title: Is age of onset of Crohn's disease governed by mutations in NOD2/caspase recruitment domains 15 and Toll-like receptor 4? Evaluation of a pediatric cohort.
abstract: Crohn's disease (CD) is caused by a combination of environmental and genetic factors. It is not clear at present whether age of onset (AOO) is a random event or dictated by genotype or environmental factors. Mutations in the NOD2/caspase recruitment domains 15 (CARD15) and in the Toll-like receptor 4 (TLR4) gene have been associated with increased susceptibility for CD. We sought to determine whether single or multiple mutations in these genes are linked to earlier susceptibility for CD. A cohort of 189 patients with CD (82 pediatric onset, 107 adult onset) were genotyped for three disease-associated single-nucleotide polymorphisms (SNPs), one haplotype association (JW1-SNP5), and one background polymorphism (P268S) of the NOD2/CARD15 gene and for two SNPs of TLR4. Analysis of heterozygosity, homozygosity, alleles, and haplotypes of cohort on age or pediatric onset was performed. AOO ranged from 8 mo to 68 y. The presence of the three NOD2/CARD15 and two TLR4 mutations, the NOD2/CARD15 JW haplotype, compound heterozygosity, and homozygosity were not associated with AOO. Presence of P268S in the absence of known NOD2/CARD15 mutations was correlated with increasing age and adult onset of CD, whereas pediatric-onset disease was associated with male gender and the wild-type NOD2/CARD15 haplotype. Mutations in NOD2/CARD15 and TLR4 are not significantly associated with AOO in our population. Mutations that are not in linkage disequilibrium with the background mutation P268S of the NOD2/CARD15 gene probably play a more significant role in pediatric-onset disease.
authors.affiliation: Molecular Genetics Laboratory, E. Wolfson Medical Center, Holon, Holon, Israel. leshinsky@wolfson.health.gov.il
authors.forename: Esther
authors.initials: E
authors.lastname: Leshinsky-Silver
authors.forename: Amir
authors.initials: A
authors.lastname: Karban
authors.forename: Erena
authors.initials: E
authors.lastname: Buzhakor
authors.forename: Marcelo
authors.initials: M
authors.lastname: Fridlander
authors.forename: Benjamin
authors.initials: B
authors.lastname: Yakir
authors.forename: Rami
authors.initials: R
authors.lastname: Eliakim
authors.forename: Shimon
authors.initials: S
authors.lastname: Reif
authors.forename: Roni
authors.initials: R
authors.lastname: Shaul
authors.forename: Mona
authors.initials: M
authors.lastname: Boaz
authors.forename: Dorit
authors.initials: D
authors.lastname: Lev
authors.forename: Arie
authors.initials: A
authors.lastname: Levine
mesh_terms: D000293:Adolescent; D017668:Age of Onset; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D003424:Crohn Disease / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism; D017931:DNA Primers; D006239:Haplotypes; D006801:Humans; D007223:Infant; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D053473:Nod2 Signaling Adaptor Protein; D051197:Toll-Like Receptor 4 / Q000235:genetics* / Q000378:metabolism
chemical_list: D017931:DNA Primers; D047908:Intracellular Signaling Peptides and Proteins; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; D051197:Toll-Like Receptor 4