Crohn Disease: Frequency and Nature of CARD15 Mutations in Ashkenazi and Sephardi/Oriental Jewish Families

Turgut Tukel, Adel Shalata, Daniel Present, Daniel Rachmilewitz, Lloyd Mayer, Deniera Grant, Neil Risch, Robert J. Desnick

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52 Scopus citations


Crohn disease (CD), an inflammatory bowel disease, is a multifactorial trait with the highest frequency in Ashkenazi Jewish (AJ) individuals of Central European origin. Recently, three common predisposing CARD15 mutations (R702W, G908R, and 1007fs) and a polymorphism (P268S) were identified. To determine whether CARD15 mutations account for the higher prevalence of CD in AJ individuals, the haplotypes and allele frequencies of the common mutations and variants were assessed in 219 members of 50 AJ and 53 members of 10 Sephardi/Oriental Jewish (SOJ) multiplex families with CD, in 36 AJ patients with sporadic CD, and in 246 AJ and 82 SOJ controls. A higher frequency of CARD15 mutations was found in AJ patients from multiplex families with CD from Central (44.0%) versus Eastern (24.0%) Europe, especially for G908R and 1007fs, and in SOJ patients (34.5%) compared with AJ (10.1%) or SOJ (5.4%) controls. Contrary to expectation, the frequency of the common mutations was slightly lower in AJ patients with CD (30.1%) than in SOJ patients with CD (34.5%). The 702W allele was associated with both the P268 and 268S alleles. CARD15 mutation frequencies were greater in affected sib pairs than in sporadic CD cases but actually decreased in families with three or more affected sibs, raising the possibility of genetic heterogeneity. Similarly, our linkage evidence on chromosome 16 was diminished in the families with three or more affected sibs compared with sib pairs. Screening the CARD15 gene for rare variants revealed five novel changes (D113N, D357A, I363F, L550V, and N852S) of which N852S occurred only in AJ individuals and may be disease predisposing. Also, there was no evidence for increased risk associated with the recently described IVS+158 single-nucleotide polymorphism. Although the AJ controls appear to have a higher frequency of CARD15 mutations than the SOJ controls, it is unlikely that this difference fully explains the excess frequency of CD in the AJ population.

Original languageEnglish
Pages (from-to)623-636
Number of pages14
JournalAmerican Journal of Human Genetics
Issue number4
StatePublished - Apr 2004
Externally publishedYes

Bibliographical note

Funding Information:
The authors wish to thank the many patients and families with CD for their participation in these studies. We especially thank the many physicians who referred patients for these studies, including David Sachar, Arthur Kornbluth, Simon Lichtiger, Adrian Greenstein, Steven H. Itzkowitz, David Jaffe, Susan Rose, Thomas Alman, Mark Babyatsky, and Saul Agus. We acknowledge Monica Erazo, Eric Smith, and Suresh Pattumudi for their excellent technical assistance. This research was supported by a grant from the New York Crohn’s Foundation.


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