Background and Aim: The nucleotide-binding oligomerization domain-1 (NOD1) gene encodes a pattern recognition receptor that senses pathogens. NOD1/caspase recruitment domain (CARD4) signaling leads to the activation of nuclear factor-kB, and plays an important role in innate immunity. Certain polymorphisms and mutations in NOD1/CARD4 might result in a dysfunctional innate immune response during bacterial recognition, which might have direct implications in inflammatory bowel disease (IBD) pathogenesis.
Methods: We carried out a systemic analysis for the presence of polymorphic variants in the intron 9 region of the leucine-rich repeat (LRR) domain encompassing the exon–intron boundaries of the NOD1 gene. To detect unknown single-nucleotide polymorphisms, we used the denaturing high-performance liquid chromatography (DHPLC) screening technique and validated our data by restriction fragment length polymorphism and direct sequencing.
Result: Genotype and allele frequencies showed significant differences in their distribution. The mutations discriminating alleles in the intron 9 region of the LRR domain of the NOD1 gene were correctly predicted by DHPLC technique and statistically verified in IBD and non-IBD individuals. Of the seven mutations detected, only four showed a significant association with disease activity. Mutations detected earlier in the exon 6 region of NOD1 were also used for the haplotype analysis. The GTTG haplotype was found to be significantly overrepresented in ulcerative colitis (UC) patients, as compared to the controls (P = 3.3726E−6).
Conclusion: Our study has revealed a polymorphism association in the LRR domain of the NOD1 gene with the severity of UC disease. This might be due to disruption of the LRR region critical for NOD1-mediated bacterial sensing. A gene-wide, haplotype-based approach shows that GTTG haplotype carriers are overrepresented in UC patients, and that could increase the risk of the disease.