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Gobert AP, Wilson KT. Induction and Regulation of the Innate Immune Response in Helicobacter pylori Infection. Cell Mol Gastroenterol Hepatol 2022; 13:1347-1363. [PMID: 35124288 PMCID: PMC8933844 DOI: 10.1016/j.jcmgh.2022.01.022] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Revised: 01/25/2022] [Accepted: 01/25/2022] [Indexed: 12/30/2022]
Abstract
Gastric cancer (GC) is the fifth most common cancer and the fourth most common cause of cancer-related death worldwide. The intestinal type of GC progresses from acute to chronic gastritis, multifocal atrophic gastritis, intestinal metaplasia, dysplasia, and carcinoma. Infection of the stomach by Helicobacter pylori, a Gram-negative bacterium that infects approximately 50% of the world's population, is the causal determinant that initiates the gastric inflammation and then disease progression. In this context, the induction of the innate immune response of gastric epithelial cells and myeloid cells by H. pylori effectors plays a critical role in the outcome of the infection. However, only 1% to 3% of infected patients develop gastric adenocarcinoma, emphasizing that other mechanisms regulate the localized non-specific response, including the gastric microbiota and genetic factors. This review summarizes studies describing the factors that induce and regulate the mucosal innate immune response during H. pylori infection.
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Affiliation(s)
- Alain P Gobert
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Nashville, Tennessee; Center for Mucosal Inflammation and Cancer, Nashville, Tennessee; Program in Cancer Biology, Nashville, Tennessee.
| | - Keith T Wilson
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Nashville, Tennessee; Center for Mucosal Inflammation and Cancer, Nashville, Tennessee; Program in Cancer Biology, Nashville, Tennessee; Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee; Veterans Affairs Tennessee Valley Healthcare System, Nashville, Tennessee.
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Association of Helicobacter pylori Infection and Host Cytokine Gene Polymorphism with Gastric Cancer. Can J Gastroenterol Hepatol 2021; 2021:8810620. [PMID: 34136433 PMCID: PMC8177986 DOI: 10.1155/2021/8810620] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2020] [Accepted: 05/18/2021] [Indexed: 12/13/2022] Open
Abstract
The global cancer burden of new cases of various types rose with millions of death in 2018. Based on the data extracted by GLOBOCAN 2018, gastric cancer (GC) is the third leading cause of mortality related to cancer across the globe. Carcinogenic or oncogenic infections associated with Helicobacter pylori (Hp) are regarded as one of the essential risk factors for GC development. It contributes to the increased production of cytokines that cause inflammation prior to their growth in the host cells. Hp infections and specific types of polymorphisms within the host cells encoding cytokines are significant contributors to the host's increased susceptibility in terms of the development of GC. Against the backdrop of such an observation is that only a small portion of the cells infected can become malignant. The diversities are a consequence of the differences in the pathogenic pathway of the Hp, susceptibility of the host, environmental conditions, and interplay between these factors. It is evident that hosts carrying cytokine genes with high inflammatory levels and polymorphism tend to exhibit an increased risk of development of GC, with special emphasis being placed on the host cytokines gene polymorphisms.
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Jonaitis P, Kupcinskas L, Kupcinskas J. Molecular Alterations in Gastric Intestinal Metaplasia. Int J Mol Sci 2021; 22:ijms22115758. [PMID: 34071181 PMCID: PMC8199079 DOI: 10.3390/ijms22115758] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 05/24/2021] [Accepted: 05/26/2021] [Indexed: 02/07/2023] Open
Abstract
Gastric cancer (GC) remains one of the most common causes of mortality worldwide. Intestinal metaplasia (IM) is one of the preneoplastic gastric lesions and is considered an essential predisposing factor in GC development. Here we present a review of recent most relevant papers to summarize major findings on the molecular alterations in gastric IM. The latest progress in novel diagnostic methods allows scientists to identify various types of molecular alterations in IM, such as polymorphisms in various genes, changes in the expression of micro-RNAs and long noncoding RNAs, and altered microbiome profiles. The results have shown that some of these alterations have strong associations with IM and a potential to be used for screening, treatment, and prognostic purposes; however, one of the most important limiting factors is the inhomogeneity of the studies. Therefore, further large-scale studies and clinical trials with standardized methods designed by multicenter consortiums are needed. As of today, various molecular alterations in IM could become a part of personalized medicine in the near future, which would help us deliver a personalized approach for each patient and identify those at risk of progression to GC.
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Yan LR, Lv Z, Jing JJ, Yuan Y, Xu Q. Single nucleotide polymorphisms of whole genes and atrophic gastritis susceptibility:a systematic review and meta-analysis. Gene 2021; 782:145543. [PMID: 33667608 DOI: 10.1016/j.gene.2021.145543] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Revised: 01/29/2021] [Accepted: 02/18/2021] [Indexed: 12/16/2022]
Abstract
BACKGROUND Atrophic gastritis (AG) is one of the important precancerous lesions of gastric cancer. Single nucleotide polymorphisms (SNPs) are closely related to AG susceptibility. However, the research conclusions on the predictive potential of SNPs are inconsistent. The study aims to retrospect the association between SNPs of whole genes and AG risk by meta-analysis. MATERIALS AND METHODS Up to April 29, 2020, a systematic literature search for the relationship of SNPs with AG susceptibility was performed utilizing PubMed, Web of Science and Chinese National Knowledge Infrastructure. The overall and stratified meta-analyses on extracted data were conducted by Stata11.2. RESULTS 33 case-control studies were enrolled containing 9951 AG patients and 17,252 healthy controls, and 17 SNPs in 12 different genes were systematically reviewed. The results indicated that 12 genes could be categorized based on their functions, including immune response, cell proliferation and apoptosis, and DNA damage repair. For the SNPs in immune response-related genes, the C allele of TLR1 rs4833095 T/C increased AG risk to 1.21-fold and the recessive model of TLR4 rs11536878 in the TLR gene family decreased AG susceptibility to 0.48-fold. The variant alleles of IL-10 rs1800871 (OR = 1.21) and IL-8 rs4073 (OR = 1.22) in the IL gene family were positively associated with AG risk. PSCA rs2294008 enhanced AG risk in all genetic models. SNPs associated with AG susceptibility were mainly focused on immune response-related genes. CONCLUSION These SNPs related to immune response could influence on AG risk and have potential to be AG predictive biomarkers. It is worth noting that the number of studies for each SNPs were insufficient due to the limited published researches and updated meta-analysis needs to be performed based on extensive relevant studies for more reliable results.
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Affiliation(s)
- Li-Rong Yan
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Affiliated Hospital of China Medical University, Key Laboratory of Cancer Etiology and Prevention, China Medical University, Liaoning Provincial Education Department, Shenyang 110001, China
| | - Zhi Lv
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Affiliated Hospital of China Medical University, Key Laboratory of Cancer Etiology and Prevention, China Medical University, Liaoning Provincial Education Department, Shenyang 110001, China
| | - Jing-Jing Jing
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Affiliated Hospital of China Medical University, Key Laboratory of Cancer Etiology and Prevention, China Medical University, Liaoning Provincial Education Department, Shenyang 110001, China
| | - Yuan Yuan
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Affiliated Hospital of China Medical University, Key Laboratory of Cancer Etiology and Prevention, China Medical University, Liaoning Provincial Education Department, Shenyang 110001, China.
| | - Qian Xu
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Affiliated Hospital of China Medical University, Key Laboratory of Cancer Etiology and Prevention, China Medical University, Liaoning Provincial Education Department, Shenyang 110001, China.
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Negovan A, Iancu M, Fülöp E, Bănescu C. Helicobacter pylori and cytokine gene variants as predictors of premalignant gastric lesions. World J Gastroenterol 2019; 25:4105-4124. [PMID: 31435167 PMCID: PMC6700706 DOI: 10.3748/wjg.v25.i30.4105] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2019] [Revised: 07/12/2019] [Accepted: 07/19/2019] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer remains the third leading cause of mortality from cancer worldwide and carries a poor prognosis, due largely to late diagnosis. The importance of the interaction between Helicobacter pylori (H. pylori) infection, the main risk factor, and host-related genetic factors has been studied intensively in recent years. The genetic predisposition for non-hereditary gastric cancer is difficult to assess, as neither the real prevalence of premalignant gastric lesions in various populations nor the environmental risk factors for cancer progression are clearly defined. For non-cardiac intestinal-type cancer, identifying the factors that modulate the progression from inflammation toward cancer is crucial in order to develop preventive strategies. The role of cytokines and their gene variants has been questioned in regard to non-self-limiting H. pylori gastritis and its evolution to gastric atrophy and intestinal metaplasia; the literature now includes various and non-conclusive results on this topic. The influence of the majority of cytokine single nucleotide polymorphisms has been investigated for gastric cancer but not for preneoplastic gastric lesions. Among the investigated gene variants onlyIL10T-819C, IL-8-251, IL-18RAP917997, IL-22 rs1179251, IL1-B-511, IL1-B-3954, IL4R-398 and IL1RN were identified as predictors for premalignant gastric lesions risk. One of the most important limiting factors is the inhomogeneity of the studies (e.g., the lack of data on concomitant H. pylori infection, methods used to assess preneoplastic lesions, and source population). Testing the modifying effect of H. pylori infection upon the relationship between cytokine gene variants and premalignant gastric lesions, or even testing the interaction between H. pylori and cytokine gene variants in multivariable models adjusted for potential covariates, could increase generalizability of results.
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Affiliation(s)
- Anca Negovan
- Department of Clinical Science-Internal Medicine, University of Medicine, Pharmacy, Sciences and Technology of Târgu Mureș, Mureș 540139, Romania
| | - Mihaela Iancu
- Department of Medical Informatics and Biostatistics, “Iuliu Hațieganu” University of Medicine and Pharmacy, Cluj-Napoca, Cluj 400349, Romania
| | - Emőke Fülöp
- Department of Morphological Sciences, Histology, University of Medicine, Pharmacy, Sciences and Technology of Târgu Mureș, Mureș 540139, Romania
| | - Claudia Bănescu
- Genetics Laboratory, Center for Advanced Medical and Pharmaceutical Research, University of Medicine, Pharmacy, Sciences and Technology of Târgu Mureș, Mureș 540139, Romania
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Martínez-Campos C, Torres-Poveda K, Camorlinga-Ponce M, Flores-Luna L, Maldonado-Bernal C, Madrid-Marina V, Torres J. Polymorphisms in IL-10 and TGF-β gene promoter are associated with lower risk to gastric cancer in a Mexican population. BMC Cancer 2019; 19:453. [PMID: 31092242 PMCID: PMC6518715 DOI: 10.1186/s12885-019-5627-z] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2018] [Accepted: 04/23/2019] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Helicobacter pylori infection is recognized as the main risk factor for gastric cancer (GC), the fifth most common neoplasia worldwide. H. pylori interacts with the immune system, disrupting the cytokine network and inducing chronic inflammation. This work aimed to evaluate the association between single nucleotide polymorphisms (SNPs) in selected cytokine gene promoters and GC. METHODS The study included 359 subjects, 125 GC patients, 109 intestinal metaplasia (IM) patients and 125 asymptomatic controls. DNA was extracted from white blood cells and nine SNPs in cytokine gene promoters were genotyped using predesigned 5'-endonulease assays. The association of the SNPs with IM and GC was evaluated using multinomial regression models. RESULTS Both genotypes, TC (OR = 0.51, 95% CI = 0.27-0.98) and TT (OR = 0.42, 95% CI = 0.20-0.91) in the locus - 509 of the TGF-β promoter were significantly associated with GC. The TT genotype in the locus - 819 of the IL-10 promoter was also significantly associated with GC (OR = 0.37, 95% CI = 0.17-0.81). No significant association was found with SNPs IL-4 -590 T/C (rs1800629), IL-6 -573G/C (rs1800796), IL-10 -592C/A (rs1800872), IL-10 -1082A/G (rs1800896), and, IFN-γ -1615C/T (rs2069705). CONCLUSIONS SNPs in TGFβ (- 509 C/T, rs1800469) and IL-10 (- 819 C/T, rs1800871) promoters were associated with a lower risk for GC in a Mexican population.
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Affiliation(s)
- Cecilia Martínez-Campos
- Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC, USA
| | - Kirvis Torres-Poveda
- Dirección de Infecciones Crónicas y Cáncer. Centro de Investigación sobre Enfermedades Infecciosas, Instituto Nacional de Salud Pública, Cuernavaca, Morelos, Mexico.,CONACyT-Instituto Nacional de Salud Pública, Cuernavaca, Morelos, Mexico
| | - Margarita Camorlinga-Ponce
- Unidad de Investigación en Enfermedades Infecciosas, UMAE Pediatría, CMN S-XXI, IMSS, Mexico City, Mexico
| | - Lourdes Flores-Luna
- Centro de investigación en Salud Poblacional, Instituto Nacional de Salud Pública, Cuernavaca, Morelos, Mexico
| | - Carmen Maldonado-Bernal
- Laboratorio de Investigación en Inmunología y Proteómica, Hospital Infantil de Mexico Federico Gómez, SS, Mexico City, Mexico
| | - Vicente Madrid-Marina
- Dirección de Infecciones Crónicas y Cáncer. Centro de Investigación sobre Enfermedades Infecciosas, Instituto Nacional de Salud Pública, Cuernavaca, Morelos, Mexico.
| | - Javier Torres
- Unidad de Investigación en Enfermedades Infecciosas, UMAE Pediatría, CMN S-XXI, IMSS, Mexico City, Mexico.
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Wang YM, Li ZX, Tang FB, Zhang Y, Zhou T, Zhang L, Ma JL, You WC, Pan KF. Association of genetic polymorphisms of interleukins with gastric cancer and precancerous gastric lesions in a high-risk Chinese population. Tumour Biol 2016; 37:2233-42. [PMID: 26358252 DOI: 10.1007/s13277-015-4022-x] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2015] [Accepted: 08/31/2015] [Indexed: 12/20/2022] Open
Abstract
Helicobacter pylori (H. pylori) infection and cytokine-mediated inflammatory responses play important roles in gastric cancer (GC) pathogenesis. To investigate an association between genetic polymorphisms in interleukin (IL)-1β, IL-4R, IL-8, IL-10, IL-16, IL-18RAP, IL-22, and IL-32 and risks of GC and its precursors, a population-based study was conducted in Linqu County. Genotypes were determined by Sequenom MassARRAY platform in 132 GC cases and 1198 subjects with gastric lesions. The H. pylori status was determined by (13)C-urea breath test ((13)C-UBT) or enzyme-linked immunosorbent assay (ELISA). Among 11 candidate single nucleotide polymorphisms (SNPs), subjects carrying IL-18RAP rs917997 AA genotype were associated with risk of GC [adjusted odds ratio (OR) = 1.83, 95 % confidence interval (CI) 1.14-2.92] or chronic atrophic gastritis (CAG; OR = 1.55, 95 % CI 1.07-2.24). The risk of GC was also increased in subjects carrying IL-32 rs2015620 A allele (AA + AT; OR = 1.92, 95 % CI 1.09-3.39). Moreover, elevated risks of CAG (OR = 2.64, 95 % CI 1.89-3.69), intestinal metaplasia (IM; OR = 5.58, 95 % CI 3.86-8.05), and dysplasia (DYS; OR = 1.64, 95 % CI 1.18-2.26) were observed in subjects with IL-22 rs1179251 CC genotype. Stratified analysis indicated that risks of GC and its precursors were elevated in subjects with IL-32 rs2015620 A allele (AA + AT) or IL-22 rs1179251 CC genotype and H. pylori infection, and significant interactions between these two SNPs and H. pylori infection were found. These findings suggested that IL-18RAP rs917997, IL-32 rs2015620, IL-22 rs1179251, and interactions between these polymorphisms and H. pylori infection were associated with risks of gastric lesions. Genetic polymorphisms of interleukins may play crucial roles in H. pylori-induced gastric carcinogenesis.
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Affiliation(s)
- Yu-Mei Wang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Cancer Epidemiology, Peking University Cancer Hospital & Institute, 52 Fu-cheng Road, Hai-dian District, Beijing, 100142, People's Republic of China
| | - Zhe-Xuan Li
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Cancer Epidemiology, Peking University Cancer Hospital & Institute, 52 Fu-cheng Road, Hai-dian District, Beijing, 100142, People's Republic of China
| | - Fu-Bing Tang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Cancer Epidemiology, Peking University Cancer Hospital & Institute, 52 Fu-cheng Road, Hai-dian District, Beijing, 100142, People's Republic of China
| | - Yang Zhang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Cancer Epidemiology, Peking University Cancer Hospital & Institute, 52 Fu-cheng Road, Hai-dian District, Beijing, 100142, People's Republic of China
| | - Tong Zhou
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Cancer Epidemiology, Peking University Cancer Hospital & Institute, 52 Fu-cheng Road, Hai-dian District, Beijing, 100142, People's Republic of China
| | - Lian Zhang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Cancer Epidemiology, Peking University Cancer Hospital & Institute, 52 Fu-cheng Road, Hai-dian District, Beijing, 100142, People's Republic of China
| | - Jun-Ling Ma
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Cancer Epidemiology, Peking University Cancer Hospital & Institute, 52 Fu-cheng Road, Hai-dian District, Beijing, 100142, People's Republic of China
| | - Wei-Cheng You
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Cancer Epidemiology, Peking University Cancer Hospital & Institute, 52 Fu-cheng Road, Hai-dian District, Beijing, 100142, People's Republic of China.
| | - Kai-Feng Pan
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Cancer Epidemiology, Peking University Cancer Hospital & Institute, 52 Fu-cheng Road, Hai-dian District, Beijing, 100142, People's Republic of China.
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Chiurillo MA. Role of gene polymorphisms in gastric cancer and its precursor lesions: Current knowledge and perspectives in Latin American countries. World J Gastroenterol 2014; 20:4503-4515. [PMID: 24782603 PMCID: PMC4000487 DOI: 10.3748/wjg.v20.i16.4503] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2013] [Revised: 12/23/2013] [Accepted: 03/13/2014] [Indexed: 02/07/2023] Open
Abstract
Latin America shows one of the highest incidence rates of gastric cancer in the world, with variations in mortality rates among nations or even within countries belonging to this region. Gastric cancer is the result of a multifactorial complex process, for which a multistep model of carcinogenesis is currently accepted. Additionally to the infection with Helicobacter pylori, that plays a major role, environmental factors as well as genetic susceptibility factors are significant players at different stages in the gastric cancer process. The differences in population origin, demographic structure, socio-economic development, and the impact of globalization lifestyles experienced in Latin America in the last decades, all together offer opportunities for studying in this context the influence of genetic polymorphisms in the susceptibility to gastric cancer. The aim of this article is to discuss current trends on gastric cancer in Latin American countries and to review the available published information about studies of association of gene polymorphisms involved in gastric cancer susceptibility from this region of the world. A total of 40 genes or genomic regions and 69 genetic variants, 58% representing markers involved in inflammatory response, have been used in a number of studies in which predominates a low number of individuals (cases and controls) included. Polymorphisms of IL-1B (-511 C/T, 14 studies; -31 T/C, 10 studies) and IL-1RN (variable number of tandem repeats, 17 studies) are the most represented ones in the reviewed studies. Other genetic variants recently evaluated in large meta-analyses and associated with gastric cancer risk were also analyzed in a few studies [e.g., prostate stem cell antigen (PSCA), CDH1, Survivin]. Further and better analysis centered in gene polymorphisms linked to other covariates, epidemiological studies and the information provided by meta-analyses and genome-wide association studies should help to improve our understanding of gastric cancer etiology in order to develop appropriate health programs in Latin America.
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Pan XF, Wen Y, Loh M, Wen YY, Yang SJ, Zhao ZM, Tian Z, Huang H, Lan H, Chen F, Soong R, Yang CX. Interleukin-4 and -8 gene polymorphisms and risk of gastric cancer in a population in Southwestern China. Asian Pac J Cancer Prev 2014; 15:2951-2957. [PMID: 24815430 DOI: 10.7314/apjcp.2014.15.7.2951] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2025] Open
Abstract
BACKGROUND Gastric carcinogenesis is a complicated process that involves environmental and genetic factors like interleukin-4 (IL-4) and IL-8. Single nucleotide polymorphisms in their genes are associated with changed levels of gene expression. Here, we investigated the association between IL4-590 C>T and IL8-251T>A and gastric cancer (GC) risk in Sichuan of Southwestern China. MATERIALS AND METHODS We surveyed the research subjects using a self-designed questionnaire with questions on demographic factors and putative risk factors. Approximately 2-5ml of whole blood was collected after field survey to analyze IL4-590 C>T and IL8-251T>A genotypes using MALDI-TOF MS. RESULTS Our study recruited 308 pairs of GC patients and controls, including 224 (72.7%) men and 84 (27.3%) women in each group. There were 99 cardia and 176 noncardia GC patients in the case group. The case and control groups had an average age of 57.7±10.6 (mean±SD) and 57.6±11.1 years. GC patients reported a significantly greater proportion of family history of cancer (29.9% vs 10.7%, p<0.01) and drinking (54.6% vs 43.2%, p<0.01) than did controls. Variant genotypes of IL-4-590 C>T and IL-8-251 T>A were not associated with overall GC risk (adjusted OR, 0.89; 95%CI, 0.61-1.28 for CT or CC vs TT; adjusted OR, 1.14; 95%CI, 0.86-1.79 for TA or AA vs TT). Stratification analysis of two SNPs for risk by subsites only found that variant IL-8-251 TA or AA genotype was associated with increased noncardia GC risk (adjusted OR, 2.58; 95%CI, 1.19-5.57). We did not observe interactions between the IL-8-251 T>A genotype and smoking (adjusted OR, 0.38; 95%CI, 0.08-1.79) or drinking (adjusted OR, 0.36; 95%CI, 0.08-1.65) for risk of noncardia GC. CONCLUSIONS Our data indicate no association between the two SNPs of IL-4-590 and IL-8-251 with overall GC risk, while the IL-8-251 TA or AA genotype conferred risk of cardia GC. Our findings contribute to the evidence body for risk of SNPs associated with the development of gastric cancer in this region.
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Affiliation(s)
- Xiong-Fei Pan
- Department of Epidemiology, West China School of Public Health, Sichuan University, Chengdu, China E-mail :
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Interleukin-4 receptor -3223T→C polymorphism is associated with increased gastric adenocarcinoma risk. CANADIAN JOURNAL OF GASTROENTEROLOGY = JOURNAL CANADIEN DE GASTROENTEROLOGIE 2012; 26:532-6. [PMID: 22891178 DOI: 10.1155/2012/804173] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
BACKGROUND Gastric cancer remains one of the most common types of cancer worldwide, with a large geographical variation in incidence and mortality rates. Cytokine polymorphisms are the most studied host polymorphisms and are associated with an increased risk of stomach cancer in many regions, but have not been studied extensively in Eastern European populations. OBJECTIVE To investigate the potential association between five cytokine promoter polymorphisms (interleukin [IL] 1b -511C→T [rs16944], IL-4 receptor [IL-4R] -3223C→T [rs2057768], IL-8 -251T→A [rs4073], IL-10 -1082A→G [rs1800896] and tumour necrosis factor-alpha -308G→A [rs1800629]) and susceptibility to gastric adenocarcinoma in a Romanian population. METHODS A total of 347 subjects, consisting of 105 patients with gastric adenocarcinoma and 242 controls, were included. All cytokine polymorphisms were genotyped using allele-specific, commercially available probes. Hardy-Weinberg equilibrium in both groups was analyzed using the chi squared test, and the relationship between targeted polymorphisms and the risk of gastric cancer was estimated using OR and 95% CI. RESULTS A significant association between the IL-4R -3223C→T polymorphism and risk of gastric cancer was found. Carriers of the IL-4R -3223TT genotype were at a 2.5-fold increased risk for gastric cancer (OR 2.51 [95% CI 1.08 to 5.84]; P=0.041). Moreover, the presence of the IL-4R -3223TT genotype was associated with an increased risk of noncardia gastric adenocarcinoma (OR 3.08 [95% CI 1.25 to 7.58]; P=0.023). No associations were found among the other polymorphisms. CONCLUSION The results suggest that the IL-4R -3223C→T polymorphism may increase the risk of gastric adenocarcinoma, mainly for the noncardia type, in the Romanian population.
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The association between GSTM1 polymorphism and gastric cancer risk: a meta-analysis. Mol Biol Rep 2011; 39:685-91. [PMID: 21553222 DOI: 10.1007/s11033-011-0786-2] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2010] [Accepted: 04/29/2011] [Indexed: 12/23/2022]
Abstract
Relationship of gastric cancer with the GSTM1 polymorphism was reported with inconsistent results. The objective of this study was to quantitatively evaluate the association between GSTM1 polymorphism and gastric cancer susceptibility. Relevant studies were identified from PubMed and references of retrieved articles. A meta-analysis was performed, which included 38 studies with 6,605 gastric cancer cases and 11,311 controls. The combined result based on all studies showed there was a significant link between GSTM1 null genotype and gastric cancer (OR=1.20, 95%CI: 1.08-1.34). When stratifying for the race, the phenomenon was found that gastric cancer case had a significantly higher frequency of GSTM1 null genotype than control in Asians (OR=1.27, 95%CI: 1.10-1.47). However, there was not enough evidence to show there was a significant difference in GSTM1 null genotype distribution between gastric cancer case and control in Caucasians (OR=1.13, 95%CI: 0.96-1.32). This meta-analysis indicated that GSTM1 null genotype might be associated with increased gastric cancer risk in Asians. However, this meta-analysis did not provide an evidence of confirming association between GSTM1 polymorphism and gastric cancer in Caucasians.
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Hishida A, Matsuo K, Goto Y, Hamajima N. Genetic predisposition to Helicobacter pylori-induced gastric precancerous conditions. World J Gastrointest Oncol 2010; 2:369-79. [PMID: 21160888 PMCID: PMC2999673 DOI: 10.4251/wjgo.v2.i10.369] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2010] [Revised: 09/20/2010] [Accepted: 09/27/2010] [Indexed: 02/05/2023] Open
Abstract
Gastric cancer is the most common malignancy of the gastrointestinal tract in East Asian populations and the second most frequent cause of cancer-related mortality in the world. While previous studies have investigated the genetic factors involved in gastric carcinogenesis, there still exist relatively few studies that have investigated the genetic traits associated with the risk of gastric precancerous conditions. In this paper we will review the biology and genetic polymorphisms involved in the genesis of gastric precancerous conditions reported to date and discuss the future prospects of this field of study. The associations of gastric precancerous conditions with polymorphisms in the cytotoxin-associated gene A-related genes (e.g. PTPN11 G/A at intron 3, rs2301756), those in the genes involved in host immunity against Helicobacter pylori (H. pylori) infection (e.g. TLR4 +3725G/C, rs11536889) or polymorphisms of the genes essential for the development/ differentiation of the gastric epithelial cells (e.g. RUNX3 T/A polymorphism at intron 3, rs760805) have been reported to date. Genetic epidemiological studies of the associations between H. pylori-induced gastric precancerous conditions and other gene polymorphisms in these pathways as well as polymorphisms of the genes involved in other pathways like oxidative DNA damage repair pathways would provide useful evidence for the individualized prevention of these H. pylori-induced gastric precancerous conditions.
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Affiliation(s)
- Asahi Hishida
- Asahi Hishida, Yasuyuki Goto, Nobuyuki Hamajima, Department of Preventive Medicine, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan
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Zhuang W, Wu XT, Zhou Y, Liu L, Liu GJ, Wu TX, Yao X, Du L, Wei ML. Interleukin10 -592 promoter polymorphism associated with gastric cancer among Asians: a meta-analysis of epidemiologic studies. Dig Dis Sci 2010; 55:1525-32. [PMID: 19669876 DOI: 10.1007/s10620-009-0922-1] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2009] [Accepted: 07/09/2009] [Indexed: 02/05/2023]
Abstract
PURPOSE Studies investigating the association between interleukin10 (IL10) -592 promoter polymorphism and gastric cancer risk report conflicting results. The objective of this study was to quantitatively summarize the evidence for such a relationship. METHODS Two investigators independently searched the MEDLINE and Embase databases. This meta-analysis included ten case-control studies, which included 1,715 gastric cancer cases and 2,783 controls. RESULTS The combined results based on all studies showed that there was no significant difference in genotype distribution (AA odds ratio [OR] = 0.88, 95% confidence interval [CI] = 0.66, 1.18; AC OR = 1.09, 95% CI = 0.95, 1.24; CC OR = 1.03, 95% CI = 0.89, 1.18) between gastric cancer and noncancer patients. When stratifying for race, the results were similar, except that patients with gastric cancer had a significantly lower frequency of AA (OR = 0.67, 95% CI = 0.52, 0.87) and a higher frequency of AC (OR = 1.34, 95% CI = 1.07, 1.68) than noncancer patients among Asians. When stratifying by the location of gastric cancer, we found that patients with cardia gastric cancer had a significantly lower frequency of AA (OR = 0.41, 95% CI = 0.20, 0.84) than those with noncardia gastric cancer among Caucasians. When stratifying by Lauren's classification of gastric cancer, we found that patients with diffuse gastric cancer had a significantly higher frequency of AA (OR = 1.91, 95% CI = 1.07, 3.41) than those with intestinal gastric cancer among Caucasians. CONCLUSIONS This meta-analysis suggests that the IL10 -592 promoter polymorphism may be associated with gastric cancer among Asians, and that differences in genotype distribution may be associated with the location and Lauren's classification of gastric cancer.
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Affiliation(s)
- Wen Zhuang
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
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Sugimoto M, Yamaoka Y, Furuta T. Influence of interleukin polymorphisms on development of gastric cancer and peptic ulcer. World J Gastroenterol 2010; 16:1188-200. [PMID: 20222161 PMCID: PMC2839170 DOI: 10.3748/wjg.v16.i10.1188] [Citation(s) in RCA: 87] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Pro-inflammatory cytokines are produced in the gastric mucosa by inflammatory cells activated by chronic Helicobacter pylori (H. pylori) infection. Polymorphisms of these cytokine genes are associated with individual differences in gastric mucosal cytokine mRNA level, which result in differences in gastric mucosal inflammation, acid inhibition and gastroduodenal disease risk in response to H. pylori infection. Although polymorphisms of interleukin (IL)-1B, IL-1RN and TNF-A have been reported to relate well with gastric cancer and peptic ulcer risk, those of IL-2, IL-4, IL-6 and IL-8 genes are unclear. In combined analyses using data from previous studies, we found that the risk of gastric non-cardia cancer development was significantly associated with IL-4-168 C allele (OR: 0.81, 95% CI: 0.69-1.00) and IL-4-590 T allele carrier status (0.61, 0.53-0.73), and IL-6-174 G/G genotype (2.02, 1.31-3.10). In peptic ulcer development, IL-2-330 G and IL-4-590 T allele carriers had a significantly decreased risk (0.37, 0.27-0.50 and 0.58, 0.34-0.99, respectively). Moreover, IL-2, IL-4, IL-6 and IL-8 gene genotypes prevalence differs among populations. The inflammatory cytokine gene polymorphisms (e.g. IL-4-590 and IL-6-572 for gastric cancer, and IL-4-590, IL-6-572 and IL-8-251 for peptic ulcer) have a more potent influence on development of gastroduodenal diseases in Western than East Asian populations. These cytokine gene polymorphisms, as well as those of IL-1B, IL-1RN and TNF-A, may be used to identify groups at higher risk of gastric cancer and peptic ulcer, and those suitable for their prevention by H. pylori eradication therapy in Western populations.
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Zhu Y, Wang J, He Q, Zhang JQ. The association between interleukin-10-592 polymorphism and gastric cancer risk: a meta-analysis. Med Oncol 2010; 28:133-6. [PMID: 20087693 DOI: 10.1007/s12032-010-9417-3] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2009] [Accepted: 01/06/2010] [Indexed: 12/27/2022]
Abstract
Relationship of gastric cancer with the presence of IL-10-592 polymorphism was reported with inconsistent results. The objective of this study was to quantitatively evaluate the association between IL-10-592 allele polymorphism and gastric cancer susceptibility. We performed an extensive search of relevant studies and made a meta-analysis, including 12 studies with 2,285 gastric cancer cases and 4,236 controls. The combined results based on all studies showed that there were no significant differences in genotype distribution between gastric cancer cases and controls, CC versus CA/AA (OR = 1.05, 95% CI: 0.92-1.18), CC/CA versus AA (OR = 1.16, 95% CI: 0.92-1.46), CC versus CA (OR = 1.03, 95% CI: 0.90-1.17), CC versus AA (OR = 1.10, 95% CI: 0.90-1.34), and CA versus AA (OR = 1.16, 95% CI: 0.92-1.45). When stratifying for the race, it was found that gastric cancer cases had a significantly higher frequency of CC/CA versus AA (OR = 1.31, 95% CI: (1.08-1.59) and a significantly upper frequency of CA versus AA (OR = 1.33, 95% CI: 1.09-1.63) than control in Asians. When stratifying for the location and the Lauren's classification of gastric cancer, there were no statistically significant differences in genotype distribution between gastric cancer cases and controls. This meta-analysis suggested that IL-10-592 allele polymorphism might be a risk factor for gastric cancer among Asians.
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Affiliation(s)
- Yu Zhu
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China
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Gao L, Weck MN, Nieters A, Brenner H. Inverse association between a pro-inflammatory genetic profile and Helicobacter pylori seropositivity among patients with chronic atrophic gastritis: Enhanced elimination of the infection during disease progression? Eur J Cancer 2009; 45:2860-6. [DOI: 10.1016/j.ejca.2009.04.015] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2009] [Revised: 04/03/2009] [Accepted: 04/07/2009] [Indexed: 01/20/2023]
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Zhu F, Loh M, Hill J, Lee S, Koh KX, Lai KW, Salto-Tellez M, Iacopetta B, Yeoh KG, Soong R. Genetic factors associated with intestinal metaplasia in a high risk Singapore-Chinese population: a cohort study. BMC Gastroenterol 2009; 9:76. [PMID: 19822020 PMCID: PMC2766386 DOI: 10.1186/1471-230x-9-76] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2009] [Accepted: 10/13/2009] [Indexed: 12/26/2022] Open
Abstract
Background Intestinal metaplasia (IM) is an important precursor lesion in the development of gastric cancer (GC). The aim of this study was to investigate genetic factors previously linked to GC risk for their possible association with IM. A total of 18 polymorphisms in 14 candidate genes were evaluated in a Singapore-Chinese population at high risk of developing GC. Methods Genotype frequencies were compared between individuals presenting with (n = 128) or without (n = 246) IM by both univariate and multivariate analysis. Results Carriers of the NQO1 609 T allele showed an association with IM in individuals who were seropositive for Helicobacter pylori (HP+; OR = 2.61, 95%CI: 1.18-5.80, P = .018). The IL-10 819 C allele was also associated with IM in HP+ individuals (OR = 2.32, 95%CI: 1.21-4.43, P = 0.011), while the PTPN11 A allele was associated with IM in HP- individuals (OR = 2.51, 95%CI: 1.16-5.40, P = 0.019), but showed an inverse association in HP+ subjects (OR = 0.46, 95%CI: 0.21-0.99, P = 0.048). Conclusion Polymorphisms in NQO1, IL-10 and PTPN11, in combination with HP status, could be used to identify individuals who are more likely to develop IM and therefore GC.
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Affiliation(s)
- Feng Zhu
- Department of Medicine, National University of Singapore, Singapore, Singapore.
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Association of gastric disease with polymorphisms in the inflammatory-related genes IL-1B, IL-1RN, IL-10, TNF and TLR4. Eur J Gastroenterol Hepatol 2009; 21:630-5. [PMID: 19295440 PMCID: PMC2802816 DOI: 10.1097/meg.0b013e3283140eea] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
OBJECTIVES This study aimed to investigate if single nucleotide polymorphisms (SNPs) in a series of inflammatory genes were associated with the development of the most common pathologies thought to precede gastric cancer development namely; Helicobacter pylori (H. pylori)-associated gastritis and intestinal metaplasia. METHODS A total of 250 patients were genotyped for 11 SNPs in the IL-1B, IL-1RN, TNF, TLR4 and IL-10 genes. The study population comprised H. pylori uninfected ('normal') control patients (n=96), H. pylori-positive gastritis (n=91) and intestinal metaplasia patients (n=63). Genotyping was performed using Taqman allelic discrimination assays. Odds ratios for gastric disease groups were adjusted for potential confounding factors. RESULTS No differences were identified in frequency of carriage, or homozygosity, for any of the 'risk' alleles investigated across the patient groups. No evidence was found to suggest an association with increased risk of developing either chronic gastritis or intestinal metaplasia with SNPs in the IL-1B, IL-1RN, TNF, TLR4 and IL-10 genes or haplotypes tested. CONCLUSION This study found no evidence of an association with increased risk of developing either chronic gastritis or intestinal metaplasia with the SNPs or haplotypes tested.
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Gao L, Weck MN, Nieters A, Brenner H. Association between a pro-inflammatory genetic profile and the risk of chronic atrophic gastritis among older adults from Germany. Eur J Cancer 2009; 45:428-34. [DOI: 10.1016/j.ejca.2008.09.019] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2008] [Accepted: 09/25/2008] [Indexed: 01/29/2023]
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Zhou Y, Li N, Zhuang W, Liu GJ, Wu TX, Yao X, Du L, Wei ML, Wu XT. Interleukin-10 -1082 promoter polymorphism associated with gastric cancer among Asians. Eur J Cancer 2008; 44:2648-54. [PMID: 18707865 DOI: 10.1016/j.ejca.2008.07.017] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2008] [Revised: 06/22/2008] [Accepted: 07/09/2008] [Indexed: 02/06/2023]
Abstract
Studies investigating the association between interleukin-10 (IL-10) -1082 promoter polymorphism and gastric cancer risk report conflicting results. The objective of this study was to quantitatively summarise the evidence for such a relationship. Two investigators independently searched the Medline and Embase databases. This meta-analysis included 13 case-control studies, which included 2227 gastric cancer cases and 3538 controls. The combined results based on all studies showed that there was no significant difference in genotype distribution [AA odds ratio (OR)=0.92, 95% confidence interval (CI)=0.73, 1.14; AG (OR=1.09, 95% CI=0.87, 1.36); GG (OR=1.03, 95% CI=0.85, 1.25)] between gastric cancer and noncancer patients. When stratifying for race, results were similar except that patients with gastric cancer had a significantly lower frequency of AA (OR=0.71, 95% CI=0.52, 0.97) and higher frequency AG (OR=1.53, 95% CI=1.15, 2.03) than noncancer patients among Asians. When stratifying by the location of gastric cancer, we found that patients with cardia gastric cancer had a significantly lower frequency of AA (OR=0.53, 95% CI=0.34, 0.83) and higher frequency AG (OR=1.50, 95% CI=1.06, 2.11) than those with noncardia gastric cancer among Caucasians. When stratifying by the Lauren's classification of gastric cancer, we observed no statistically significant differences in genotype distribution. This meta-analysis suggests that the IL-10 -1082 promoter polymorphism may be associated with gastric cancer among Asians, and that differences in genotype distribution may be associated with the location of gastric cancer.
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Affiliation(s)
- Yong Zhou
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, China
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IL-4 -588C>T polymorphism and IL-4 receptor alpha [Ex5+14A>G; Ex11+828A>G] haplotype concur in selecting H. pylori cagA subtype infections. Clin Chim Acta 2007; 389:139-45. [PMID: 18179773 DOI: 10.1016/j.cca.2007.12.008] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2007] [Revised: 12/07/2007] [Accepted: 12/07/2007] [Indexed: 12/13/2022]
Abstract
BACKGROUND The Th2 cytokine IL-4 might limit H. pylori associated gastric inflammation and favour H. pylori clearance. The aim of the study was to verify whether IL-4 -588C>T SNP, or two SNPs of the gene coding the alpha chain of IL-4 receptor (IL-4RA Ex5+14A>G, IL-4RA Ex11+828A>G) considered singly or as haplotypes, are correlated with H. pylori virulence genes or H. pylori associated diseases. METHODS We studied 144 patients with non-cardia gastric cancer (NCGC)(41/50 with present or past H. pylori infection), 75 with duodenal ulcer (DU)(66 H. pylori infected) and 171 with gastritis (CG)(107 H. pylori infected). cagA gene was present in 24/28 NCGC, 45/59 DU and 56/107 CG. RESULTS All SNPs were in Hardy-Weinberg equilibrium. IL-4RA haplotypes frequencies were estimated using Arlequin software. Neither the SNPs nor the IL-4RA haplotype correlated with disease diagnosis, H. pylori infection, degree of mucosal inflammation or intestinal metaplasia. IL-4 -588T allele (OR=3.69, 95% CI:1.34-10.16) and IL-4RA GA haplotype (p<0.05) enhanced the risk for cagA positive infections. IL-4RA GA haplotype correlated with IL-4 protein levels in H. pylori infected gastric mucosa. CONCLUSIONS IL-4 and IL-4RA gene polymorphisms concur in selecting the H. pylori infecting strain, probably influencing the IL-4 signalling pathway.
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Plummer M, van Doorn LJ, Franceschi S, Kleter B, Canzian F, Vivas J, Lopez G, Colin D, Muñoz N, Kato I. Helicobacter pylori cytotoxin-associated genotype and gastric precancerous lesions. J Natl Cancer Inst 2007; 99:1328-34. [PMID: 17728213 DOI: 10.1093/jnci/djm120] [Citation(s) in RCA: 81] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Helicobacter pylori infection is associated with the development of gastric cancer. Although infection with an H. pylori strain containing the cytotoxin-associated (cag A) gene (a marker for a pathogenicity island) may increase the risk of atrophic gastritis and gastric cancer, the relationship of variants in pathogenic H. pylori genes to the severity and progression of precancerous lesions is not well defined. METHODS Gastric biopsy specimens were obtained at enrollment from 2145 participants in a chemoprevention trial in Tachira State, Venezuela, and examined histologically to determine the severity of precancerous lesions. The presence of H. pylori DNA in gastric biopsies and the strain type according to presence or absence of the cagA gene were detected by polymerase chain reaction and specific probes. The relationship between H. pylori DNA and histologic diagnosis was analyzed by polytomous logistic regression. Rates of progression and regression of precancerous lesions were determined from biopsies from additional annual gastroscopies (mean follow-up = 3.5 years). All statistical tests were two-sided. RESULTS At enrollment, there was a strong association between cagA-positive H. pylori infection and the severity of gastric precancerous lesions, but cagA-negative H. pylori was associated only with chronic gastritis. Using individuals with normal mucosa or superficial gastritis as control subjects, the odds ratio for dysplasia was 15.5 (95% confidence interval [CI] = 6.42 to 37.2) in cagA-positive individuals compared with uninfected individuals and 0.90 (95% CI = 0.37 to 2.17) for individuals infected with cagA-negative H. pylori compared with uninfected individuals. Individuals infected with cagA-positive H. pylori appeared more likely to experience progression (and less likely to experience regression) of precancerous lesions than those infected with cagA-negative H. pylori, but the differences did not attain statistical significance. CONCLUSIONS This large epidemiologic study shows a strong relationship between the presence of H. pylori DNA in gastric biopsies and the severity of precancerous lesions that is specific to cagA-positive strains. The association between H. pylori and gastric carcinoma may have been previously underestimated due to the poor accuracy of serologic H. pylori markers and lack of discrimination by cagA genotype.
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Affiliation(s)
- Martyn Plummer
- International Agency for Research on Cancer, 150 cours Albert Thomas, 69372 Lyon Cedex 08, France.
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