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Introduction: Inflammatory bowel disease (IBD) is thought to occur due to an environmental insult in a genetically susceptible individual. Multiple genetic variants have been identified to be associated with IBD. The tight junction complex (TJ) is part of the intestinal epithelial barrier and has been shown to be altered in patients with IBD. The purpose of this study was to identify genetic variants in the TJ complex that may be associated with IBD.

Methods: DNA from members of our IBD registry was previously collected and stored. Initially 284 members of our IBD registry and non-diseased controls underwent genotyping for 25 TJ single nucleotide polymorphisms (SNP) on an Illumina^TM platform. Genes studied coded for both transmembrane and membrane associated proteins. Based on initial screening results, a total of 670 IBD patients and non-diseased controls were genotyped for the rs260526 SNP by polymerase chain reaction (PCR). IBD patients were subdivided into familial (at least one family member with IBD besides the index patient) or sporadic (no family members with IBD). Three genetic models (general, additive, and dominant) were used to quantify the initial genotyping. For rs260526, groups were compared with a two-sided Fisher’s exact test.

Results: Of the 25 initial SNPs only rs260526, a SNP in the ZO-1 gene, was shown to be statistically significant by all three genetic models when comparing IBD patients to non-diseased controls. ZO-1 is a key protein in the TJ complex and has been shown to be altered in IBD. Therefore, additional IBD patients and non-diseased controls were genotyped for rs260526 by PCR. When the IBD patients were subdivided, this ZO-1 SNP was found to be statistically significant when comparing patients with familial IBD to non-diseased controls, p = 0.0213, OR = 0.468, Cl = [0.225, 0.911]). The mutation was more common in the non-diseased controls, and therefore protective against IBD.

Conclusions: 1. Of all the TJ SNPs studied, only a mutation in the ZO-1 gene was associated with IBD. 2. This SNP was found to be protective against the development of familial IBD. Lack of significance of this SNP in sporadic IBD supports a different pathogenesis for familial and sporadic IBD. 4. Alteration of the ZO-1 protein by the SNP may lead to conformational changes or alterations in binding sites that make it resistant to degradation in IBD. Further study of the changes in the ZO-1 protein by a mutation at rs260526 may lead to a better understanding of the role of ZO-1 in IBD.