P0134 PP EFFECT OF POLYMORPHISMS IN THE NOD2, TOLL LIKE RECEPTOR 4 AND TNF ALPHA PROMOTER GENES ON PEDIATRIC ONSET AND PHENOTYPE OF CROHN???S DISEASE: COMPARISON TO AN ADULT COHORT

Abstract

Introduction: Studies suggest that juvenile onset Crohn’s disease (CD) may demonstrate more frequent colonic location and male gender in comparison to adults. This may suggest a different genetic basis for a pediatric CD phenotype. Mutations in NOD2 have been linked to ileal disease, while polymorphisms in the Toll like receptor 4 (TLR4) and TNF alpha promoter region have been reportedly associated with IBD and colonic involvement. We evaluated the association between mutations in these genes, age at diagnosis and location of disease. Methods: Two cohorts of CD patients (N=189, 83 pediatric, 106 adult onset, range 8 months -65 years) were evaluated for age of onset, gender, origin and location. They were genotyped for the presence of polymorphisms in NOD2 (G908R, R702W, fs 1007, the P268S background polymorphism), TLR4 (Asp299Gly, Thr399Ili ) and in the TNF alpha promoter region( -308A, -238A, -857C, -863T). Results: Male gender ( p=0.04) and upper intestinal involvement, (p=0.009) were associated with earlier age of onset. Patients with isolated colitis tended to be younger (ns). Single or multiple NOD2 disease- associated mutations were associated with ileal involvement but not age of onset, whereas P268S was associated with older adult age of onset (p=0.05), especially in haplotypes naive for other NOD2 mutations ((p=0.004). TLR4 polymorphisms were not associated with age at onset or location. TNF alpha promoter polymorphisms were not associated with age of onset. Presence of -863T was associated with isolated colitis (p=0.018), while absence of 238A was associated with upper intestinal involvement (p=0.05). Conclusion: Disease location may be independently affected by age of onset, and the presence of mutations in NOD2, -863 T and -238A. Pediatric onset CD was not related to he defined NOD2 disease associated mutations or those in TLR4 and TNF alpha promoter. Unidentified mutations in linkage disequilibrium with P268S of the NOD2 gene appear to be associated with adult onset disease.