Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gastrointestinal (GI) tract, comprised of Crohn's disease (CD) and ulcerative colitis (UC). Over the past century, Northern Europe and North America have witnessed a significant rise in incidences of IBD . The inflammatory response in CD patients is described by transmural inflammation in any portion of the gastrointestinal tract while that of UC is usually limited to the mucosa and submucosa of the colon and rectum . Although the exact pathogenesis is not completely known in IBD, our current understanding suggests a disease etiology dependent upon a multifaceted interaction between genetic, environmental, and clinical factors.
Evidence of genetic factors implicated in this condition is supported by increased rates of IBD in monozygotic twins, and the ethnic differences in IBD frequency . In addition, different races and ethnic groups have different degrees of susceptibility to IBD . A number of studies have shown an association between IBD susceptibility and the nucleotide-binding oligomerization domain 2 gene (NOD2, also known as CARD15), interleukin-23 receptor gene (IL23r), organic cation transporter novel type 1 gene (OCTN1), and the intergenic region (IGR) variants [6–9]. NOD2 gene mutations have been extensively studied and described in the literature in terms of IBD susceptibility. Loss-of-function mutations in NOD2 gene appear to be the most significant for development of IBD, although the mechanism that increases disease susceptibly is poorly understood. One report suggests that NOD2 contributes a protective function in host defense that when compromised elicits a loss in immune bacterial recognition . The NOD2 gene on chromosome 16 has been specifically implicated in susceptibility to CD with 30-50% of Caucasian CD patients having variants of this gene . The three NOD2 variant single nucleotide polymorphisms (SNPs) (rs2066844, rs2066845, and rs5743293) have been strongly associated with clinical presentation of inflammatory bowel disease [1, 11].
Environmental factors are likely to contribute to IBD susceptibility; however, they are poorly understood and insufficiently described. The recent alarming rise in IBD incidence in the US points to changes in environmental factors rather than drastic alterations in allele frequency, since genetic remodeling could not occur over such a brief time . It seems plausible that environmental influences play as significant a role as their genetic counterparts and their combined actions dramatically affect disease presentation .
The objective of this study is to examine the gene-environment interaction which may influence the causation of IBD. We aimed to:
1. Study the incidence of SNP variants in NOD2, IL23r, OCTN1, and the IGR genes in a unique well-characterized rural Caucasian IBD population.
2. Examine haplotype frequencies in NOD2, IL23r, and IGR genes in both CD and UC patients.
3. Explore the SNPs' interaction, their possible effect on IBD susceptibility, and report a possible signature interaction model that could differentiate CD and UC patients.
4. Report risk factors that could serve as clinical predictors of IBD susceptibility