title: Crohn disease: frequency and nature of CARD15 mutations in Ashkenazi and Sephardi/Oriental Jewish families.
abstract: 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.
authors.affiliation: Department of Human Genetics, Mount Sinai School of Medicine of New York University, New York 10029, USA.
authors.forename: Turgut
authors.initials: T
authors.lastname: Tukel
authors.forename: Adel
authors.initials: A
authors.lastname: Shalata
authors.forename: Daniel
authors.initials: D
authors.lastname: Present
authors.forename: Daniel
authors.initials: D
authors.lastname: Rachmilewitz
authors.forename: Lloyd
authors.initials: L
authors.lastname: Mayer
authors.forename: Deniera
authors.initials: D
authors.lastname: Grant
authors.forename: Neil
authors.initials: N
authors.lastname: Risch
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Desnick
mesh_terms: D000483:Alleles; D044466:Asian People / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics*; D003424:Crohn Disease / Q000235:genetics*; D004252:DNA Mutational Analysis; D005787:Gene Frequency / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics; D014644:Genetic Variation / Q000235:genetics; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D007585:Jews / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D053473:Nod2 Signaling Adaptor Protein; D020641:Polymorphism, Single Nucleotide / Q000235:genetics
chemical_list: D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein