**4. AHR and its role in regulating intestinal inflammation**

Tryptophan metabolism plays important roles in the pathogenesis and therapeutics of IBD [30]. Recent study investigates the interaction between Card9 and the gut microbiota in the generation of the microbiota-derived tryptophan metabolite [2].

Tryptophan can be metabolized either by the gut bacteria into indole derivatives, such as indole-3-acetic acid (IAA), or by host cells into kynurenine (Kyn) via indoleamine 2,3-dioxygenase 1 (IDO1) [31].

Kyn derived from host metabolism, and indole-derived tryptophan metabolites produced by gut microbiota are endogenous ligands of aryl hydrocarbon receptor (AHR), an important regulator of immune response. AHR disturbance results in disordered immune responses, including decreased Treg cell levels and increased TNF-α levels, and a modified timeframe of IL-10 and IL-12 secretion. Elevated the serum levels of tryptophan metabolites including kynurenic acid (KA) is potential aryl hydrocarbon receptor (AHR) ligands to impact colitis. Several findings suggest that KA and other tryptophan metabolites inhibit the colonic inflammation [30].

Although polymorphisms in AHR have not yet been associated with IBD, AHR is known to play a central role in the regulation of intestinal inflammation and is upregulated in the inflamed gut [12].

SNPs are common, single-nucleotide genetic variants that can influence protein function, protein stability, or gene expression. Genome-wide association studies and candidate gene studies have identified SNPs near AHR target genes that are significantly associated with AHR-regulated phenotypes, such as psoriasis (CYP1A1) and systemic lupus erythematous (CYP1A1). These findings suggest that SNPs near AHR-binding sites might impact AHR target gene expression and contribute to individual variation in disease risk and pharmacotherapy phenotypes. Of interest, that SNP is distant from an AHR response element (AHRE) but still influences AHR binding and CYP1A1 expression after AHR agonist treatment, which suggests that it may influence the stability of the AHR complex and its ability to regulate CYP1A1 gene expression [32].

It is also important that over the last years, some functions of noncoding DNA have been discovered, and the role of regulatory sequences in transcriptional regulation, development of the disease process, and determination of cell type specificity is nowadays widely appreciated [11].

In the latest research, Boyd et al. [33] presented Cap Analysis of Gene Expression (CAGE) analysis on biopsies from the descending colon from 94 IBD patients and controls. These data enabled annotation of IBD-regulated enhancers and transcription start sites (TSSs) and characterization of IBD-associated

**47**

**7. Conclusion**

*Single-Nucleotide Polymorphisms in Inflammatory Bowel Disease*

**5. SNPs in the multi-drug resistance 1 gene**

the distal small bowel and colon [35].

patients gave conflicting results [34].

**6. SNPs in the neutrophil cytosolic factor 4 gene**

DMBT1 in intestinal epithelial cells in IBD [27].

symptoms and effects of the disease [37, 38].

SNPs in such regions. Researchers have shown that clear overrepresentation of IBD-associated SNPs in both IBD upregulated enhancer and promoter regions also presented regions that had the largest IBD heritability enrichment compared to other genomic regions. The results of these studies carried out many resources for

interpretation of the functional impact of noncoding genetic variants [33].

cells and epithelial surfaces, including the epithelium of GI tract [34].

gastrointestinal tract and maintenance of intestinal homeostasis [34].

Another of the genes whose mutations may play a role in the pathogenesis of IBD is multi-drug resistance 1 (*MDR1)* gene. *MDR1* encodes P-glycoprotein 170 (P-gp), an ATP-dependent drug transport efflux pump, which highly expressed in many

In the gut, P-gp is expressed on the apical surfaces of the superficial columnar epithelial cells in the intestine with the levels of expression gradually rising from the duodenum to the distal parts of the intestine with the highest levels of expression in

It is now known that substrates for the P-gp pump include a variety of structurally and pharmacologically distinct hydrophobic compounds, such as drugs and toxins, and P-gp might also play a critical role in host bacterial interactions in the

SNPs of *MDR1* can occur naturally in humans, but some of them were related to altered P-gp expression and function. Three most common SNPs that have been repeatedly shown to predict changes in the function of P-gp are synonymous SNPs C1236T (rs1128503) in exon 12 and C3435T (rs1045642) in exon 26 and nonsynonymous, triallelic SNP G2677T/A (Ala893Ser/Thr or rs2032582) located in exon 21. In German, studies have been shown that both T allele and TT genotype of C3435T polymorphism were more frequently present among UC subjects, and the association of G allele of 2677 and IBD was also shown in North American study. However, further research that analyzed different allele combinations of those SNPs in IBD

More recently, GWAS has identified a number of new genetic susceptibility factors for IBD. Of these, new candidates have confirmed the association of the proinflammatory cytokine interleukin-23 receptor subunit (IL-23R) with CD and UC and a second gene, neutrophil cytosolic factor 4 (*NCF4*) with CD [36].

Researchers, Nuij et al. [27], have demonstrated that an IBD-associated SNP in the neutrophil cytosolic factor 4 (*NCF4*) gene results in a decreased antimicrobial function of granulocytes, as demonstrated by a reduced production of reactive oxygen species by these cells [27]. Moreover, as recently shown, SNPs in the interleukin 23 receptor gene (IL23R) have affected to express the anti-microbial peptide

Chronic inflammatory bowel disease is a subject of great interest among researchers because the pathomechanism of these conditions is difficult to explain, and thus far there is no optimal therapeutic process completely eliminating the

*DOI: http://dx.doi.org/10.5772/intechopen.92051*

*The Recent Topics in Genetic Polymorphisms*

However, some of the studies show that a knock-in mouse model expressing A*TG16L1* T300A does not develop spontaneous inflammation, but it exhibits morphological defects in both Paneth cells and goblet cells, and the presence of the T300A mutation in *ATG16L1* leads to aberrant functionality of Paneth cells. These findings indicate a close relationship between *ATG16L1* variants and Paneth cells [15]. Recent data GWAS identified the single-nucleotide polymorphism (SNP) rs13361189—a SNP lying immediately upstream of the autophagy gene *IRGM*, and many studies have investigated *IRGM* gene variants both in adult and pediatric and in UC, confirming its role in the IBD pathogenesis. It was shown that SNP rs13361189, the deletion allele, modulated the expression of *IRGM* in transformed cells [29]. Other study demonstrated functional effects of the synonymous SNP rs10065172 (c.313C > T). This synonymous variant rs10065172 in *IRGM* alters a binding site for certain microRNAs, miR-196, and causes deregulation of *IRGM-*

dependent xenophagy of bacteria in patients with CD [29].

indoleamine 2,3-dioxygenase 1 (IDO1) [31].

upregulated in the inflamed gut [12].

specificity is nowadays widely appreciated [11].

**4. AHR and its role in regulating intestinal inflammation**

Tryptophan metabolism plays important roles in the pathogenesis and therapeutics of IBD [30]. Recent study investigates the interaction between Card9 and the gut microbiota in the generation of the microbiota-derived tryptophan metabolite [2]. Tryptophan can be metabolized either by the gut bacteria into indole derivatives, such as indole-3-acetic acid (IAA), or by host cells into kynurenine (Kyn) via

Kyn derived from host metabolism, and indole-derived tryptophan metabolites produced by gut microbiota are endogenous ligands of aryl hydrocarbon receptor (AHR), an important regulator of immune response. AHR disturbance results in disordered immune responses, including decreased Treg cell levels and increased TNF-α levels, and a modified timeframe of IL-10 and IL-12 secretion. Elevated the serum levels of tryptophan metabolites including kynurenic acid (KA) is potential aryl hydrocarbon receptor (AHR) ligands to impact colitis. Several findings suggest that KA and other tryptophan metabolites inhibit the colonic inflammation [30]. Although polymorphisms in AHR have not yet been associated with IBD, AHR is known to play a central role in the regulation of intestinal inflammation and is

SNPs are common, single-nucleotide genetic variants that can influence protein function, protein stability, or gene expression. Genome-wide association studies and candidate gene studies have identified SNPs near AHR target genes that are significantly associated with AHR-regulated phenotypes, such as psoriasis (CYP1A1) and systemic lupus erythematous (CYP1A1). These findings suggest that SNPs near AHR-binding sites might impact AHR target gene expression and contribute to individual variation in disease risk and pharmacotherapy phenotypes. Of interest, that SNP is distant from an AHR response element (AHRE) but still influences AHR binding and CYP1A1 expression after AHR agonist treatment, which suggests that it may influence the stability of

It is also important that over the last years, some functions of noncoding DNA

have been discovered, and the role of regulatory sequences in transcriptional regulation, development of the disease process, and determination of cell type

In the latest research, Boyd et al. [33] presented Cap Analysis of Gene Expression (CAGE) analysis on biopsies from the descending colon from 94 IBD patients and controls. These data enabled annotation of IBD-regulated enhancers and transcription start sites (TSSs) and characterization of IBD-associated

the AHR complex and its ability to regulate CYP1A1 gene expression [32].

**46**

SNPs in such regions. Researchers have shown that clear overrepresentation of IBD-associated SNPs in both IBD upregulated enhancer and promoter regions also presented regions that had the largest IBD heritability enrichment compared to other genomic regions. The results of these studies carried out many resources for interpretation of the functional impact of noncoding genetic variants [33].
