Elsevier

Gene Reports

Volume 20, September 2020, 100735
Gene Reports

What are the effects of IL-1β (rs1143634), IL-17A promoter (rs2275913) and TLR4 (rs4986790) gene polymorphism on the outcomes of infection with H. pylori within as Iranian population; A systematic review and meta-analysis

https://doi.org/10.1016/j.genrep.2020.100735Get rights and content

Abstract

Helicobacter pylori (H. pylori) is one of the most important etiologic agents for peptic ulcer and gastric cancer. Since <25% of H. pylori infected people have gastrointestinal disorders, the precise molecular mechanisms of H. pylori pathogenesis have not been identified. Despite the above explanation, studies have demonstrated that infection with H. pylori leads to the formation of active chronic gastritis lesions, which in turn can progress to acute gastritis, peptic ulcer or gastric atrophy, and ultimately gastric cancer. Depending on several factors such as bacterial virulence factors, immune response, host genetic and other conditions such as gastric acid secretion and type of nutrition, the pathologic effects of this bacterium can be different. Recent studies have shown that the single nucleotide polymorphisms (SNPs) have a critical role in the alternation of body responses and play a pivotal role in the outcomes of H. pylori infection. However, due to their prominent role in immune-pathogenesis of this bacterium, SNPs of IL-1β, IL-17A promoter and TLR4 genes has been extensively considered and can be regarded as a prognostic factor for susceptibility to peptic ulcer or gastric cancer diseases. In the present study, a meta-analysis was performed on the information of 1307 Iranian patients with gastritis, peptic ulcers and gastric cancer to determine the role of each of the SNPs in the formation of peptic ulcers and gastric cancer.

Introduction

Helicobacter pylori (H. pylori) is a gram-negative, microaerophilic, spiral-shaped bacterium that inhabits in the human gastric sub-mucosa tissue, and according to literature, it has been colonized in over 50% of the population worldwide (Keikha et al., 2019). These bacteria are the etiologic cause of gastroduodenal disorders including gastritis, gastric and duodenal ulcers, gastric adenocarcinoma and mucosa-associated lymphoid tissue lymphoma (MALT) (Keikha et al., 2019; Yousefi et al., 2019). The colonization pattern with H. pylori varies in different geographic regions; the prevalence of H. pylori infection in the Western countries is about 10–60%, while in some developing countries it is reported around 100% (Graham et al., 1991). However, most of colonized individuals with H. pylori are as asymptomatic carriers and only 10–20% of people would be affected by peptic ulcers, as well as 1% by gastric cancer and less than 1% by MALT (Czinn and Blanchard, 2011). It should be noted that according to the WHO statement, H. pylori has been identified as Class-I carcinogen and its eradication will reduce the rate of gastric cancer (Yousefi et al., 2019; Czinn and Blanchard, 2011). Although gastric cancer is currently considered as one of the most common cancers in the world, but, till the occurrence of gastric cancer, infected people with H. pylori remain asymptomatic. Due to this poor prognosis, it is essential to identify the H. pylori infection in individuals and also determine the risk factors for the susceptibility to gastric cancer (Czinn and Blanchard, 2011; Marrelli et al., 2009). Based on studies, the patients who have the pathologic feature of antral-predominant gastritis, often progress to gastritis and peptic ulcers, while those affected by corpus-predominant gastritis develop to gastric atrophy, intestinal metaplasia, and ultimately gastric adenocarcinoma (Suerbaum and Michetti, 2002). However, the precise mechanism of pathogenicity this mysterious microbe has not yet been elucidated. The H. pylori genome has about 1.65 million base pairs, which encode 1500 different proteins, of which, only a very limited number have been identified. Moreover, the host immune responses, genetic host condition and the environment are also involved in this trend (Suerbaum and Michetti, 2002; Tomb et al., 1997). The first detectable pathologic phenomenon in the early stages of H. pylori infection is the chronic active gastritis which can be observed in all the H. pylori positive subjects (Kusters et al., 2006). Upon entrance into the stomach, H. pylori usually binds to the gastric epithelium cells through its surface proteins, including BabA, SabA, SabB, AlpA, and AlpB. Subsequent to the binding and formation of type IV secretion system (T4SS), it induces the production of pro-inflammatory cytokines e.g. IL-8, IL-1, IL-6, TNF-α, and RANTES (CCL5), which in turn are caused the infiltration of the inflammatory cells, especially neutrophils and macrophages to the site of infection (Kusters et al., 2006; Backert and Clyne, 2011). In addition, the bacterium can also stimulate the NF-κB and AP-1 signaling pathways via its lipopolysaccharide (LPS) component by binding to Toll-like receptors (TLRs) 2 and 4, and since the LPS is a Lewis-like antigen, it provides the basis for the production of autoantibodies against the canaliculi and H/K ATPase pump, and consequently autoimmune diseases (Appelmelk et al., 1998; Raghavan et al., 2003). During infection, and following the recruitment of lymphocytes in the infection site, bacteria use of several mechanisms for evading from the immune system. The T helper 1 (Th1) cells through the production of some cytokines such as IFN-γ, TNF-α, and IL-1β cause tissue destruction and increase of gastric acid secretion and is considered a risk factor for the peptic ulcer, whereas Th2 and T regulatory (T reg) cells induce anergy phenomenon and are considered as basis for the gastric atrophy and cancer by suppressing the immune activity (Lohoff et al., 2000; Gabitass et al., 2011; Whary et al., 2005). Nevertheless, intragastric distribution and final outcomes of chronic gastritis are unpredictable and the factors such as the colonizing strain, host genetics, immune responses, host conditions such as the rate of gastric acid secretion and environmental conditions are involved and effective in the process of immune-pathogenesis of H. pylori infection (Yousefi et al., 2019; Kusters et al., 2006).

According to recent studies, IL-1β is one of the most important cytokines that has a pro-inflammatory response in infection and also stimulates inflammation (Sutton et al., 2000). Infection with H. pylori induces IL-1β production, and several studies have demonstrated that the infected individuals with H. pylori have higher IL-1β levels than the control groups (Lee et al., 2003). Based on the available evidence, IL-1β is able to inhibit gastric acid secretion and leads to hypochlorhydria transition, which results to the increased colonization of H. pylori in the stomach (Wilson and Crabtree, 2007). The decreased gastric acid secretion and hypochlorhydria can be the origin for the gastric atrophy and gastric cancer (Wilson and Crabtree, 2007; Garza-González et al., 2005). Howbeit, IL-1β modulates immune system responses and leads to the increase of expression of IL-6 and IL-12, which may be a trigger for peptic ulcer (Zhang et al., 2007). Meanwhile, it has been found that the polymorphisms of this gene, including −511 (NT-022135.14: g.2392610C > T), −31 (NT-022135.14: g.2302130C > T), and + 3953 (NT-022135.14: g.2306115C > T) can be resulted to the change of IL-1β expression rate in the patients and affects the final outcomes of infection with H. pylori (Takhsh et al., 1992; Stokkers et al., 1998). To date, numerous studies have been performed on the role of IL-1β gene polymorphisms in infections and cancers, in particular gastric and colorectal cancers. It seems that some polymorphisms increase the IL-1β gene expression and thus the risk of atrophy of gastric tissue (Lu et al., 2005). According to Elomar et al., the individuals with IL-1β + 3954TT who are infected with H. pylori infection are susceptible to the peptic ulcers and gastritis (El-Omar et al., 2000). Another cytokine, IL-17, also is one of the most important mediators of the immune system which regulates both innate and adaptive immunity responses and affects a wide range of host cell lines (Bagheri et al., 2015a). IL-17, along with TNF-α, IL-1β and IL-10, regulates inflammatory processes in the gastric mucosa and is associated with an increased risk of peptic ulcer and gastric cancer (Bagheri et al., 2015a; Yuzhalin, 2011). Based on the recent studies, it has been found that the gastric cancer patients have higher rate of Th17 compared to healthy individuals (Zhang et al., 2008). In addition, the IL-17 gene promoter is in a close contact with Nuclear Factor Activated T cell binding motifs (NFAT), therefore different polymorphisms in this region lead to structural deformation and alteration in the transcription, affecting the dependent responses to the T cells. Guanine and adenine polymorphisms have increased the risk of gastric cancer in the Japanese and Chinese populations (Wu et al., 2010; Liu et al., 2004; Shibata et al., 2009). TLR4 is one of the components of the innate immune system which detects the LPS of gram-negative bacteria and stimulates a pro-inflammatory response through NF-κB signaling pathway (Schmaußer et al., 2005). Evidence has shown that TLR4 mRNA levels increase in the H. pylori-infected gastric epithelial cells (Su et al., 2003). Based on the relevant studies, two types of polymorphisms are identified at positions 299 and 896 of TLR4 gene and some of its polymorphisms decrease the response to LPS (Arbour et al., 2000; Norata et al., 2005). Different polymorphisms of this gene increase the risk of septic shock, malaria, atherosclerosis, and peptic ulcer in patients infected with H. pylori (Liu et al., 2016; Kiechl et al., 2003; Mockenhaupt et al., 2006; Lorenz et al., 2001). Regarding the key role of IL-1β, IL17 and TLR4 genes in the pathogenesis of H. pylori and the determinant role of polymorphisms of these genes in the outcomes of H. pylori infection, we considered and pooled all the available articles from the Iranian patients. The present meta-analysis study was done for assessing the morphisms of these genes and their association with the gastrointestinal disorders caused by the infection with H. pylori in Iranian population.

Section snippets

Search strategy

Using the PRISMA criteria, the articles were searched, and have been shown in the flowchart in Fig. 1. At first, the selective documents were independently collected by two authors through searching the PubMed, Scopus, Embase, Google Scholar, and also Iranian medical databases. The articles were searched by combining the keywords such as Helicobacter pylori, polymorphism, IL-1β, IL-17A, TLR4, mutation, variation, single nucleotide polymorphism or SNP, without considering the language and date

Results

The initial search revealed 149 studies, out of which 10 case control studies were included in the present analysis based on the eligibility criteria, after elimination of duplicates and irrelevant articles (Fig. 1).

In this study, a population including both 1307 infected cases and 1787 individuals as the controls were evaluated for the required purpose. Approximately 67.87% of the patients were male and the mean age in the “case” group was 49.7 ± 2. None of the studies had simultaneously

Discussion

The effect of SNPs on IL-1β, IL-17A promoter, and TLR4 genes in relation to H. pylori pathogenesis has not yet been fully elucidated. Following the alteration of spatial shape of DNA and changing the affinity of the regulatory proteins, the created polymorphisms may dysregulate the responses of the host immunity system, and eventually promote the patient's pathologic conditions to the peptic ulcer or gastric cancer (Ying et al., 2016). The present study was the first meta-analysis regarding the

Declaration of competing interest

The authors of the manuscript have no conflict of interest.

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