A novel NOD2/CARD15 haplotype conferring risk for Crohn disease in Ashkenazi Jews.
Crohn disease (CD) exhibits a 2-4-fold increased frequency in Jews as compared with other ethnic/racial groups. Three coding variants of the NOD2/CARD15 have been reported as independent disease-predisposing mutations (DPMs), but these were found in only 30%-40% of patients with CD and could not account for all the linkage between CD and the IBD1 locus. The aim of the present study was to explore whether additional DPMs at the IBD1 locus exist in the high-risk Jewish group. Sixty-four Ashkenazi Jewish and 147 non-Jewish white families were studied. Six microsatellite markers spanning IBD1 were genotyped for linkage analysis in subgroups stratified on NOD2/CARD15 DPM status. SNPs in NOD2/CARD15 (R702W, G908R, 1007fs, and S268P) were then genotyped in family and independent case-control samples. On the basis of initial results, sequencing was done on NOD2/CARD15-translated regions in 12 Jewish individuals. Subsequently, a new NOD2/CARD15 variant was genotyped and analyzed. After excluding the influence of the three DPMs, significant linkage of IBD1 to CD in Jews remained with two peaks at D16S403 (mean allele sharing [MAS] = 0.70] and D16S411 (MAS = 0.59). Further, we observed an increased frequency of a haplotype carrying only the 268S variant in Jewish patients (OR = 3.13, P=.0023) but not in non-Jews, suggesting the existence of a Jewish-specific additional disease-predisposing factor on this haplotype. Sequencing of this haplotype revealed a new variant (IVS8+158; JW1). The 268S-JW1 combination exhibited a further increased risk (OR = 5.75, P=.0005) and the highest population-attributable risk (15.1%) for CD among reported DPMs in Jews. In Ashkenazi Jews, unrecognized population-specific predisposing factor(s) exist on the 268S-JW1 haplotype at the IBD1 locus. This factor may contribute to the higher risk for CD in Ashkenazi Jews as compared with non-Jews.
Sugimura
Kazuhito
K
Division of Medical Genetics and Inflammatory Bowel Disease Research Center, Department of Medicine, Steven Spielberg Pediatric Research Center, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
Taylor
Kent D
KD
Lin
Ying-chao
YC
Hang
Tieu
T
Wang
Dai
D
Tang
Yong-Ming
YM
Fischel-Ghodsian
Nathan
N
Targan
Stephan R
SR
Rotter
Jerome I
JI
Yang
Huiying
H
D019943:Amino Acid Substitution; D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics*; D016022:Case-Control Studies; D002874:Chromosome Mapping; D003424:Crohn Disease / Q000235:genetics*; D017931:DNA Primers; D005060:Europe / Q000208:ethnology; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D007585:Jews / Q000235:genetics*; D018895:Microsatellite Repeats; D053473:Nod2 Signaling Adaptor Protein; D010802:Phylogeny; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D044465:White People / Q000235:genetics
D002352:Carrier Proteins; D017931:DNA Primers; D047908:Intracellular Signaling Peptides and Proteins; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein