TITLE

COMPLEX GENETIC INTERACTIONS REVEALED IN AN IBD GENOME SCAN STRATIFIED BY CROHN'S DISEASE ASSOCIATED VARIANTS

AUTHOR(S)
van Heel, D.A.; Dechairo, B.M.; Dawson, G.; McGovern, D.P.B.; Negoro, K.; Carey, A.H.; Cardon, L.R.; MacKay, I.; Jewell, D.P.; Lench, N.J.
PUB. DATE
April 2003
SOURCE
Gut;Apr2003 Supplement 1, Vol. 52, pA12
SOURCE TYPE
Academic Journal
DOC. TYPE
Article
ABSTRACT
Background and Aims: Genetic studies in inflammatory bowel disease (IBD) have identified multiple susceptibility loci. The significance of these findings depends on verification in independent cohorts. Genetic variants associated with Crohn's disease have now been identified on chromosomes 5 (IBD5 risk haplotype) and 16 (IBD1 locus, CARD15/NOD2 mutations). These variants now allow stratification of linkage analyses, which will improve the ability to identify other loci, and allow assessment of potential complex interactions between genetic factors. Such gene-gene interactions have been shown to occur in animal models of IBD. Methods We performed a genome-wide scan of 228 IBD families. Multipoint linkage was assessed using MERLIN for IBD (288 affected relative pairs), Crohns disease (CD, 137 pairs) and ulcerative colitis (UC, 95 pairs) phenotypes. CD analyses were further stratified by common CARD15/NOD2 mutations and the BD5 haplotype. Results: We confirmed loci on chromosomes 3q (CD, LOD 2.1; p = 0.0009), 6p ( BD, LOD 2.2 p = 0.0008) and Xp (CD, LOD 2.0; p = 0.001 ). Linkage (CD, LOD 2.2; p = 0.0007 was observed 25cM q telomeric to CARD15 in CARD15 negative CD affected. The chromosome 19q locus, also demonstrated in a Canadian CD population, showed significant genetic heterogeneity with CARD15 (significance test p = 0.002, LOD 2.9; p = 0.0001 in CARD15 negative CD) and epistasis with the IBD5 haplotype (significance test p = 0.02, LOD 2.4; p = 0.0005 in CD IBD5 carriers). Conclusions: Stratification of a genome scan by Crohn's disease associated variants demonstrates the complex genetic basis to IBD, with genetic heterogeneity and epistatic interactions between loci. Our data support previous suggestions of a second chromosome 16 locus.
ACCESSION #
9747331

 

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