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Abstract:
Background
A previous study suggested an association of the single nucleotide
polymorphism (SNP) rs72796353 (IVS4+ 10 A>C) in the NOD2 gene with
susceptibility to Crohn's disease (CD). However, this finding has not
been confirmed. Given that NOD2 variants still represent the most
important predictors for CD susceptibility and phenotype, we evaluated
the association of rs72796353 with inflammatory bowel disease (IBD)
susceptibility and the IBD phenotype.
Methodology
Genomic DNA from 2256 Caucasians, including 1073 CD patients, 464
patients with ulcerative colitis (UC), and 719 healthy controls, was
genotyped for the NOD2 SNP rs72796353 and the three main CD-associated
NOD2 mutations rs2066844, rs2066845, and rs2066847. Subsequently, IBD
association and genotype-phenotype analyses were conducted.
Results
In contrast to the strong associations of the NOD2 SNPs rs2066844
(p=3.51 x 10(-3)), rs2066845 (p=1.54 x 10(-2)), and rs2066847 (p=1.61 x
10(-20)) with CD susceptibility, no significant association of
rs72796353 with CD or UC susceptibility was found. However, in CD
patients without the three main CD-associated NOD2 mutations, rs72796353
was significantly associated with the development of perianal fistulas
(p=2.78 x 10(-7), OR 5.27, [95% CI 2.75-10.12] vs. NOD2 wild-type
carriers).
Conclusion/Significance
Currently, this study represents the largest genotype-phenotype analysis
of the impact of the NOD2 variant rs72796353 on the disease phenotype in
IBD. Our data demonstrate that in CD patients the IVS4+ 10 A>C variant
is strongly associated with the development of perianal fistulas. This
association is particularly pronounced in patients who are not carriers
of the three main CD-associated NOD2 mutations, suggesting rs72796353 as
additional genetic marker for the CD disease behaviour.
