disease in Israeli Jews and more frequent extraintestinal manifestations in Sephardic Jews. Most studies that have examined the prevalence of ileal-only disease have found that approximately 30% of patients have ileal-only disease. By contrast, Fidder et al. 6 observed that 48% of patients had ileal-only disease. Patients with ileal disease were more likely to develop fibrostenosing complications. These observations have important implications for stratification of disease subtypes. We and others have recently reported that patients with mutations in the CARD15/NOD2 gene are significantly more likely to develop fibrostenosing disease of the small bowel. 8 We have also described new CARD15/NOD2 mutations in Jewish patients. 5 Thus, the findings by Fidder et al. 6 of frequent fibrostenotic disease of the ileum may be partially explained by mutations in the CARD15/NOD2 gene or other novel disease susceptibility genes. Extraintestinal manifestations of Crohn's disease also appear to have a heritable component, given the 70% concordance of extraintestinal symptoms in families with multiply affected members. 9 Because Sephardic Jews have more frequent extraintestinal manifestations, this group of patients would be ideal to identify genetic or immunologic characteristics that are specific to this clinical phenotype.
Fidder et al. 6 have used the Vienna classification to assign patients into groups. This system of classification obligates clinicians to choose between perforating disease or stricturing disease. Patients with both manifestations are categorized as perforating. It is not clear, however, that these designations are rooted in distinct pathogenetic mechanisms. Vasiliauskas et al. 16 found that patients with either stricturing or perforating complications were more likely to express antibodies to Saccharomyces cerevisiae, suggesting that there is a common immunologic signature underlying both processes. We observed that patients with fibrostenosing disease had more frequent carriage of CARD15/NOD2 mutations, 4 regardless of concurrent perforating complications. These data suggest that by subsuming patients with fibrostenosing disease into the perforating category, we may miss certain clinical and pathogenetic associations related to fibrostenosing disease. In the Fidder study, 6 no mention is made of differences between Ashkenazi and Sephardic Jews with respect to fibrostenosing or fistulizing complications, but it is possible to miss such an association with the Vienna classification.
The Fidder study also highlights important differences in environmental factors that may modify disease activity. 6 Smoking is associated with exacerbations in Crohn's disease. Fidder et al. found no increase in disease severity with smoking, which concurs with previous Israeli studies. 10,11 The limitation of the current study is that disease severity was defined by patients on immunomodulators and/or those who had required surgery. These criteria may not adequately represent disease severity but rather clinician practices. The adverse relationship of smoking with Crohn's disease has been described in studies from North America, Western Europe and Scandinavia. 12–14 Many of these countries have small Jewish populations, and some cannot ascertain which patients within their cohorts are Jewish. It is not clear from the published literature that smoking is a significant risk for Jewish patients. These discordant observations suggest that the adverse effect of smoking on Crohn's disease might be a consequence of the interaction between smoking and genetic and/or environmental factors not present in the Israeli Jewish community. Finally, Fidder et al. 6 observed that 19% of Ashkenazi Jews reported a positive family history for inflammatory bowel disease, which is similar to the 23% found in American Ashkenazi Jews. 15 The prevalence of Crohn's disease in American Ashkenazi Jews is greater, however, than that in Israeli Ashkenazi Jews. 7 These results suggest that in spite of environment, Ashkenazi Jews in Israel and the United States have similar familial risks. This is an additional piece of evidence that genetic factors play a predominant role in the Jewish population, as previously discussed.
The careful characterization of Israeli Jewish patients by Fidder et al. 6 provides a foundation on which we can study specific subtypes of Crohn's disease in genetically homogeneous patient groups. By categorizing patients according to discrete clinical phenotypes, we can increase our power to detect genetic and immunologic associations. It stands to reason that the pathogenetic mechanisms that result in colonic Crohn's disease are different than those resulting in pure ileal disease. The Fidder study tells us that even within the Jewish population, distinct genetic and/or environmental factors may result in diverse clinical manifestations. We need to compare apples to apples and, sometimes, red apples to red apples to make progress toward finding the underlying causes of Crohn's disease.
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