W1236 NOD2 Mutations Compromise Host Defense Mechanisms to Enteric Bacteria as Shown by Decreased NF-kB in Human B Cells After Muramyl Dipeptide (MDP) Stimulation

Abstract

Background. Clinical data support the existence of discrete subsets of Crohn's disease (CD) patients by disease location. Previous genotype-phenotype analyses have linked the NOD2 and ATG16L1 risk alleles with ileal disease location. Aim. To elucidate novel genotypesubphenotype correlations between 28 established CD risk alleles and disease location (Montreal classification).Methods. We reviewed our established inflammatory bowel disease relational genotypic-phenotypic database. We identified 600 CD patients that had been genotyped for 28 established CD risk alleles that were selected based on previous genome wide association studies [Barrett et al. Nature Genetics 2008; 40:955]. Genotyping was conducted using Taqman allelic discrimination and Sequenom MassARRAY®. The patients were classified as risk (at least one risk allele) or non-risk (no risk allele). In addition, the three major NOD2 risk alleles (Leu1007fs, R702W and G908R) were combined as a single superallele where the NOD2 risk group harbored at least one of the three risk alleles and the NOD2 non-risk group had none of the three risk alleles. The patients were subphenotyped with respect to their maximal disease location using the Montreal classification. Genotypesubphenotype analysis was carried out usingmultinomial logistic regression analysis.Results. The distribution of disease locations were 274 for L1 (ileal), 126 for L2 (colonic), 187 for L3 (ileocolonic), and 3 for L4 (upper small bowel). Five CD risk alleles were significantly associated with disease location (L1 vs L2 vs L3, P<0.05, see Table 1). We detected no effect of gender, race or smoking on disease location. Conclusions. These results support the concept that there is a genetic basis for CD subphenotypes by disease location. Although both NOD2 and ATG16L1 have been associated with ileal disease, harboring a NOD2 risk allele is associated with L1 disease location, whereas harboring the ATG16L1T300A risk allele is associated with L3 disease location. The TNSF15 risk allele is associated with L2 disease location, whereas the X21q21 risk allele is associated with L3 disease location. Table 1. Significant CD risk alleles