7e078deb-9cab-465e-92bf-bfa2e76b913f
title
Crohn disease: frequency and nature of  CARD15  mutations in Ashkenazi and Sephardi/Oriental Jewish families.
323a392e-a2f5-4467-acd3-d84c5a62f47e
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.