title: Variation at NOD2/CARD15 in familial and sporadic cases of Crohn's disease in the Ashkenazi Jewish population.
abstract: OBJECTIVE
  Recent reports indicate that allelic variants in NOD2/CARD15 are associated with Crohn's disease (CD) susceptibility, and that homozygosity or compound heterozygosity at this locus for any of three recently defined sequence variants confers a greatly increased risk of CD. These sequence changes include two missense mutations, R702W and G908R, and a frameshift insertion, 1007insC. The aim of this study was to determine the frequency of these NOD2/CARD15 variants in familial and sporadic CD patients in the Ashkenazi population and to determine their effects on disease susceptibility and age of disease onset (AOO).
  
  
  METHODS
  Allele and genotype frequencies of these three variants were determined in 481 CD patients of Jewish descent and 110 Jewish controls; 169 patients had a family history of CD, and 312 were "sporadic" cases. Variants were detected by polymerase chain reaction using allele-specific primers labeled with fluorescent dye.
  
  
  RESULTS
  Familial cases had a significantly higher frequency of the G908R variant than sporadic cases (0.127 vs 0.059, p = 0.0003) and correspondingly, a significantly higher proportion of homozygotes and compound heterozygotes (11.8% vs 4.5%, p = 0.0027). Homozygotes and compound heterozygotes had an OR for CD of 14.6 for familial cases and 5.1 for sporadic cases. There was no increased risk of CD for simple heterozygotes. The AOO was significantly lower for CD patients who were homozygotes and compound heterozygotes for NOD2/CARD15 (17.5 vs 22.4 yr, p = 0.04), but only for familial cases.
  
  
  CONCLUSIONS
  NOD2/CARD15 contributes more to CD susceptibility in familial cases than in sporadic cases, and to an earlier AOO. There is no increased risk of CD for individuals carrying only a single copy of these NOD2/ CARD15 variants, whereas individuals carrying two copies have a 5-15-fold increased risk. The penetrance of the NOD2/CARD15 mutations was estimated at less than 1%.
authors.affiliation: Division of Molecular Medicine, Department of Medicine, North Shore University Hospital/New York University School of Medicine, Manhasset 11030, USA.
authors.forename: Zhifeng
authors.initials: Z
authors.lastname: Zhou
authors.forename: Xing-Yu
authors.initials: XY
authors.lastname: Lin
authors.forename: Pradip N
authors.initials: PN
authors.lastname: Akolkar
authors.forename: Beena
authors.initials: B
authors.lastname: Gulwani-Akolkar
authors.forename: Jeremiah
authors.initials: J
authors.lastname: Levine
authors.forename: Seymour
authors.initials: S
authors.lastname: Katz
authors.forename: Jack
authors.initials: J
authors.lastname: Silver
mesh_terms: D017668:Age of Onset; D000483:Alleles; D001483:Base Sequence / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics*; D003424:Crohn Disease / Q000453:epidemiology / Q000208:ethnology* / Q000235:genetics*; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics; D014644:Genetic Variation; D005838:Genotype; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D007585:Jews / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation; D053473:Nod2 Signaling Adaptor Protein; D019683:Penetrance
chemical_list: D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein