Inflammatory bowel disease (IBD) mainly includes ulcerative colitis (UC) and Crohn’s disease (CD). Both conditions are characterized by chronic inflammation of the gastrointestinal tract, with alternating periods of relapse and remission. Both forms of IBD involve an uncontrolled inflammatory process in the intestines, leading to worsening quality of life and requiring long-term medical and/or surgical intervention. Epidemiological and clinical studies suggest that the pathogenesis of inflammatory bowel disease is strongly linked to genetic predisposition. CD and UC are considered polygenic diseases in which familial clustering is observed in 5–10% of patients. Among genetic factors associated with IBD development, it has been found that many single nucleotide polymorphisms are associated with susceptibility to IBD progression. SNP can affect the production or function of a protein and thus affect the development of the disease. However, although the overall role of genes involved in the development of IBD is already in most cases known, as of today it is unclear how the SNPs in these genes affect cellular function, or how such changed cellular functions would contribute to the development of IBD. In the present work several selected polymorphisms in genes involved in IBD development are discussed.
- ulcerative colitis
- Crohn’s disease
- single-nucleotide polymorphisms
Inflammatory bowel disease (IBD) mainly includes ulcerative colitis (UC) and Crohn’s disease (CD). Both conditions are characterized by chronic inflammation of the gastrointestinal tract, with alternating periods of relapse and remission. Both forms of IBD involve an uncontrolled inflammatory process in the intestines, leading to worsening quality of life and requiring long-term medical and/or surgical intervention .
The pathomechanism of IBD is still not well explain, but evidence suggests that it results from perturbation of the homeostasis between the intestinal microbiota and the mucosal immune system, with the involvement of both genetic and environmental factors .
Ulcerative colitis is a chronic inflammatory disease, which mainly affects the large intestine. Typical clinical symptoms of UC are diarrhea, rectal bleeding, and abdominal pain. Nonspecific symptoms include fever, appetite loss, and weight loss. The disease significantly affects the patient’s quality of life due to its repeated remissions and relapses .
UC is characterized by recurring episodes of inflammation limited to the mucosal layer of the colon and practically invariably involves the rectum and may extend in a proximal and continuous fashion to involve other portions of the colon. Endoscopic features of inflammation include loss of vascular markings, granularity and friability of the mucosa, and erosions. In the setting of severe inflammation is observed deep ulcerations and spontaneous bleeding  (Figure 1). CD is described by transmural rather than superficial mucosal inflammation and by skip lesions rather than continuous disease .
In Crohn’s disease, inflammatory changes may occur in all parts of the gastrointestinal tract, from the oral cavity to the rectum, but are usually localized in the terminal segment of the small intestine, that is, the ileum. Inflammatory changes are discontinuous and affect the entire thickness of the intestinal wall. The most common symptoms of CD are abdominal pain, fever, weight loss, and diarrhea .
The commonly used instrument for evaluating the disease severity of CD is Crohn’s Disease Activity Indicator (CDAI; remission <150 score, severe disease >450 score). Whereas the Mayo score (0—normal, 3—severe disease) is used to assess the severity of ulcerative colitis .
The optimal goal of management in IBD is a durable period of steroid-free remission and the induction and subsequent maintenance of mucosal healing . Mucosal healing is predominantly defined by endoscopic assessment of intestinal inflammation and is referred to as the absence of mucosal ulcerations in CD, while in UC, an international consensus defined it as the absence of friability, blood, erosions, and ulcers of the gut mucosa. However, these indices allow to determine improvements of endoscopic lesions, even when the rather rigid endpoint of mucosal healing, and thereby the total disappearance of all mucosal ulcerations is not met  (Figure 2).
Many genes, which may be linked to IBD, are believed to be associated with microbiological defense mechanisms involving the epithelial barrier and innate, adaptive immune systems .
In the result of large cohort genome-wide association studies (GWAS) of cases and controls, over 200 IBD susceptibility loci have now been reported .
GWAS research was aimed at searching the SNPs that are over-represented in IBD patients when compared with healthy controls. SNPs that occurred more frequently in IBD patients are thus called disease-associated variants .
Among the genetic factors involved, there are several single-nucleotide polymorphisms (SNP) associated with the susceptibility to IBD progression. Many of these mutations regulate immune responses with several being enriched in immune cells, in particular CD4+ T cells and dendritic cells .
2. Single-nucleotide polymorphisms in innate and adaptive immunity genes in IBD
The latest research on genetics and immunology has confirmed that the innate immune system is of great importance in inducing intestinal inflammation , and the publication of Dudzińska et al. , “Single nucleotide polymorphisms in selected genes in inflammatory bowel disease,” is dedicated to this issue. This paper attempts to demonstrate polymorphisms
Today more than 60 polymorphisms of this gene have been identified; however, three common mutations Leu1007fsinsC, Arg702Trp, and Gly908Arg have been specifically associated with ileal involvement, stricturing complications, and earlier age of onset .
While the gene
Thus, it can be assumed that
Our research in the group of patients diagnosed with CD and UC is related to the occurrence of polymorphisms in the
The test material was blood collected from patients on an empty stomach after 12 hours of rest. In addition, medical history was taken with regard to the occurrence of extraintestinal symptoms and autoimmune diseases in the family. The family history of all subjects was negative. DNA was isolated using a QIAamp DNA Blood Mini Kit (QIAgen), followed by quantitative and qualitative evaluation of the isolated DNA samples.
The following primers were used for PCR: (F) GACTCTTTTGGCCTTTTCAGATT and (R) CCAATGGTCTTTTTTCCTTACTCC for
The PCR product was sequenced, and the sequences obtained were recorded in FASTA format. The nucleotide sequences of the
The size of the analyzed
Although numerous reports confirm that
One of the most common single-nucleotide polymorphisms of the
The size of the
Despite numerous reports indicating the presence of polymorphisms of the
3. The role of autophagy genes in the pathogenesis of IBD
Autophagy is a conserved lysosome-dependent catabolic process, degrading and recycling protein aggregates or damaged organelle. Autophagy affects the pathogenesis of IBD in multiple ways, including secretion of antimicrobial materials from Paneth cells, clearance of invading pathogens, presentation of antigen, or proinflammatory cytokine production by macrophages .
SNPs of autophagy genes such as autophagy-related gene 16 like 1 (
There is some overlap in these autophagy-related genetic variants in both CD and UC, but majority of the identified variants are more associated with ileal CD. Despite this association, the positive predictive value for disease development in individuals carrying autophagy variants is low because the
However, some of the studies show that a knock-in mouse model expressing A
Recent data GWAS identified the single-nucleotide polymorphism (SNP) rs13361189—a SNP lying immediately upstream of the autophagy gene
Other study demonstrated functional effects of the synonymous SNP rs10065172 (c.313C > T). This synonymous variant rs10065172 in
4. AHR and its role in regulating intestinal inflammation
Tryptophan metabolism plays important roles in the pathogenesis and therapeutics of IBD . Recent study investigates the interaction between Card9 and the gut microbiota in the generation of the microbiota-derived tryptophan metabolite .
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) .
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 .
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 .
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 .
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 .
In the latest research, Boyd et al.  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 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 .
5. SNPs in the multi-drug resistance 1 gene
Another of the genes whose mutations may play a role in the pathogenesis of IBD is multi-drug resistance 1 (
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 the distal small bowel and colon .
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 gastrointestinal tract and maintenance of intestinal homeostasis .
6. SNPs in the neutrophil cytosolic factor 4 gene
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 (
Researchers, Nuij et al. , have demonstrated that an IBD-associated SNP in the neutrophil cytosolic factor 4 (
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 symptoms and effects of the disease [37, 38].
CD and UC are considered polygenic diseases in which familial clustering is observed in 5–10% of patients .
Among genetic factors associated with IBD development, it has been found that many single-nucleotide polymorphisms are associated with susceptibility to IBD progression. SNP can affect the production or function of a protein and thus affect the development of the disease .
However, although the overall role of genes involved in the development of IBD is already in most cases known, as of today it is unclear how the SNPs in these genes affect cellular function, or how such changed cellular functions would contribute to the development of IBD . Therefore, further research is needed to demonstrate how gene polymorphism leads to the development of IBD.