title: CARD15/NOD2 risk alleles in the development of Crohn's disease in the Australian population.
abstract: We have previously reported strong evidence for linkage between IBD1 and Crohn's disease (CD) in Australian Crohn's disease families. Three risk alleles for Crohn's disease, (Arg702Trp (C/T), Gly908Arg (G/C) and 980fs981 (-/C), were recently identified in the CARD15/NOD2 gene on chromosome 16, implicating this as the IBD1 locus. Using a novel diagnostic PCR-RFLP, we have examined the frequency of these alleles in 205 multiplex IBD families, 107 sporadic Crohn's disease cases and 409 normal individuals. We demonstrate that the three risk alleles are more frequent in Crohn's disease, than in controls, with allelic frequencies of 0.11, 0.02 and 0.07 respectively. Heterozygosity for individual variants conferred a three-fold increase in risk for Crohn's disease while substantially higher risks were associated with being homozygous or compound heterozygous. Despite a significantly lower population allele frequency for the frameshift mutation than reported by other groups, we see a similar contribution by this allele to the risk of developing Crohn's disease. While the three risk alleles influence susceptibility to Crohn's disease in Australia, we show that these alleles do not fully explain the linkage evidence and suggest that there are very likely additional IBD1 susceptibility alleles yet to be described in Australian CD at the NOD2 locus. We also show a second linkage peak in Australian CD that provides some support for a second disease susceptibility locus on chromosome 16.
authors.affiliation: The Canberra Hospital, Gilmore Crescent, Garran, ACT 2606. Juleen.Cavanaugh@anu.edu.au
authors.forename: J A
authors.initials: JA
authors.lastname: Cavanaugh
authors.forename: K E
authors.initials: KE
authors.lastname: Adams
authors.forename: E J
authors.initials: EJ
authors.lastname: Quak
authors.forename: M E
authors.initials: ME
authors.lastname: Bryce
authors.forename: N J
authors.initials: NJ
authors.lastname: O'Callaghan
authors.forename: H J
authors.initials: HJ
authors.lastname: Rodgers
authors.forename: G R
authors.initials: GR
authors.lastname: Magarry
authors.forename: W J
authors.initials: WJ
authors.lastname: Butler
authors.forename: J A
authors.initials: JA
authors.lastname: Eaden
authors.forename: I C
authors.initials: IC
authors.lastname: Roberts-Thomson
authors.forename: P
authors.initials: P
authors.lastname: Pavli
authors.forename: S R
authors.initials: SR
authors.lastname: Wilson
authors.forename: D F
authors.initials: DF
authors.lastname: Callen
mesh_terms: D000483:Alleles; D001315:Australia / Q000453:epidemiology; D002352:Carrier Proteins / Q000235:genetics*; D002885:Chromosomes, Human, Pair 16; D003424:Crohn Disease / Q000453:epidemiology / Q000208:ethnology / Q000235:genetics*; D005787:Gene Frequency; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D009154:Mutation; D053473:Nod2 Signaling Adaptor Protein; D012307:Risk Factors
chemical_list: D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein