I am Jewish: What is my risk of developing Crohnʼs disease?

The association between the risk of developing Crohn's disease (CD) and persons of Jewish descent dates back to the original description of CD. Many of the patients in the original article were Jewish. Initially, there was some doubt because of inherent biases that included that Dr. Crohn practiced at the Mt. Sinai Hospital in New York, a hospital supported and used by the Jewish community. Many of the patients seen by Dr. Crohn were of Jewish descent, giving a false impression of an association. It was initially speculated that physicians may have investigated patients with abdominal systems who were Jews more aggressively than similar patients who were gentiles. Proper case-controlled studies needed to be performed in order to definitively answer whether the association was true or tainted by bias. The results of the case-controlled studies have been conflicting. This may be due to changing genetic patterns in the Jewish community. A key concept is to divide those of Jewish faith based on ancestry, the Ashkenazi (Az) and the Sephardi (Sp). The distribution of these 2 groups differ widely, with the Az living mainly in Europe and North America and the Sp living in the Middle East. The first epidemiological cohort studies date back to the 1960s. These studies were performed in populations from the USA, Europe, and South Africa. They indicated a 2–4-fold increased risk of CD in Jews. However, data from Israel did not show this trend. Rozen et al1 completed a survey of the Jewish population in Tel-Aviv–Yafo from 1970–1976 and found an incidence of 1.28/105 and a prevalence of 12.31/105. This was similar or lower than data published from the USA and Europe in the same timeframe. Interestingly, they found the prevalence in Az Jews was 4 times higher than non-Az Jews (16.69 versus 4.19/105, respectively). Krawiec et al2 analyzed the epidemiology of CD in Beer Sheva, Israel, from 1960 to 1980. The mean annual incidence was similar to Rozen et al, at 1.1/105 and 1.8/105 for the period of 1976–1980. The unadjusted prevalence rates were 6.9, 24.6, and 19.4/105 for Israeli born, American/European born, and Asian/African born Jews, respectively. When adjusting for age, however, the differences are not as pronounced, with prevalence rates of 9.7, 15.8, and 12.5/105, respectively. It is likely that age distribution, geographical location, and being Az may account for differences between various studies. Odes et al3 compared the prevalence of CD in southern Israeli Jews with Arabs in the same region. Cases were identified from hospital and outpatient records from 1968–1992 and were confirmed by contact with family practitioners and specialists. The prevalence was 55/105, 58.7/105, and 8.2/105 for Asia/Africa born Jews, European/American born Jews, and Bedouin Arabs, respectively. This suggests that CD is 6 times higher in Jews compared to Arabs. However, the study design is open to significant errors including misclassification, missing data, lack of pathological confirmation, and medical-seeking practices of the different groups. In a community-based survey in 1997 of Israelis in kibbutz settlements,4 the mean annual incidence over a 10-year period (1987–1997) was 5/105 and prevalence of 65/105 in 1997. This was a significant rise from 25.5/105 in 1987. While no non-Jewish groups were present in these settlements, the prevalence is similar to the data from Odes et al. This population-based study likely represents an accurate estimate of the true incidence and prevalence in this area. All cases were identified by contacting kibbutz clinics in 269 settlements with a defined population. There was 100% compliance and only confirmed CD diagnoses were included. The rising incidence and prevalence may be from Westernization of culture within this Israeli population, similar to what has been seen in other areas of the Middle East. The rates, however, compare lower than population-based data from the same time period in primarily non-Jewish North American communities, for example, Manitoba, Canada,5 with an incidence and prevalence of 14.6/105 and 198.5/105, respectively; and Olmsted County, Minnesota,6 with 6.9/105 and 144/105, respectively. Roth et al7,8 indicated a higher incidence of IBD in Jews originating in Middle Europe (Az) compared to those from Poland or Russia (Sp). The incidence of CD is 2–4 times higher in Az Jews compared to the non-Jewish white population, and the prevalence is 2.2–9.4 times higher. When assessing for empiric familial risk, 23.4% of patients had a family history, and the risk of an offspring, sibling, or parent developing CD was 8.9%, 8.8%, and 3.5%, respectively. This study, however, was from a single gastroenterology practice, which may lead to referral bias. Eighty-two percent were Az, but how Az was determined was not defined. Furthermore, assessment of family history from the patient was done through a phone survey. This leads to significant information bias, which may have led to false conclusions of increased risk. Yang et al9 further assessed the empiric risk of developing CD in the Jewish versus non-Jewish populations with a family history. In all, 291 Jewish and 236 non-Jewish patients with IBD in southern California were questioned about inflammatory bowel disease in first-degree relatives (total of 2493 individuals). The lifetime risk of developing CD disease in a non-Jewish individual was 5.2% compared to 7.8% in a Jewish individual when a first-degree relative proband had CD (P = 0.028). This retrospective cohort study is again prone to information bias, both from recall bias of the probands and lack of information of the proband of family members. There are significant differences with regard to study timeframe, populations, and geographical locations. This may lead to variations in risk, incidence, and prevalence rates of CD in Jews. Nevertheless, there is likely an increased risk of CD, particularly in Az Jews. A genetic predisposition is a possible explanation for this trend. The discovery of the IBD-1 susceptibility locus on chromosome 16 encoding for NOD2/CARD15 has led to numerous studies on the pathogenesis of CD, suggesting its involvement in intracellular bacterial clearance.10 In non-Jewish patients with CD, 10%–30% will be simple heterozygotes and 3%–15% will be homozygote or compound heterozygote for NOD2/CARD15 mutations.11 Simple heterozygotes convey a relative risk of 3 (absolute risk of 0.002) for developing CD, while compound heterozygotes and homozygotes convey a risk of 38–40 (absolute risk of 0.03). In healthy controls, 8%–15% will be simple heterozygotes and 0%–1% homozygotes.11 Numerous genetic studies in (Az) Jews have demonstrated a high prevalence of NOD2/CARD15 mutations, conferring a higher risk for developing disease, particularly of early onset within familial cases.12,13 In comparison between Israeli Jews and Arabs with CD, 38.1% versus 7.6%, respectively, carried a CARD15 mutation, of which 16% of Jews with CD were compound heterozygotes or homozygotes compared to 0% in Arabs with CD and Arab/Jewish controls.14 Fidder et al15 found a mutation carrier rate of 27% in Israeli Jews, with a 37% and 26% carrier rate in Az and non-Az Jews, respectively (P = 0.188). Other reports have shown increased CARD15 mutations in Az versus Sp Jews. Karban et al16 found a significantly higher carrier rate in Az versus Sp Jews with CD (47.4% versus 27.45%, P = 0.034), with 7.8% compound heterozygote/homozygote, compared to a 10.7% carrier rate and 0% compound heterozygote/homozygote rate in controls. Tukel et al17 found a carrier rate of 44% in Az Jews of central Europe compared to 34.5% of Sp Jews. The risk of developing disease may also be dependent on the mutation haplotype. Sugimura et al18 recently described a new variant, called 268S-JW1, exhibiting the highest population attributable risk in Az Jews compared to non-Jews (15.1% versus 0.3%). This increased rate of CARD15 mutations in Az Jews would likely explain the increased prevalence of CD. It is evident that Az Jews are at increased risk of developing CD compared to non-Jewish ethnic groups. The increased frequency of the CARD15 mutation is a partial explanation. Whether additional risk factors exist, including environmental factors, has never been adequately studied. There likely remains an interplay between genetic predisposition and environmental exposure. Primary prevention, including avoidance of smoking and nonsteroidal antiinflammatory medications, should be advocated for those at risk, namely, Az Jews with a family history of inflammatory bowel disease.

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