Abstract
BackgroundCrohn's disease (CD) and ulcerative colitis (UC), the two main types of inflammatory bowel disease (IBD), are multifactorial conditions of unknown etiology. The objective of this study is to examine the combined gene-environment interactions influencing IBD susceptibility in a well-defined Caucasian cohort in rural mid-America.MethodsPatients were diagnosed to have CD or UC using conventional radiologic, endoscopic, and/or histopathologic findings. Histological diagnosis was made by a single specialist gastrointestinal pathologist with a particular interest in IBD. Information regarding cigarette smoke exposure was obtained by administration of the Behavioral Risk Factor Surveillance System Survey (BRFSS) to all patients. Genomic DNA was extracted from peripheral blood leukocytes, and polymerase chain reaction (PCR) amplification and genotyping were performed for 11 Single Nucleotide Polymorphisms (SNP) in NOD2, IL23r, OCTN1 genes along with IGR.ResultsOur cohort consists of 1196 patients: 435 controls, 485 CD patients, and 276 UC patients. Only patients with genotype data for at least 7 of 11 SNPs were included in our data analysis. The control groups for all 11 SNPs were in Hardy-Weinberg Equilibrium. In genotype-association SNP analysis, all NOD2 SNPs (rs5743293, rs2066844, rs2066845) and the IL23r SNP (rs11465804) showed a significant association to IBD (p < 0.03). A multiple gene-interaction analysis showed an association between NOD2 and IL23r with UC (p = 0.04). There were no associations between any OCTN1 and IGR SNPs and IBD in this cohort. A multivariable logistic regression analysis showed that female gender, "current" or "former" smoking status, family history of IBD, and NOD2 SNP minor alleles were associated with CD.ConclusionIBD remains to be challenging to properly diagnose, characterize, and treat. Our study proposes a combined genetic, phenotypic, and environmental approach in an attempt to better understand IBD. Previously demonstrated associations between OCTN1 and IGR and IBD were not confirmed.
Highlights
Crohn’s disease (CD) and ulcerative colitis (UC), the two main types of inflammatory bowel disease (IBD), are multifactorial conditions of unknown etiology
A number of studies have shown an association between IBD susceptibility and the nucleotide-binding oligomerization domain 2 gene (NOD2, known as CARD15), interleukin-23 receptor gene (IL23r), organic cation transporter novel type 1 gene (OCTN1), and the intergenic region (IGR) variants [6,7,8,9]
Population Description For the purposes of our genetic and clinical comparisons, we only examined the Caucasian subset in order to maintain statistical and descriptive homogeneity
Summary
Crohn’s disease (CD) and ulcerative colitis (UC), the two main types of inflammatory bowel disease (IBD), are multifactorial conditions of unknown etiology. Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gastrointestinal (GI) tract, comprised of Crohn’s disease (CD) and ulcerative colitis (UC). 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[3]. 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, the mechanism that increases disease susceptibly is poorly understood. 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]
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