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Karbalaei M, Khorshidi M, Sisakht-pour B, Ghazvini K, Farsiani H, Youssefi M, Keikha M. 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. GENE REPORTS 2020; 20:100735. [DOI: 10.1016/j.genrep.2020.100735] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
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Pachathundikandi SK, Blaser N, Bruns H, Backert S. Helicobacter pylori Avoids the Critical Activation of NLRP3 Inflammasome-Mediated Production of Oncogenic Mature IL-1β in Human Immune Cells. Cancers (Basel) 2020; 12:E803. [PMID: 32230726 PMCID: PMC7226495 DOI: 10.3390/cancers12040803] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2020] [Revised: 03/03/2020] [Accepted: 03/13/2020] [Indexed: 02/07/2023] Open
Abstract
Helicobacter pylori persistently colonizes the human stomach, and is associated with inflammation-induced gastric cancer. Bacterial crosstalk with the host immune system produces various inflammatory mediators and subsequent reactions in the host, but not bacterial clearance. Interleukin-1β (IL-1β) is implicated in gastric cancer development and certain gene polymorphisms play a role in this scenario. Mature IL-1β production depends on inflammasome activation, and the NLRP3 inflammasome is a major driver in H. pylori-infected mice, while recent studies demonstrated the down-regulation of NLRP3 expression in human immune cells, indicating a differential NLRP3 regulation in human vs. mice. In addition to the formation of mature IL-1β or IL-18, inflammasome activation induces pyroptotic death in cells. We demonstrate that H. pylori infection indeed upregulated the expression of pro-IL-1β in human immune cells, but secreted only very low amounts of mature IL-1β. However, application of exogenous control activators such as Nigericin or ATP to infected cells readily induced NLRP3 inflammasome formation and secretion of high amounts of mature IL-1β. This suggests that chronic H. pylori infection in humans manipulates inflammasome activation and pyroptosis for bacterial persistence. This inflammasome deregulation during H. pylori infection, however, is prone to external stimulation by microbial, environmental or host molecules of inflammasome activators for the production of high amounts of mature IL-1β and signaling-mediated gastric tumorigenesis in humans.
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Affiliation(s)
- Suneesh Kumar Pachathundikandi
- Department of Biology, Division of Microbiology, Friedrich-Alexander University Erlangen-Nuremberg, Staudtstr. 5, D-91058 Erlangen, Germany;
| | - Nicole Blaser
- Department of Biology, Division of Microbiology, Friedrich-Alexander University Erlangen-Nuremberg, Staudtstr. 5, D-91058 Erlangen, Germany;
| | - Heiko Bruns
- Department of Internal Medicine 5, Hematology and Oncology, University Hospital Erlangen, Friedrich-Alexander University, D-91058 Erlangen, Germany;
| | - Steffen Backert
- Department of Biology, Division of Microbiology, Friedrich-Alexander University Erlangen-Nuremberg, Staudtstr. 5, D-91058 Erlangen, Germany;
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Gene polymorphisms in the interleukins gene and the risk of acute pancreatitis: A meta-analysis. Cytokine 2019; 115:50-59. [PMID: 30634098 DOI: 10.1016/j.cyto.2018.12.003] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2018] [Revised: 10/25/2018] [Accepted: 12/10/2018] [Indexed: 02/08/2023]
Abstract
Single nucleotide polymorphisms (SNPs) within the interleukins (IL) gene may affect the risk of acute pancreatitis. Many epidemiological studies have reported an association between the IL gene and acute pancreatitis risk, but the results remain inconsistent. Given the controversial available data, we carried out a meta-analysis to systematically evaluate and clarify the association between IL gene polymorphisms and AP. A systematic search of studies for this association was obtained from the PubMed, EMBASE, Web of Science and Chinese National Knowledge Infrastructure (CNKI) databases until June 1, 2017. We also searched the references of the included studies to identify additional studies. Odds ratios (ORs) with 95% confidence intervals (95% CIs) were used to pool the effect size. Stata12.0 was used for whole statistical analysis. Fifteen studies that contained 3371 AP cases and 3506 controls were included in final combination. Overall, a significant association was found between the IL-8-251 T/A (rs4073) polymorphism, the IL-10-1082 A/G (rs1800896) polymorphism and the AP risk in four genetic models (homozygote model, recessive model, dominant model, allele model). Meanwhile, individuals with IL-1β+3954 C/T (rs1143634, (homozygote model, recessive model)), IL-1β -511 C/T (rs16944, (dominant model)) and IL-6-634C/G (rs1800796, (allele model)) polymorphism were associated with an increased risk of AP. No evidence of an association was found between IL and 10-592 C/A (rs1800872) and IL-10-819 C/T (rs1800871) polymorphism and AP risk.
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Helicobacter pylori, Peptic Ulcer Disease and Gastric Cancer. GASTROINTESTINAL DISEASES AND THEIR ASSOCIATED INFECTIONS 2019. [DOI: 10.1016/b978-0-323-54843-4.00002-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Lin TJ, Lee HC, Lin CL, Wang CK, Chen KY, Wu DC. CYP2C19 polymorphism has no influence on rabeprazole-based hybrid therapy for Helicobacter pylori eradication. World J Clin Cases 2018; 6:514-520. [PMID: 30397607 PMCID: PMC6212610 DOI: 10.12998/wjcc.v6.i12.514] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2018] [Revised: 08/08/2018] [Accepted: 08/30/2018] [Indexed: 02/05/2023] Open
Abstract
AIM To evaluate the impact of cytochrome P450 2C19 (CYP2C19) and interleukin-1β (IL-1β) polymorphisms on the efficacy of Helicobacter pylori (H. pylori) eradication by using rabeprazole-based hybrid therapy.
METHODS A total of 88 H. pylori-infected patients were recruited to receive 14-d of hybrid therapy from March 2013 to May 2014. Three patients were excluded from analysis because of incomplete compliance. Either a follow-up endoscopy or 13C-urea test was performed to determine the results of H. pylori eradication therapy. The genotypes of CYP2C19 and IL-1β were analyzed to investigate the impact on treatment effect.
RESULTS The total eradication rate of H. pylori was 92.94% (79/85). According to the CYP2C19 genotypes, the rates of H. pylori eradication were 89.19% in extensive metabolizers (EM) and 95.83% in non-EM. The H. pylori eradication rates regarding the IL-1β genotypes were 92.59% in the normal acid secretion group and 93.10% in the low acid secretion group. After multivariable logistic regression analysis, both the genotypes of CYP2C19 and IL-1β had no significant influences on the eradication rates of H. pylori.
CONCLUSION The CYP2C19 and IL-1β polymorphisms are not significantly independent factors of H. pylori eradication using rabeprazole-based hybrid therapy.
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Affiliation(s)
- Tsung-Jung Lin
- Department of Health care and Social Work, Taipei University of Marine Technology, New Taipei 25172, Taiwan
- Department of Gastroenterology, Taipei City Hospital, Taipei 10629, Taiwan
| | - Hsi-Chang Lee
- Department of Gastroenterology, Taipei City Hospital, Taipei 10629, Taiwan
| | - Chih-Lin Lin
- Department of Gastroenterology, Taipei City Hospital, Taipei 10629, Taiwan
| | - Chung-Kwe Wang
- Department of Gastroenterology, Taipei City Hospital, Taipei 10629, Taiwan
| | - Kuan-Yang Chen
- Department of Gastroenterology, Taipei City Hospital, Taipei 10629, Taiwan
- Institute of Clinical Medicine, National Yang-Ming University, Taipei 11221, Taiwan
- Institute of Neuroscience, National Chengchi University, Taipei 11651, Taiwan
| | - Deng-Chyang Wu
- Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan
- Division of Internal Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Center for Infectious Disease and Cancer Research, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
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Goh KL. Lessons learnt from the epidemiology of Helicobacter pylori infection in Malaysia: JGHF Marshall and Warren Lecture 2017. J Gastroenterol Hepatol 2018; 33:1177-1184. [PMID: 29498759 DOI: 10.1111/jgh.14131] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2018] [Revised: 02/16/2018] [Accepted: 02/19/2018] [Indexed: 12/12/2022]
Abstract
The study of Helicobacter pylori in Malaysia has given several important insights into the epidemiology of the infection and pathogenesis of disease. Malaysia has a multiracial Asian population with three major Asian races living together-Malay, Chinese, and Indian. Races remain fairly distinct because of a paucity of interracial marriages. The "Racial Cohort Hypothesis" proposes that the infection occurs within racial groups rather than between. As such, the high prevalence among Indians (> 50%) and Chinese (40-50%) reflects the high prevalence in their countries of origin even though migration had taken place more than two generations before. The Malays have a comparatively low prevalence of about 10-20%. Despite the high prevalence of H. pylori, the Indians have a low gastric cancer incidence of less than 10 per 100 000 per year. This is in contrast to the Chinese who has an incidence in excess of 20 per 100 000 per year. We have called this the "Indian Enigma." The reason for this enigma is unclear and is the result of interaction between bacterial virulence factors, host susceptibility, and environmental factors. Phylogenetically, Chinese bacterial strains are distinct from Indians and Malays and are predominantly hpEastAsia/hsp EAsia. CagA EPIYA motifs among Chinese belong predominantly to the more virulent ABD motif. There is no clear distinguishing profile among host genetic factors. Environmental factors particularly diet may play an important role. Indians consume chilies and curries, which may be gastro protective, whereas Chinese consume more preserved and salted foods, which are thought to be carcinogenic.
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Affiliation(s)
- Khean-Lee Goh
- Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
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Lin TJ, Lee HC, Lin CL, Wang CK, Chen KY, Wu DC. CYP2C19 polymorphism has no influence on rabeprazole-based sequential therapy. ADVANCES IN DIGESTIVE MEDICINE 2017. [DOI: 10.1002/aid2.12134] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Affiliation(s)
- Tsung-Jung Lin
- Department of Gastroenterology; Taipei City Hospital, Ren-Ai Branch; Taipei Taiwan
- Department of Health Care and Social Work; Taipei University of Marine Technology; New Taipei Taiwan
| | - Hsi-Chang Lee
- Department of Gastroenterology; Taipei City Hospital, Ren-Ai Branch; Taipei Taiwan
| | - Chih-Lin Lin
- Department of Gastroenterology; Taipei City Hospital, Ren-Ai Branch; Taipei Taiwan
| | - Chung-Kwe Wang
- Department of Gastroenterology; Taipei City Hospital, Ren-Ai Branch; Taipei Taiwan
| | - Kuan-Yang Chen
- Department of Gastroenterology; Taipei City Hospital, Ren-Ai Branch; Taipei Taiwan
- Institute of Clinical Medicine; National Yang-Ming University; Taipei Taiwan
- Institute of Neuroscience; National Chengchi University; Taipei Taiwan
| | - Deng-Chyang Wu
- Division of Gastroenterology; Department of Internal Medicine, Kaohsiung Medical University Hospital; Kaohsiung Taiwan
- Division of Internal Medicine, Kaohsiung Municipal Ta-Tung Hospital; Kaohsiung Medical University; Kaohsiung Taiwan
- Center for Infectious Disease and Cancer Research; Kaohsiung Medical University; Kaohsiung Taiwan
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Raza Y, Khan A, Khan AI, Khan S, Akhter S, Mubarak M, Ahmed A, Kazmi SU. Combination of Interleukin 1 Polymorphism and Helicobacter pylori Infection: an Increased Risk of Gastric Cancer in Pakistani Population. Pathol Oncol Res 2017; 23:873-880. [PMID: 28110439 DOI: 10.1007/s12253-017-0191-9] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2016] [Accepted: 01/09/2017] [Indexed: 02/07/2023]
Abstract
Helicobacter pylori is one of the major risk factors involved in the development ofgastritis and gastric cancer (GC). H. pylori infection leads to increased production of pro-inflammatory cytokines by the host. Carriage of specific polymorphisms in cytokine genes may be associated with host susceptibility to the development of GC. We investigated the role of host genetic factors including polymorphisms of IL-1B and IL-1RN in correlation with gastritis and GC in H. pylori infected Pakistani population. A total of 230 gastritis cases and 100 GC cases were genotyped for IL 1B-511 and IL-1RN penta-allelic variable number of tandem repeats (VNTRs). A combination of IL-1B-511*T and IL-1RN*2 alleles (OR 19.064; 95% CI 2.319-156.7; p = 0.001) in H. pylori infected individuals had markedly increased risk of GC development. In Pakistani population, an increased risk of GC development is associated with the carriage of IL-1B-511*T and IL-1RN*2 alleles. Synergistic effect of H. pylori infection and IL-1B-511*T/IL-1RN*2 genotypes was also observed in association with significantly higher risk of developing GC. Further prospective and large scale studies are needed to establish the clinical impact of these findings.
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Affiliation(s)
- Yasir Raza
- Stem Cell Research Laboratory, Sindh Institute of Urology and Transplantation, Deewan Farooq Medical Complex, Chand Bibi Road, Karachi, Pakistan.
- Immunology and Infectious Diseases Research Laboratory, Department of Microbiology, University of Karachi, Karachi, Pakistan.
| | - Adnan Khan
- Immunology and Infectious Diseases Research Laboratory, Department of Microbiology, University of Karachi, Karachi, Pakistan
| | - Asif Iqbal Khan
- Department of Molecular Pathology, Dow University of Health and Sciences, Karachi, Pakistan
| | - Saeed Khan
- Department of Molecular Pathology, Dow University of Health and Sciences, Karachi, Pakistan
| | - Shakeel Akhter
- Department of Surgery and Medicine, Civil Hospital Karachi, Karachi, Pakistan
| | - Muhammad Mubarak
- Department of Histopathology, Sindh Institute of Urology and Transplantation, Karachi, Pakistan
| | - Ayaz Ahmed
- Dr. Panjwani Center For Molecular Medicine And Drug Research, Karachi, Pakistan
| | - Shahana Urooj Kazmi
- Immunology and Infectious Diseases Research Laboratory, Department of Microbiology, University of Karachi, Karachi, Pakistan
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Ng GZ, Menheniott TR, Every AL, Stent A, Judd LM, Chionh YT, Dhar P, Komen JC, Giraud AS, Wang TC, McGuckin MA, Sutton P. The MUC1 mucin protects against Helicobacter pylori pathogenesis in mice by regulation of the NLRP3 inflammasome. Gut 2016; 65:1087-99. [PMID: 26079943 DOI: 10.1136/gutjnl-2014-307175] [Citation(s) in RCA: 86] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2014] [Accepted: 03/11/2015] [Indexed: 12/16/2022]
Abstract
OBJECTIVES The mucin MUC1, best known for providing an epithelial barrier, is an important protective host factor in both humans and mice during Helicobacter pylori pathogenesis. This study aimed to identify the long-term consequences of MUC1 deficiency on H. pylori pathogenesis and the mechanism by which MUC1 protects against H. pylori gastritis. DESIGN Wildtype and Muc1(-/-) mice were infected for up to 9 months, and the gastric pathology, immunological response and epigenetic changes assessed. The effects of MUC1 on the inflammasome, a potent inflammatory pathway, were examined in macrophages and H. pylori-infected mice deficient in both MUC1 and inflammasome components. RESULTS Muc1(-/-) mice began to die 6 months after challenge, indicating Muc1 deficiency made H. pylori a lethal infection. Surprisingly, chimaeric mouse infections revealed MUC1 expression by haematopoietic-derived immune cells limits H. pylori-induced gastritis. Gastritis in infected Muc1(-/-) mice was associated with elevated interleukin (IL)-1β and epigenetic changes in their gastric mucosa similar to those in transgenic mice overexpressing gastric IL-1β, implicating MUC1 regulation of an inflammasome. In support of this, infected Muc1(-/-)Casp1(-/-) mice did not develop severe gastritis. Further, MUC1 regulated Nlrp3 expression via an nuclear factor (NF)-κB-dependent pathway and reduced NF-κB pathway activation via inhibition of IRAK4 phosphorylation. The importance of this regulation was proven using Muc1(-/-)Nlrp3(-/-) mice, which did not develop severe gastritis. CONCLUSIONS MUC1 is an important, previously unidentified negative regulator of the NLRP3 inflammasome. H. pylori activation of the NLRP3 inflammasome is normally tightly regulated by MUC1, and loss of this critical regulation results in the development of severe pathology.
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Affiliation(s)
- Garrett Z Ng
- Centre for Animal Biotechnology, Faculty of Veterinary and Agricultural Sciences, University of Melbourne, Parkville, Victoria, Australia Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, Victoria, Australia
| | - Trevelyan R Menheniott
- Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, Victoria, Australia
| | - Alison L Every
- Centre for Animal Biotechnology, Faculty of Veterinary and Agricultural Sciences, University of Melbourne, Parkville, Victoria, Australia
| | - Andrew Stent
- Centre for Animal Biotechnology, Faculty of Veterinary and Agricultural Sciences, University of Melbourne, Parkville, Victoria, Australia
| | - Louise M Judd
- Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, Victoria, Australia
| | - Yok Teng Chionh
- Centre for Animal Biotechnology, Faculty of Veterinary and Agricultural Sciences, University of Melbourne, Parkville, Victoria, Australia
| | - Poshmaal Dhar
- Centre for Animal Biotechnology, Faculty of Veterinary and Agricultural Sciences, University of Melbourne, Parkville, Victoria, Australia Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, Victoria, Australia
| | - Jasper C Komen
- Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, Victoria, Australia
| | - Andrew S Giraud
- Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, Victoria, Australia
| | - Timothy C Wang
- Division of Digestive and Liver Diseases, Department of Medicine, Columbia University, New York, USA
| | - Michael A McGuckin
- Mucosal Diseases Program, Mater Research Institute-University of Queensland, Translational Research Institute, Woolloongabba, Queensland, Australia
| | - Philip Sutton
- Centre for Animal Biotechnology, Faculty of Veterinary and Agricultural Sciences, University of Melbourne, Parkville, Victoria, Australia Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, Victoria, Australia
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Drici AEM, Moulessehoul S, Tifrit A, Diaf M, Turki DK, Bachir M, Tou A. Effect of IL-1β and IL-1RN polymorphisms in carcinogenesis of the gastric mucosa in patients infected with Helicobacter pylori in Algeria. Libyan J Med 2016; 11:31576. [PMID: 27340011 PMCID: PMC4919366 DOI: 10.3402/ljm.v11.31576] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2016] [Accepted: 05/27/2016] [Indexed: 12/12/2022] Open
Abstract
Background Infection with Helicobacter pylori is considered a potential risk of developing gastric cancer in association with contributing host genetic factor. IL-1β and IL-1RN polymorphisms appear to maintain and promote Helicobacter pylori infection and to stimulate neoplastic growth of the gastric mucosa. Objective and methods In order to elucidate the effect of these polymorphisms in combination with gastric cancer in a population from northwestern Algeria, a case-control study was carried out on 79 patients infected with H. pylori with chronic atrophic gastritis and/or gastric carcinoma, and 32 subjects were recruited as case-control. IL-1β-31 bi-allelic and IL-1β-511 bi-allelic polymorphisms and IL-1RN penta-allelic were genotyped. Results IL-1β-31C was associated with an increased risk of developing gastric carcinoma (OR=4.614 [1.43−14.81], p=0.01). However, IL-1RN2 heterozygous allele type was significantly associated with chronic atrophic gastritis (OR=4.2 [1.23−3.61], p=0.022). IL-1β-511T was associated with an increased risk of development of chronic atrophic gastritis (OR=4.286 [1.54−11.89], p=0.005). Conclusion IL-1β and IL-1RN polymorphisms associated with H. pylori infection contribute to the development of chronic atrophic gastritis and gastric carcinomas in an Algerian population. The alleles IL-1β-31C and IL-1RN were associated with an increased risk of developing gastric carcinoma, and IL-1β-511T with an increased risk of developing chronic atrophic gastritis with no significant association of developing gastric carcinoma.
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Affiliation(s)
- Amine El-Mokhtar Drici
- Department of Biology, Faculty of Natural and Life Sciences, Djillali LIABES University, Sidi-Bel-Abbes, Algeria;
| | - Soraya Moulessehoul
- Department of Biology, Faculty of Natural and Life Sciences, Djillali LIABES University, Sidi-Bel-Abbes, Algeria
| | - Abdelkarim Tifrit
- Department of Biology, Faculty of Natural and Life Sciences, Djillali LIABES University, Sidi-Bel-Abbes, Algeria
| | - Mustapha Diaf
- Department of Biology, Faculty of Natural and Life Sciences, Djillali LIABES University, Sidi-Bel-Abbes, Algeria
| | - Douidi Kara Turki
- Department of Gastroenterology, University Hospital of Sidi-Bel-Abbes, Sidi-Bel-Abbes, Algeria
| | - Meryem Bachir
- Department of Biology, Faculty of Sciences, Hassiba Ben Bouali University, Chlef, Algeria
| | - Abdenacer Tou
- Anatomopathology Department, University Hospital of Sidi-Bel-Abbes, Sidi-Bel-Abbes, Algeria
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Choi YJ, Kim N, Jang W, Seo B, Oh S, Shin CM, Lee DH, Jung HC. Familial Clustering of Gastric Cancer: A Retrospective Study Based on the Number of First-Degree Relatives. Medicine (Baltimore) 2016; 95:e3606. [PMID: 27196462 PMCID: PMC4902404 DOI: 10.1097/md.0000000000003606] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
This comprehensive cross-sectional study aimed to identify factors contributing to familial aggregation of gastric cancer (GC). A total of 1058 GC patients and 1268 controls were analyzed separately according to the presence or absence of a first-degree relative of GC (GC-relative). Logistic regression analysis adjusted for age, gender, residence during childhood, smoking, alcohol intake, monthly income, spicy food ingestion, Helicobacter pylori status and host cytokine polymorphisms was performed. Cytotoxin-associated gene A (cagA) positivity was a distinctive risk factor for GC in the family history (FH)-positive group (odds ratio [OR], 2.39; 95% confidence interval [CI], 1.42-4.00), while current/ex-smoker, moderate to strong spicy food ingestion, and non-B blood types were more closely associated with GC in the FH-negative group. Among the FH-positive group, alcohol consumption showed a synergistic carcinogenic effect in the at least 2 GC-relatives group compared to the 1 GC-relative group (1.71 vs. 9.58, P for interaction = 0.026), and this was dose-dependent. In the subjects with ≥2 GC-relatives, TGFB1-509T/T was a risk factor for GC (OR 23.74; 95% CI 1.37-410.91), as were rural residency in childhood, alcohol consumption, spicy food ingestion, and cagA positivity. These results suggest that subjects with FH may be a heterogeneous group in terms of gastric cancer susceptibility. Especially, subjects with ≥2 GC-relatives should undergo risk stratification including TGFB1-509T/T and alcohol consumption.
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Affiliation(s)
- Yoon Jin Choi
- From the Department of Internal Medicine (YJC, NK, CMS and DHL), Seoul National University Bundang Hospital, Seongnam; Department of Internal Medicine and Liver Research Institute (NK, SO, DHL and HCJ), Seoul National University College of Medicine; and Department of Statistics (WJ, BS), College of Science, Seoul National University, Seoul, South Korea
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Hudler P. Challenges of deciphering gastric cancer heterogeneity. World J Gastroenterol 2015; 21:10510-10527. [PMID: 26457012 PMCID: PMC4588074 DOI: 10.3748/wjg.v21.i37.10510] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2015] [Revised: 06/19/2015] [Accepted: 08/31/2015] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer is in decline in most developed countries; however, it still accounts for a notable fraction of global mortality and morbidity related to cancer. High-throughput methods are rapidly changing our view and understanding of the molecular basis of gastric carcinogenesis. Today, it is widely accepted that the molecular complexity and heterogeneity, both inter- and intra-tumour, of gastric adenocarcinomas present significant obstacles in elucidating specific biomarkers for early detection of the disease. Although genome-wide sequencing and gene expression studies have revealed the intricate nature of the molecular changes that occur in tumour landscapes, the collected data and results are complex and sometimes contradictory. Several aberrant molecules have already been tested in clinical trials, although their diagnostic and prognostic utilities have not been confirmed thus far. The gold standard for the detection of sporadic gastric cancer is still the gastric endoscopy, which is considered invasive. In addition, genome-wide association studies have confirmed that genetic variations are important contributors to increased cancer risk and could participate in the initiation of malignant transformation. This hypothesis could in part explain the late onset of sporadic gastric cancers. The elaborate interplay of polymorphic low penetrance genes and lifestyle and environmental risk factors requires additional research to decipher their relative impacts on tumorigenesis. The purpose of this article is to present details of the molecular heterogeneity of sporadic gastric cancers at the DNA, RNA, and proteome levels and to discuss issues relevant to the translation of basic research data to clinically valuable tools. The focus of this work is the identification of relevant molecular changes that could be detected non-invasively.
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Changes of immunocytic phenotypes and functions from human colorectal adenomatous stage to cancerous stage: Update. Immunobiology 2015; 220:1186-96. [PMID: 26153874 DOI: 10.1016/j.imbio.2015.06.003] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2015] [Revised: 05/27/2015] [Accepted: 06/01/2015] [Indexed: 02/07/2023]
Abstract
It is believed that chronic inflammation as seen in patients with ulcerative colitis significantly increases the colorectal cancer (CRC) risk and functions as the main driving force for the development of colitis associated CRC. Recently, increasing evidences suggest that inflammation is also involved in the processing of sporadic CRCs that mostly develop from the preformed adenomas through a long-term progression. Within the adenoma/CRC tumor microenvironment, high dense immunocytes with significant phenotypic and functional changes have been observed. These cells might produce high level of inflammatory mediators and then affect the adenoma-cancer transition. In this review, we summarize the update on altered phenotypes and inflammatory mediators within the tumor microenvironment from the adenomatous stage to the cancerous stage, and discuss the significance of inflammatory mediators as biomarkers in predicating the progression from the premalignant adenoma lesion to the sporadic CRC lesion and the potential as therapeutic targets.
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Datta De D, Roychoudhury S. To be or not to be: The host genetic factor and beyond in Helicobacter pylori mediated gastro-duodenal diseases. World J Gastroenterol 2015; 21:2883-2895. [PMID: 25780285 PMCID: PMC4356907 DOI: 10.3748/wjg.v21.i10.2883] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2014] [Revised: 08/28/2014] [Accepted: 01/08/2015] [Indexed: 02/06/2023] Open
Abstract
Helicobacter pylori (H. pylori) have long been associated with a spectrum of disease outcomes in the gastro-duodenal system. Heterogeneity in bacterial virulence factors or strains is not enough to explain the divergent disease phenotypes manifested by the infection. This review focuses on host genetic factors that are involved during infection and eventually are thought to influence the disease phenotype. We have summarized the different host genes that have been investigated for association studies in H. pylori mediated duodenal ulcer or gastric cancer. We discuss that as the bacteria co-evolved with the host; these host gene also show much variation across different ethnic population. We illustrate the allelic distribution of interleukin-1B, across different population which is one of the most popular candidate gene studied with respect to H. pylori infections. Further, we highlight that several polymorphisms in the pathway gene can by itself or collectively affect the acid secretion pathway axis (gastrin: somatostatin) thereby resulting in a spectrum of disease phenotype
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Helicobacter pylori Infection in Gastroesophageal Reflux Disease in the Asian Countries. Gastroenterol Res Pract 2015; 2015:985249. [PMID: 25642246 PMCID: PMC4302361 DOI: 10.1155/2015/985249] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2014] [Accepted: 12/23/2014] [Indexed: 12/17/2022] Open
Abstract
Helicobacter pylori infection, a common infection in many countries, is related to the clinical course of upper gastrointestinal diseases. Gastroesophageal reflux disease (GERD) is a common esophageal disease in Western countries and its prevalence is increasing in Asian countries. The pathophysiology of GERD is multifactorial. Although no single factor has been isolated as the cause of GERD, a negative association between the prevalence of H. pylori and the severity of GERD, including Barrett's esophagus, has been demonstrated in epidemiological studies. The high prevalence of H. pylori infection affects the incidence of GERD in Asian countries. In the subjects with East Asian CagA-positive strains, acid injury may be minimized by hypochlorhydria from pangastritis and gastric atrophy. Additionally, host genetic factors may affect the development of GERD. The interactions between genetic factors and the virulence of H. pylori infection may be the reason for the low prevalence of GERD in Asian countries. H. pylori eradication is not considered pivotal in GERD exacerbation based on evidence from Western studies. A recent meta-analysis demonstrated that eradication therapy of H. pylori was related to a higher risk of developing de novo GERD in Asian studies. H. pylori infection remains an inconclusive and important issue in GERD in Asian countries.
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Irtiza S, Samie AU, Ali S, Siddiqi MA, Naqash SH, Sameer AS. IL-1β polymorphism and expression associated with decreased risk of gastric carcinoma: a case control study in the ethnic Kashmiri population, India. Asian Pac J Cancer Prev 2015; 16:1987-1992. [PMID: 25773799 DOI: 10.7314/apjcp.2015.16.5.1987] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
The aim of this research was to investigate the possible association between gastric carcinoma (GC) and polymorphisms of the IL-1β gene in the Kashmiri population using peripheral blood DNA from 150 gastric carcinoma cases and 250 population controls with detailed data for clinicopathological characteristics of the disease. Two SNPs in the IL-1β gene were selected for this study. Expression of IL-1β was studied in 50 gastric carcinoma cases using immunohistochemistry and RT-PCR and then correlated with genotype. The frequency of the IL-1β-511 C allele was significantly higher in the GC case group (53.3%) than in controls (45.4%) with an odds ratio (OR) of 0.73 and a P value of 0.03. Multivariate regression analysis showed associations of gastric carcinoma with mutant form of IL-1β-511 TT (OR 0.309; P value <0.001) and the CC genotype of IL-1β-31 (OR 0.313; P value of 0.002). Haplotype analysis of IL-1β-31 and IL-1β-511 showed decreased association of IL- 1β-31 T with IL-1β-511 C with gastric carcinoma (OR 0.728; P value 0.03). Expression study of 50 samples by immunohistochemistry (IHC) and RT-PCR showed association with grade III and stage III+IV. After correlating the expression with polymorphism no association was found.
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Affiliation(s)
- Syed Irtiza
- Department of Biochemistry, Faculty of Life Sciences, Jamia Hamdard University, New Delhi, India E-mail :
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Abstract
Gastric cancer remains highly prevalent and accounts for a notable proportion of global cancer mortality. This cancer is also associated with poor survival rates. Understanding the genetic basis of gastric cancer will offer insights into its pathogenesis, help identify new biomarkers and novel treatment targets, aid prognostication and could be central to developing individualized treatment strategies in the future. An inherited component contributes to <3% of gastric cancers; the majority of genetic changes associated with gastric cancer are acquired. Over the past few decades, advances in technology and high-throughput analysis have improved understanding of the molecular aspects of the pathogenesis of gastric cancer. These aspects are multifaceted and heterogeneous and represent a wide spectrum of several key genetic influences, such as chromosomal instability, microsatellite instability, changes in microRNA profile, somatic gene mutations or functional single nucleotide polymorphisms. These genetic aspects of the pathogenesis of gastric cancer will be addressed in this Review.
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Affiliation(s)
- Mairi H McLean
- National Cancer Institute, Laboratory of Molecular Immunoregulation, Cancer &Inflammation Program, 1050 Boyles Street, Frederick, MD 21702-1201, USA
| | - Emad M El-Omar
- Division of Applied Medicine, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB51 5ER, UK
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Kulmambetova GN, Imanbekova MK, Logvinenko AA, Sukashev AT, Filipenko ML, Ramanсulov EM. Association of Cytokine Gene Polymorphisms with Gastritis in a Kazakh Population. Asian Pac J Cancer Prev 2014. [DOI: 10.7314/apjcp.2014.15.18.7763] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
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The IL-1RN and IL-4 gene polymorphisms are potential genetic markers of susceptibility to bladder cancer: a case-control study. World J Urol 2014; 33:389-95. [PMID: 24850227 DOI: 10.1007/s00345-014-1323-4] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2013] [Accepted: 05/12/2014] [Indexed: 10/25/2022] Open
Abstract
PURPOSE We investigated the relationship between the distribution of the IL-1RN, TNF-β and IL-4 polymorphism and the clinical features of bladder cancer. MATERIALS AND METHODS A total of 100 patients with bladder carcinoma and 102 healthy control subjects were enrolled in the study. The IL-1RN, IL-4 and TNF-β gene polymorphisms were identified by PCR restriction fragment length polymorphism-based analysis. Allelic frequencies were compared between patient and the controls. Tumor stage, histopathological grade, tumor size/number and smoking condition were evaluated with IL-1RN, IL-4 and TNF-β gene polymorphisms. RESULTS Allele distribution frequencies of IL-1RN and IL-4 gene polymorphisms were significantly different between patients and control groups. However, allele distribution of TNF-β gene was not statistically significant. There was no difference in allele distribution of the three genes in both groups regarding stage, tumor size, number of tumors and smoking condition. Although allele distribution of IL-4 gene showed significant difference considering histopathological grades in both smoking and total patients group, allele distribution of IL-1RN and TNF-β was not different. CONCLUSION The present research suggests that the IL-1RN and IL-4 gene polymorphisms are potential genetic markers of susceptibility to bladder cancer. In the future, clinical improvements on diagnosis, treatment and prognosis of bladder carcinoma are expected owing to development of more sensitive and specific tests for genetic polymorphisms of cytokines that are effective on inflammation.
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Lakhanpal M, Yadav DS, Devi TR, Singh LC, Singh KJ, Latha SP, Chauhan PS, Verma Y, Zomavia E, Sharma J, Chandra Kataki A, Saxena S, Kapur S. Association of interleukin-1β -511 C/T polymorphism with tobacco-associated cancer in northeast India: a study on oral and gastric cancer. Cancer Genet 2014; 207:1-11. [PMID: 24561215 DOI: 10.1016/j.cancergen.2014.01.002] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2013] [Revised: 11/10/2013] [Accepted: 01/09/2014] [Indexed: 12/11/2022]
Abstract
The IL-1β -511 C/T polymorphism is associated with increased IL-1 production and with increased risk of developing cancers. In this study, 251 patients (125 with gastric cancer [GC] and 126 with oral cancer [OC]) and 207 normal controls from northeast (NE) India were genotyped for the IL-1β -511 C/T polymorphism by PCR-restriction fragment length polymorphism (RFLP) and sequencing. Analysis of results showed betel-quid chewing to be a major risk factor (OR = 2.01, 95% CI = 1.05-3.87; P = 0.035) for OC. Inheritance of the IL-1β -511 CT or TT resulted in a 2.6- to 3.05-fold increase in the risk of developing OC relative to that of participants who possessed the reference genotype (OR = 2.57, 95% CI = 1.06-6.22; P = 0.036 and OR = 3.05, 95% CI = 1.22-7.63; P = 0.017), after adjusting for potential confounders. The dominant genetic model also confirmed the presence of the T allele as a significant risk factor for OC (OR = 2.72, 95% CI = 1.15-6.42; P = 0.02). In GC, interaction of the CT genotype with tobacco and betel-quid chewing habits conferred a significant 78% and 89% reduced risk of cancer, respectively. In conclusion, for the NE Indian population, the IL-1β -511 CC and CT genotypes were significantly associated with increased risk of OC. However, the interaction of the CT genotype with risk habits may play a preventive role for GC but not for OC.
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Affiliation(s)
- Meena Lakhanpal
- National Institute of Pathology, Safdarjang Hospital Campus, Indian Council of Medical Research, New Delhi, India
| | - Dhirendra Singh Yadav
- National Institute of Pathology, Safdarjang Hospital Campus, Indian Council of Medical Research, New Delhi, India
| | - Thoudam Regina Devi
- National Institute of Pathology, Safdarjang Hospital Campus, Indian Council of Medical Research, New Delhi, India
| | - Laishram Chandreshwor Singh
- National Institute of Pathology, Safdarjang Hospital Campus, Indian Council of Medical Research, New Delhi, India
| | | | - Santhi P Latha
- National Institute of Pathology, Safdarjang Hospital Campus, Indian Council of Medical Research, New Delhi, India
| | - Pradeep Singh Chauhan
- National Institute of Pathology, Safdarjang Hospital Campus, Indian Council of Medical Research, New Delhi, India
| | | | | | | | | | - Sunita Saxena
- National Institute of Pathology, Safdarjang Hospital Campus, Indian Council of Medical Research, New Delhi, India
| | - Sujala Kapur
- National Institute of Pathology, Safdarjang Hospital Campus, Indian Council of Medical Research, New Delhi, India.
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Moon HS, Mantzoros CS. Adiponectin and metformin additively attenuate IL1β-induced malignant potential of colon cancer. Endocr Relat Cancer 2013; 20:849-59. [PMID: 24157941 DOI: 10.1530/erc-13-0240] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Both adiponectin (AD) and metformin (Met) have been proposed to downregulate cell proliferation of colon cancer cells, but whether their effect might be additive has not been studied to date. Genetic studies in humans have suggested an important role for interleukin 1β (IL1β) in cancer pathogenesis. Direct evidence that IL1β contributes to the development of colon cancer has not yet been fully confirmed and no previous studies have evaluated how IL1β may interact with AD and/or Met to regulate malignant potential and intracellular signaling pathways in human and mouse colon cancer cells. We conducted in vitro studies using human (LoVo) and mouse (MCA38) colon cancer cell lines to evaluate whether AD and Met alone or in combination may antagonize IL1β-regulated malignant potential in human and mouse colon cancer cell lines. IL1β increased malignant potential and regulated the expression of tumor suppressor (p53) and cell cycle regulatory genes (p21, p27, and cyclin E2) in human and mouse colon cancer cell lines. These effects were reversed by co-administration of AD and/or Met and were additively altered by AD and Met in combination in a STAT3- and AMPK/LKB1-dependent manner. We also observed using fluorescence activated cell sorter analysis that IL1β-regulated cell cycle progression is altered by AD and Met alone or in combination. Our novel mechanistic studies provide evidence for an important role for IL1β in colon cancer and suggest that AD and/or Met might be useful agents in the management or chemoprevention of IL1β-induced colon carcinogenesis.
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Affiliation(s)
- Hyun-Seuk Moon
- Division of Endocrinology, Diabetes, and Metabolism, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA Section of Endocrinology, Boston VA Healthcare System, Harvard Medical School, JP9B52A, 150 South Huntington Avenue, Boston, Massachusetts 02130, USA
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Interleukin-1 gene polymorphisms in chronic gastritis patients infected with Helicobacter pylori as risk factors of gastric cancer development. Arch Immunol Ther Exp (Warsz) 2013; 61:503-12. [PMID: 23995914 PMCID: PMC3898137 DOI: 10.1007/s00005-013-0245-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2012] [Accepted: 08/05/2013] [Indexed: 12/20/2022]
Abstract
Epidemiological investigations indicated association of the Helicobacter pylori infections with the occurrence of inflammatory conditions of the gastric mucosa and development of chronic gastritis and intestinal type of gastric cancer. IL1A and IL1B genes have been proposed as key factors in determining risk of gastritis and malignant transformation. The aim of this paper was to evaluate association of interleukin-1 gene polymorphisms with chronic gastritis, atrophy, intestinal metaplasia, dysplasia and intestinal type of gastric cancer in H. pylori-infected patients. Patients subjected to analysis represent group of 144 consecutive cases that suffered from dyspepsia with coexisting infection of H. pylori and chronic gastritis, chronic atrophic gastritis, intestinal metaplasia, dysplasia or gastric cancer. Molecular studies involved analysis of –889C>T polymorphism of IL1A gene and +3954C>T polymorphism of IL1B gene. Statistical analysis of association of polymorphism –889C>T of gene IL1A with changes in gastric mucosa showed lack of significance, whereas +3954C>T polymorphism of IL1B gene showed significant association. Frequency of allele T of +3954C>T polymorphism of IL1B gene was higher in group of patients with chronic gastritis, atrophy, intestinal metaplasia, dysplasia or intestinal type of gastric cancer (32.1 %) as compared with population group (23 %), χ2 = 4.61 and p = 0.03. This corresponds to odds ratio: 1.58, 95 % CI: 1.04–2.4. Our results indicate that +3954C>T polymorphism of IL1B gene increase susceptibility to inflammatory response of gastric mucosa H. pylori-infected patients and plays a significant role in the development of chronic gastritis, atrophy, intestinal metaplasia, dysplasia and the initiation of carcinogenesis.
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Interleukin-1β induced by Helicobacter pylori infection enhances mouse gastric carcinogenesis. Cancer Lett 2013; 340:141-7. [PMID: 23920123 DOI: 10.1016/j.canlet.2013.07.034] [Citation(s) in RCA: 57] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2013] [Revised: 07/14/2013] [Accepted: 07/28/2013] [Indexed: 12/18/2022]
Abstract
Interleukin-1β (Il1b) is considered to be involved in Helicobacter pylori (HP)-induced human gastric carcinogenesis, while the role of its polymorphisms in gastric cancer susceptibility remains controversial. Here, we aimed to clarify the role of HP infection-induced IL1B in gastric inflammation and carcinogenesis using Il1b(-/-) (Il1b-null) mice. In gastric mucosa of the Il1b(+/+) (WT) mice, HP infection induced Il1b expression and severe inflammation. In contrast, in Il1b-null mice, recruitment of neutrophils and macrophages by HP infection was markedly suppressed. In a carcinogenicity test, the multiplicity of gastric tumors was significantly suppressed in theIl1b-null mice (58% of WT; P<0.005). Mechanistically, HP infection induced NF-κB activation both in the inflammatory and epithelial cells in gastric mucosae, and the activation was attenuated in the Il1b-null mice. Accordingly, increased proliferation and decreased apoptosis of gastric epithelial cells induced by HP infection in the WT mice were attenuated in the Il1b-null mice. These results demonstrated that the IL1B physiologically induced by HP infection enhanced gastric carcinogenesis by affecting both inflammatory and epithelial cells.
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Kim JJ, Kim N, Hwang S, Kim JY, Kim JY, Choi YJ, Lee DH, Jung HC. Relationship of interleukin-1β levels and gastroesophageal reflux disease in Korea. J Gastroenterol Hepatol 2013; 28:90-8. [PMID: 23020284 DOI: 10.1111/j.1440-1746.2012.07274.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/27/2012] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIM Gastric mucosal expression of interleukin (IL)-1β may alter acid secretion and influence the development of gastroesophageal reflux disease (GERD). The relationship of gastric mucosal IL-1β level and GERD was evaluated in the Korean population. METHODS Genotypes of IL-1B-511 and IL-1RN VNTR polymorphism and clinical characteristics were analyzed in 44 patients with erosive esophagitis (EE), 32 patients with minimal change lesions (MCL), 54 patients with non-erosive reflux disease (NERD) and 113 controls. Gastric mucosal IL-1β levels were measured by enzyme linked immunosorbent assay. RESULTS Significant differences were found between the EE and the control group with respect to sex, body mass index, and Helicobacter pylori infection. On the other hand, the MCL and the NERD group showed similar characteristics to that of the control group. IL-1B-511 genetic polymorphism showed relationship with gastric mucosal IL-1β levels. That is, T/T group (112.4 ± 14.3 pg/mg) had higher IL-1β level than C/C group (59.5 ± 11.6, P = 0.011). T carriers (92.8 ± 7.6 pg/mg) showed higher level than T non-carrier group (P = 0.050). In addition, mucosal IL-1β level of the EE group (52.3 ± 9.9 pg/mg) was lower than that of the control (107.8 ± 12.6 pg/mg, P = 0.001), the MCL (103.1 ± 13.5 pg/mg, P = 0.004), and the NERD group (83.8 ± 14.5 pg/mg, P = 0.079). However, genetic polymorphisms of IL-1B-511 and IL-1RN VNTR did not reach statistical significance among four groups. CONCLUSION Gastric mucosal IL-1β level might be one factor in the development of GERD.
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Affiliation(s)
- Jin Joo Kim
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
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Zhao JD, Geng PL, Li ZQ, Cui S, Zhao JH, Wang LJ, Li JZ, Ji FX, Li GY, Shen GS, Lin MZ, Shen CF, Cao CZ. Associations between interleukin-1 polymorphisms and gastric cancers among three ethnicities. World J Gastroenterol 2012; 18:7093-9. [PMID: 23323013 PMCID: PMC3531699 DOI: 10.3748/wjg.v18.i47.7093] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2012] [Revised: 10/29/2012] [Accepted: 11/08/2012] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the associations between interleukin (IL)-1B and IL-1RN polymorphisms and gastric cancers among the Tibet, Hui and Han ethnicities. METHODS Genomic DNA was extracted from peripheral blood of 210, 205, and 202 healthy volunteers and from 155, 158, and 197 gastric cancer patients from the Tibet, Hui, and Han populations, respectively. Polymorphisms in IL-1B and IL-1RN were analyzed by denaturing high-performance liquid chromatography. RESULTS Carriers of the IL-1B-31 CC genotype had an increased risk of intestinal type gastric cancer [odds ratio (OR) = 2.17, P = 0.037] in the Tibet ethnicity. Carriers of the IL-1B 2/L genotype had an increased risk of both intestinal and diffuse types of gastric cancer (OR = 2.08, 2.31, P = 0.007, 0.016, respectively) in the Hui ethnicity. In the Han population, carriers of the IL-1B-31 CC, IL-1B-511CT, TT genotypes had increased risk of intestinal type gastric cancer (OR = 2.51, 2.74, 5.66, P = 0.005, 0.002, 0.000, respectively). CONCLUSION IL-1B and IL-RN genotypes may differentially contribute to gastric cancer among the Tibet, Hui, and Han ethnicities in the Qinghai area of China.
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Burada F, Angelescu C, Mitrut P, Ciurea T, Cruce M, Saftoiu A, Ioana M. Interleukin-4 receptor -3223T→C polymorphism is associated with increased gastric adenocarcinoma risk. CANADIAN JOURNAL OF GASTROENTEROLOGY = JOURNAL CANADIEN DE GASTROENTEROLOGIE 2012; 26:532-536. [PMID: 22891178 PMCID: PMC3414475 DOI: 10.1155/2012/804173] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/23/2011] [Accepted: 12/05/2011] [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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Affiliation(s)
| | | | - Paul Mitrut
- Department of Internal Medicine, University of Medicine and Pharmacy of Craiova, Craiova, Romania
| | | | - Mihai Cruce
- Research Center of Gastroenterology and Hepatology
| | | | - Mihai Ioana
- Research Center of Gastroenterology and Hepatology
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Shin WG, Kim HJ, Cho SJ, Kim HS, Kim KH, Jang MK, Lee JH, Kim HY. The COX-2-1195AA Genotype Is Associated with Diffuse-Type Gastric Cancer in Korea. Gut Liver 2012; 6:321-7. [PMID: 22844559 PMCID: PMC3404168 DOI: 10.5009/gnl.2012.6.3.321] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2011] [Accepted: 11/28/2011] [Indexed: 01/18/2023] Open
Abstract
BACKGROUND/AIMS The potential role of the cyclooxygenase (COX)-2 polymorphism has been reported in relation to the risk of gastrointestinal tract malignancies. Therefore, we investigated whether COX-2 polymorphisms are associated with the risk of gastric cancer (GC) in Korea, one of the areas with a high prevalence of this condition. METHODS We evaluated the genotypic frequencies of COX-2-765 and -1195 in 100 peptic ulcer patients, 100 GC patients, and 100 healthy controls. The polymorphisms of the COX-2-765 and -1195 genes were analyzed by polymerase chain reaction and restriction fragment length polymorphisms. RESULTS The frequencies of the COX-2-1195 GG, GA, and AA genotype were 20%, 60%, and 20% in intestinal-type GC and 8%, 48%, and 44% in diffuse-type GC, respectively (p=0.021). There were no significant differences in the frequency of COX-2-765 genotypes between intestinal-type GC and diffuse-type GC (p=0.603). Age- and sex-adjusted logistic regression analysis showed that the COX-2-1195 AA genotype was the independent risk factor of diffuse-type GC compared with the COX-2-1195 GG genotype (p=0.041; odds ratio, 6.22; 95% confidence interval, 1.077 to 35.870). CONCLUSIONS The COX-2-1195 AA genotype may render subjects more susceptible to diffuse-type GC.
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Affiliation(s)
- Woon Geon Shin
- Department of Internal Medicine, Hallym University College of Medicine, Seoul, Korea
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Kang JM, Kim N, Shin CM, Lee HS, Lee DH, Jung HC, Song IS. Predictive factors for improvement of atrophic gastritis and intestinal metaplasia after Helicobacter pylori eradication: a three-year follow-up study in Korea. Helicobacter 2012; 17:86-95. [PMID: 22404438 DOI: 10.1111/j.1523-5378.2011.00918.x] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIMS To date, data on the effects of anti-Helicobacter therapy on the improvement of atrophic gastritis (AG) and intestinal metaplasia (IM) have been conflicting. This study was performed to investigate whether eradication of H. pylori could lead to the improvement of AG and IM, and the prognostic factors associated with the improvement of AG and IM. METHODS Four hundred patients consisting of H. pylori-negative (n = 116) and H. pylori-positive (n = 284) groups were followed up 1 and 3 years after initial H. pylori tests. Serum levels of pepsinogen (PG), bacteria, environmental factors, and genetic polymorphisms were determined. RESULTS The grade of corpus atrophy decreased at 1 and 3 years after successful eradication (p < .001 and p = .033, respectively). However, there was no significant change in the IM in the antrum and in the corpus. Prediction factors for the improvement of corpus AG by H. pylori eradication were baseline low PG I/II ratio (≤3), high salt intake, and corpus-predominant gastritis. IM improvement was also associated with spicy food intake and high baseline grade of IM, in addition to these factors. In addition, IL-1B-511 C/T and IL-6-572 C/G alleles were found to inhibit IM improvement. However, H. pylori-negative and noneradicated group did not show any significant change in AG or IM. CONCLUSION Corpus AG was reversed by H. pylori eradication, and improvement of IM by H. pylori eradiation was more definite in patients with severe IM, low PG I/II ratio, and corpus-predominant gastritis, suggesting that H. pylori eradication is valuable even in severe cases.
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Affiliation(s)
- Jung Mook Kang
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
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Wu JCY. Does Helicobacter pylori infection protect against esophageal diseases in Asia? Indian J Gastroenterol 2011; 30:149-53. [PMID: 21870139 DOI: 10.1007/s12664-011-0124-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2011] [Accepted: 08/12/2011] [Indexed: 02/04/2023]
Abstract
The speculations on the protective role of Helicobacter pylori against gastroesophageal reflux disease (GERD) originated from epidemiological observations. These studies have shown that the rising trend of GERD is coincident with declining prevalence of H. pylori and peptic ulcer disease in Asia. Furthermore, most case-control and population-based studies suggest a negative association between H. pylori infection and GERD. It is generally believed that the preponderance of cagA+ and vacA+ virulent strains and proinflammatory interleukin-1 beta polymorphism increase the risk of hypochlohydria and protects against the development of GERD in Asian population. Recovery of gastric acid secretion and emergence of reflux esophagitis has been reported after H. pylori eradication in patients with corpus gastritis and atrophic gastritis. Recent studies have also reported that H. pylori eradication leads to recovery of ghrelin secreting cells in the gastric corpus and a rise in plasma ghrelin levels, which may contribute to obesity through its appetite-stimulating action and predispose to GERD. The prevalence of H. pylori infection is generally lower in younger Asians who enjoy improved socioeconomic status and sanitation compared with their older counterparts. The Asian population is probably facing a rising generation with high gastric acid and ghrelin secretion rates. These physiological changes may contribute to increased dietary calorie intake, obesity and increased prevalence of GERD.
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Affiliation(s)
- Justin C Y Wu
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, China.
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Polymorphisms in interleukin-1B (IL-1B) and interleukin 1 receptor antagonist (IL-1RN) genes associate with gastric cancer risk in the Chinese population. Dig Dis Sci 2011; 56:2017-23. [PMID: 21243433 DOI: 10.1007/s10620-010-1557-y] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2010] [Accepted: 12/31/2010] [Indexed: 12/12/2022]
Abstract
BACKGROUND Gastric cancer is one of the most common malignancies afflicting the Chinese population. Polymorphisms in interleukin-1B (IL-1B) and interleukin-1 receptor antagonist (IL-1RN) genes have been associated with increased gastric cancer risk. AIMS A case-control study enrolled 392 gastric cancer patients and 508 healthy were carried out to investigate the association between polymorphisms in IL-1B and IL-1RN and gastric cancer risk. METHODS Polymerase chain reaction (PCR)-restriction fragment length polymorphism was used for detection of two potentially functional polymorphisms (IL-1B-31 and IL-1B-511) in the IL-1B gene promoter and PCR was used for detection of the variable tandem repeat in the second intron of IL-1RN. RESULTS The data showed that the IL-1B-31CC genotype increased gastric cancer risk to an adjusted odd of 2.27 (95% CI, 1.49-3.46), IL-1B-31CT to 1.48 (95% CI, 1.01-2.16) and IL-1B-31CT/CC to 1.68 (95% CI, 1.17-2.40), while IL-1B-51TT genotype associated with increased gastric cancer risk to an adjusted odd of 2.53 (95% CI, 1.67-3.84), IL-1B-511TC to 1.45 (95% CI, 1.02-2.06), and IL-1B-511TC TT/TC to 1.72 (95% CI, 1.23, 2.39). Furthermore, IL-1RN heterogeneity genotype (IL-1RN2L) was associated with gastric cancer risk to an adjusted odd of 1.70 (95% CI, 1.05-2.74) compared to the wild-type homozygote (IL-1RNLL). In addition, H. pylori infection enhanced gastric cancer risk through these SNPs. CONCLUSIONS The data from the current study demonstrated that the genotype CC or CT of IL-1B-31, TT or CT of IL-1B-511, and 2L of IL-1RN increased risk of gastric cancer in this Chinese population and the risk was further enhanced by H. pylori.
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He B, Zhang Y, Pan Y, Xu Y, Gu L, Chen L, Wang S. Interleukin 1 beta (IL1B) promoter polymorphism and cancer risk: evidence from 47 published studies. Mutagenesis 2011; 26:637-42. [PMID: 21653279 DOI: 10.1093/mutage/ger025] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Interleukin 1β (IL-1B) is a pro-inflammatory cytokine against infection, playing an important role in the pathogenesis of cancers. The -31T/C polymorphism of the interleukin 1β gene (IL1B) has been implicated in cancer risk through its influence on the IL1B transcription. However, results from studies are conflicting. To clarify the association, a meta-analysis was performed for 11 125 cases and 14 415 controls from 47 published case-control studies. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of the association. No significant associations were observed for total cancer from all the comparisons. Through the stratified analyses, there was a statistically significant decreased risk of hepatocellular cancer in carriers of the C allele than non-carriers (CC versus TT: OR = 0.87, 95% CI: 0.77-0.98, P(heterogeneity) = 0.103; TC versus TT: OR = 0.77, 95% CI: 0.62-0.95, P(heterogeneity) = 0.734; TC + CC versus TT: OR = 0.74, 95% CI: 0.61-0.91, P(heterogeneity) = 0.472). Similarly, decreased risk was observed for gastric cancer of the C/C genotype compared with the T/T genotype (OR = 0.87, 95% CI: 0.77-0.98, P(heterogeneity) = 0.103). Using the recessive model, a significantly decreased risk was observed for gastric cancer (OR = 0.88, 95% CI: 0.80-0.97, P(heterogeneity) = 0.158), European population (OR = 0.84, 95% CI: 0.73-0.97, P(heterogeneity) = 0.070) and positive infection-matched studies (OR = 0.75, 95% CI: 0.60-0.94, P(heterogeneity) = 0.220); however, an increased risk was found for breast cancer (OR = 1.34, 95% CI: 1.18-1.61, P(heterogeneity) = 0.116). Although some modest bias could not be eliminated, this meta-analysis suggests that the IL1B -31C allele is a low-penetrance protective factor for the development of cancer, in particular for that associated with infection.
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Affiliation(s)
- Bangshun He
- Central Laboratory, Nanjing First Hospital Affiliated to Nanjing Medical University, 68 Changle Road, Nanjing 210006, Jiangsu, China
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Tahara T, Shibata T, Nakamura M, Yamashita H, Yoshioka D, Okubo M, Yonemura J, Kamiya Y, Ishizuka T, Hirata I, Arisawa T. Effect of polymorphisms of IL-1β and TNF-α genes on CpG island hyper methylation (CIHM) in the nonneoplastic gastric mucosa. Mol Carcinog 2011; 50:835-45. [PMID: 21400614 DOI: 10.1002/mc.20759] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2010] [Revised: 01/05/2011] [Accepted: 02/02/2011] [Indexed: 01/26/2023]
Abstract
CpG island hyper methylation (CIHM) is one of the major events in gastric carcinogenesis. To evaluate the influence of host genetic factors in CIHM related carcinogenesis, we investigated the association between common polymorphisms in IL-1β and TNF-α genes, with CIHM status in the nonneoplastic gastric mucosa. Polymorphisms in the IL-1β gene (-31T>C and -511C>T) and the TNF-α gene (-857C>T) were genotyped in 385 cancer-free subjects. CIHM of four candidate genes: p16 (INK4a), p14 (ARF), E-cadherin (CDH1), and death-associated protein kinase (DAP-kinase), were determined by methylation-specific-polymerase chain reaction (MSP). CIHM high was defined as two or more CpG islands methylated. CIHM of all four genes and CIHM high were significantly associated with Helicobacter pylori infection status. In over all, significant marginal association was found between IL-1β-511 TT genotype and reduced susceptibility to CIHM of DAP-kinase (adjusted OR = 0.48, 95% CI = 0.29-0.78) and CIHM high (adjusted OR = 0.53, 95% CI = 0.32-0.86). This association was more enhanced in subjects 65 yr or younger age. We also found positive association between TNF-α-857T carrier and increased susceptibility to CIHM of CDH (adjusted OR = 1.78, 95% CI = 1.01-3.16), and CIHM high (adjusted OR = 1.86, 95% CI = 1.04-3.33) in the same generation. The mean number of CIHM was lower in subjects with IL-1β-511TT genotype, while the mean number was higher in subjects with TNF-α-857 T carrier especially in subjects 65 yr and younger patients. IL-1β-511 TT genotype is associated with reduced susceptibility to CIHM especially in younger generation. Furthermore, the TNF-α-857T carrier is associated with increased susceptibility of CIHM in the same generation.
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Affiliation(s)
- Tomomitsu Tahara
- Department of Gastroenterology, Fujita Health University School of Medicine, Toyoake, Aichi, Japan
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Why is the coexistence of gastric cancer and duodenal ulcer rare? Examination of factors related to both gastric cancer and duodenal ulcer. Gastric Cancer 2011; 14:4-12. [PMID: 21249411 DOI: 10.1007/s10120-011-0005-9] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2010] [Accepted: 09/16/2010] [Indexed: 02/07/2023]
Abstract
The coexistence of gastric cancer with duodenal ulcer has been found empirically to be rare, but why it is rare is difficult to explain satisfactorily. To elucidate this question, we carried out a literature review of the subject. The frequency with which the two diseases coexist is 0.1-1.7%, and the main factor associated with both gastric cancer and duodenal ulcer is Helicobacter pylori infection. However, there are marked differences between the disorders of hyperchlorhydria in duodenal ulcer, and hypochlorhydria in gastric cancer. The most acceptable view of the reason for the difference may be that the acquisition of H. pylori infection occurs mainly in childhood, so that the time of acquisition of atrophic gastritis may be the most important, and if atrophic gastritis is not acquired early, high levels of gastric acid may occur, and consequently acute antral gastritis and duodenal ulcer may occur in youth, whereas, in elderly individuals, persistent H. pylori infections and the early appearance of atrophic gastritis may be the causes of low gastric acid, and consequently gastric cancer may occur. In patients with duodenal ulcer, factors such as nonsteroidal anti-inflammatory drugs (NSAIDs) and dupA-H. pylori strains may contribute to preventing the early acquisition of atrophic gastritis, while acid-suppressive therapy and vascular endothelial growth factor and other entities may inhibit atrophic gastritis. In contrast, in gastric cancer, factors such as excessive salt intake, acid-suppressive therapy, polymorphisms of inflammatory cytokines, and the homB-H. pylori strain may contribute to the early acquisition of atrophic gastritis, while factors such as NSAIDs; fruits and vegetables; vitamins A, C, and E; and good nutrition may inhibit it.
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Persson C, Canedo P, Machado JC, El-Omar EM, Forman D. Polymorphisms in inflammatory response genes and their association with gastric cancer: A HuGE systematic review and meta-analyses. Am J Epidemiol 2011; 173:259-70. [PMID: 21178102 DOI: 10.1093/aje/kwq370] [Citation(s) in RCA: 138] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
To evaluate the association between gastric cancer susceptibility and inflammation-related gene polymorphisms, the authors conducted a series of meta-analyses using a predefined protocol. Genes investigated were those coding for the interleukin (IL) proteins (IL1B, IL1RN, IL8, and IL10) and for tumor necrosis factor-alpha. Gastric cancers were stratified by histologic subtype and anatomic subsite, by Helicobacter pylori infection status, by geographic location (Asian or non-Asian study population), and by a quantitative index of study quality. All published literature and meeting abstracts from the period 1990-2006 were considered. Results consistently supported increased cancer risk for IL1RN2 carriers; the increased risk was specific to non-Asian populations and was seen for intestinal and diffuse cancers, distal cancers, and, to a lesser extent, cardia cancers. Analyses restricted to high-quality studies or H. pylori-positive cases and controls also showed significant associations with both carrier status and homozygosity status. In Asian populations, reduced risk was observed in association with IL1B-31C carrier status. This effect was also observed in analyses restricted to high-quality studies. These results indicate the importance of stratification by anatomic site, histologic type, H. pylori infection, and country of origin. Study quality considerations, both laboratory and epidemiologic, can also affect results and may explain, in part, the variability in results published to date.
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Affiliation(s)
- Christina Persson
- Hormonal and Reproductive Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA.
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Martínez-Carrillo DN, Garza-González E, Betancourt-Linares R, Mónico-Manzano T, Antúnez-Rivera C, Román-Román A, Flores-Alfaro E, Illades-Aguiar B, Fernández-Tilapa G. Association of IL1B -511C/-31T haplotype and Helicobacter pylori vacA genotypes with gastric ulcer and chronic gastritis. BMC Gastroenterol 2010; 10:126. [PMID: 20979650 PMCID: PMC2988070 DOI: 10.1186/1471-230x-10-126] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2010] [Accepted: 10/27/2010] [Indexed: 02/08/2023] Open
Abstract
Background The association between proinflammatory cytokine gene polymorphisms and gastric diseases related to Helicobacter pylori varies by population and geographic area. Our objective was to determine if the IL-1B -511 T>C and -31 C>T polymorphisms and H. pylori vacA genotypes are associated with risk of chronic gastritis and gastric ulcer in a Mexican population. Methods We conducted endoscopic studies in 128 patients with symptoms of dyspepsia. We took two biopsies from the body, antrum, or ulcer edge from each patient, and classified our histopathological findings according to the Sydney System. H. pylori infection and vacA genotyping were accomplished via PCR from total DNA of the gastric biopsies. We confirmed the presence of anti-H. pylori serum IgG and IgM in 102 control subjects. In both case subjects and control subjects, the IL-1B -511 T>C polymorphism was genotyped by PCR-RFLPs and the IL-1B -31 C>T polymorphism was genotyped by pyrosequencing. Results Sixty-two point seven (62.7%) of the 102 control subjects were H. pylori-seropositive. Among the case subjects, 100 were diagnosed with chronic gastritis and 28 with gastric ulcer. We found that 77% of the patients with chronic gastritis and 85.7% of the patients with gastric ulcer were H. pylori-positive. The predominant H. pylori genotype was vacA s1m1 (58.4%) and the most frequent subtype was vacA s1. The -511 TC, (rs16944 -511 T>C) genotype and the -511C allele were associated with chronic gastritis (OR = 3.1, 95% CI = 1.4-6.8 and OR = 3.0, 95% CI = 1.4-6.0, respectively). The subjects carrying -31T (rs1143627 -31 C>T) were found to be at a higher risk of having chronic gastritis (OR = 2.8, 95% CI = 1.3-5.8). The IL-1B -511C/-31T haplotype was associated with chronic gastritis (OR = 2.1, 95% CI = 1.2-3.8) but not with gastric ulcer. Conclusions The H. pylori vacA genotypes identified herein were similar to those reported for other regions of Mexico. The vacA s1m1 genotype was not associated with gastric ulcer. In the southern Mexican population, the IL-1B -511C and -31T alleles and the -511C/-31T and -511T/-31T haplotypes are associated with increased risk of chronic gastritis and gastric ulcer.
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Affiliation(s)
- Dinorah N Martínez-Carrillo
- Laboratorio de Investigación Clínica, Unidad Académica de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Av, Lázaro Cárdenas S/N, Ciudad Universitaria, Colonia Haciendita, Chilpancingo, Guerrero, C,P, 39090, México
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Xue H, Lin B, Ni P, Xu H, Huang G. Interleukin-1B and interleukin-1 RN polymorphisms and gastric carcinoma risk: a meta-analysis. J Gastroenterol Hepatol 2010; 25:1604-17. [PMID: 20880168 DOI: 10.1111/j.1440-1746.2010.06428.x] [Citation(s) in RCA: 99] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIM We aimed to explore the role of interleukin (IL)-1B cluster gene polymorphisms at positions -511, -31, and +3954 and the receptor IL-1RN variable number tandem repeat polymorphisms in the susceptibility to gastric carcinoma through a systematic review and meta-analysis. METHODS Each initially included article was scored for quality appraisal. The desirable data were extracted and registered into databases. Studies that deviated from Hardy-Weinberg equilibrium were excluded. Eighteen studies were ultimately eligible for the meta-analysis of IL1B-511, 21 studies for IL1B-31, 10 studies for IL1B+3954, and 20 studies for IL1RN variable number tandem repeat genetic polymorphisms, respectively. Original groups were collapsed and re-grouping was adopted in line with the most probably appropriate genetic models. Potential sources of heterogeneity were sought out via stratification and sensitivity analyses, and biases across studies were estimated. RESULTS The pooled odds ratios (95% confidence intervals, P-value) associated with IL-1B -511 T carriers versus CC genotypes and with RN *2 carriers versus L/L were 1.23 (1.04-1.45, P = 0.015) and 1.26 (1.06-1.51, P = 0.010), respectively, for overall gastric carcinoma; 1.31 (1.04-1.64, P = 0.020) and 1.47 (1.21-1.79, P = 0.000), respectively, for non-cardia gastric cancer; 1.55 (1.05-2.28, P = 0.026) and 1.66 (1.23-2.25, P = 0.001), respectively, for intestinal type gastric carcinoma; and 1.33 (1.04-1.71, P = 0.023) and 1.31 (1.07-1.61, P = 0.010), respectively, in Caucasians for overall gastric carcinoma. The pooled odds ratio (95% confidence interval, P-value) regarding IL-1B-31 CC plus TT versus CT was 0.73 (0.60-0.89, P = 0.002) for intestinal type gastric carcinoma. Genotyping methods and publication time could constitute the sources of heterogeneity across studies. Publication biases were not found. CONCLUSION IL-1B -511 T allele and IL-1 RN *2 VNTR are significantly associated with an increased risk of developing gastric carcinoma and even more significantly with non-cardia gastric carcinoma or with intestinal-type gastric carcinoma. Both are significantly associated with an increased risk of developing gastric carcinoma among Caucasians, but not among Asians or Hispanics.
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Affiliation(s)
- Huiping Xue
- Department of Gastroenterology, Shanghai Institute of Gastrointestinal Diseases, Shanghai, China
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Hamajima N, Hishida A. Genetic traits for the persistence of Helicobacter pylori infection. Per Med 2010; 7:249-262. [PMID: 29776221 DOI: 10.2217/pme.10.14] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Helicobacter pylori infection elevates the risk of gastric diseases, including peptic ulcer and gastric cancer. Persistent infection is the first step to induce H. pylori-induced multistage diseases. Although the roles of genetic traits on persistent infection have not yet been elucidated, some individuals escape from persistent infection. Possible favorable conditions for H. pylori seem to be low acid secretion, reduced innate immune responses, and easier binding to gastric epithelial cells. IL-1β and TNF-α inhibit acid secretion. The genetic polymorphisms associated with both molecules have the potential to be the genetic traits underlying persistent infection. Functional polymorphisms associated with innate immune responses could also be involved with the genetic traits, but no polymorphisms with consistent associations have been identified so far. The polymorphisms associated with molecules for adhesion to epithelial cells are candidates of genetic traits, but more research is needed.
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Affiliation(s)
| | - Asahi Hishida
- Department of Preventive Medicine, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan
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Zhang L, Du C, Guo X, Yuan L, Niu W, Yu W, Er L, Wang S. Interleukin-8-251A/T polymorphism and Helicobacter pylori infection influence risk for the development of gastric cardiac adenocarcinoma in a high-incidence area of China. Mol Biol Rep 2010; 37:3983-9. [PMID: 20300863 DOI: 10.1007/s11033-010-0057-7] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2009] [Accepted: 03/05/2010] [Indexed: 02/07/2023]
Affiliation(s)
- Liwei Zhang
- Department of Endoscopy, The 4th Affiliated Hospital, Hebei Medical University, 12 Jiankang Road, Shijiazhuang, Hebei, 050011, People's Republic of China
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Peleteiro B, Lunet N, Carrilho C, Durães C, Machado JC, La Vecchia C, Barros H. Association between cytokine gene polymorphisms and gastric precancerous lesions: systematic review and meta-analysis. Cancer Epidemiol Biomarkers Prev 2010; 19:762-76. [PMID: 20200422 DOI: 10.1158/1055-9965.epi-09-0917] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Polymorphisms within interleukin-1 (IL1) and tumor necrosis factor alpha (TNFA) gene clusters are associated with an increased risk of gastric cancer. However, their role in gastric precancerous lesions remains poorly understood. Our objective was to perform a meta-analysis of studies addressing the association between IL1B-511, IL1RN variable number of tandem repeat, and TNFA-308 gene polymorphisms and gastric precancerous lesions, including original data from Portugal and Mozambique. Published studies on the association between these cytokine gene polymorphisms and gastric precancerous lesions were identified by systematic review, and estimates of the association were combined using random-effects meta-analysis taking into account new data obtained from Portuguese volunteer shipyard workers (n = 215) and Mozambican dyspeptic patients (n = 96) who underwent endoscopic and pathologic evaluation following the same protocol. Odds ratio (OR) estimates for intestinal metaplasia were 2.83 [95% confidence interval (95% CI), 1.15-6.96] for the IL1RN*22 genotype, 1.86 (95% CI, 1.03-3.36) for IL1B-511 T carriers, and 0.59 (95% CI, 0.12-3.04) for the TNFA-308*AA genotype in the Portuguese sample. All Mozambican subjects with intestinal metaplasia were T carriers for IL1B-511 and none had the 2 allele for IL1RN. In meta-analysis, IL1RN*22 genotype was associated with an increased risk of gastric precancerous lesions (22 versus LL: OR, 2.27; 95% CI, 1.40-3.70; I(2) = 26.4%; 12 studies). No such association was found for the IL1B-511 (TT versus CC: OR, 1.34; 95% CI, 0.87-2.07; I(2) = 65.7%; 13 studies) or TNFA-308 genotypes (AA versus GG: OR, 0.93; 95% CI, 0.35-2.43; I(2) = 0.0%; 7 studies). The IL1RN*22 genotype seems to consistently increase the risk of gastric precancerous lesions, supporting a role for this polymorphism in the early stages of gastric carcinogenesis.
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Affiliation(s)
- Bárbara Peleteiro
- Serviço de Higiene e Epidemiologia, Faculdade de Medicina da Universidade do Porto, Al. Prof. Hernâni Monteiro, 4200-319 Porto, Portugal.
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Yu J, Zeng Z, Wang S, Tian L, Wu J, Xue L, Lee CW, Zhang M, Goggins WB, Chen M, Hu P, Sung JJY. IL-1B-511 polymorphism is associated with increased risk of certain subtypes of gastric cancer in Chinese: a case-control study. Am J Gastroenterol 2010; 105:557-64. [PMID: 19904240 DOI: 10.1038/ajg.2009.644] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES The association of interleukin-1B (IL-1B)-511 polymorphism with gastric cancer is still controversial, and the association of IL-1B-511 polymorphism with subtypes of gastric cancer is still largely unknown. We investigated whether the association between IL-1B-511 polymorphism and gastric cancer risk varies by clinically important tumor characteristics and the prognostic value of this polymorphism in a large population-based case-control study among Chinese. METHODS A population-based case-control study was conducted between 1999 and 2006 in Guangdong Province, China. A total of 1,010 gastric cancer patients and 1,500 healthy controls were enrolled in this study. Polymorphism in IL-1B-511 was analyzed by PCR-restriction fragment length polymorphism on 501 gastric cancers and 500 healthy controls. RESULTS Compared with the CC genotype, carriers of IL-1B-511 TT genotype had an increased gastric cancer risk (odds ratio (OR)=1.97, 95% confidence interval (CI)=1.29-3.01, P=0.0016). TT genotype was significantly associated with intestinal type of gastric cancer (OR=3.16, 95% CI=1.74-5.71, P=0.0001) but not with diffuse or mixed-type gastric cancer. The test for OR heterogeneity between the intestinal-type and non-intestinal-type gastric cancers was statistically significant (P=0.02). In subgroup analyses, TT genotype was found to be associated with poorly differentiated gastric cancer (OR=3.31, 95% CI=1.43-3.60, P<0.0001), but not with moderately or well-differentiated gastric cancer. IL-1B-511 genotypes were not associated with the prognosis of gastric cancer patients. CONCLUSIONS IL-1B polymorphism influences certain subtypes of gastric cancer according to the clinical and pathological features. Understanding the etiologic heterogeneity of gastric cancer may result in improvements in controlling this disorder.
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Affiliation(s)
- Jun Yu
- Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China.
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Sugimoto M, Furuta T, Yamaoka Y. Influence of inflammatory cytokine polymorphisms on eradication rates of Helicobacter pylori. J Gastroenterol Hepatol 2009; 24:1725-1732. [PMID: 20136959 PMCID: PMC3128255 DOI: 10.1111/j.1440-1746.2009.06047.x] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Pro-inflammatory cytokines and anti-inflammatory cytokines are produced in gastric mucosa from inflammatory cells activated by Helicobacter pylori (H. pylori) infection. Of the inflammatory cytokines, interleukin (IL)-1beta and tumor necrosis factor (TNF)-alpha have a potent inhibitive effect on gastric acid production. Polymorphisms in these genes are associated with individual differences in cytokine messenger RNA levels, which result in different gastric mucosal inflammation, different acid inhibition and different gastroduodenal disease risks in response to H. pylori infection. The sustained higher intragastric pH during an eradication therapy is known to be one of the therapeutic determinants of the H. pylori eradication as well as antibiotics resistance and poor compliance. The IL-1B-511 polymorphism is related to eradication rate, and, in combined analysis of previous reports, the eradication rate in patients with the IL-1B-511 C/C genotype (77.4%, 209/270), low IL-1beta producer genotype, is lower than that of the IL-1B-511 C/T and T/T genotypes (87.2%, 631/724) (Odds ratio for eradication failure: 1.98, 95% confidence interval: 1.38-2.84, P = 0.0002). Moreover, the odds ratio of combined CYP2C19 rapid metabolizer-IL-1B-511 C/C type for eradication failure is 11.15 (5.23-23.78) times that of the CYP2C19 poor metabolizer-IL-1B-511 non-C/C type. However, there is no positive data indicating the role of other inflammatory cytokine polymorphisms (e.g. IL-1RN, TNF-A or IL-10) in eradication therapy. Nevertheless, the studies show that inflammatory cytokine polymorphisms, especially the IL-1B-511 T/T genotype, are the determinants of eradication by affecting gastric acid secretion and mucosal inflammation. Therefore, the tailored eradication therapy, considering inflammatory cytokine polymorphisms, may be effective for the higher eradication rates.
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Affiliation(s)
- Mitsushige Sugimoto
- Department of Medicine-Gastroenterology, Michael E. DeBakey Veterans Affairs Medical Center and Baylor College of Medicine, Houston, Texas, USA.
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Hishida A, Matsuo K, Goto Y, Naito M, Wakai K, Tajima K, Hamajima N. Associations of a PTPN11 G/A polymorphism at intron 3 with Helicobactor pylori seropositivity, gastric atrophy and gastric cancer in Japanese. BMC Gastroenterol 2009; 9:51. [PMID: 19589142 PMCID: PMC2715419 DOI: 10.1186/1471-230x-9-51] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2008] [Accepted: 07/09/2009] [Indexed: 12/12/2022] Open
Abstract
Background Previous studies have revealed the significance of Helicobacter pylori (H. pylori) infection as a risk factor of gastric cancer. Cytotoxin-associated gene A (cagA) positivity has been demonstrated to determine the clinical outcome of H. pylori infection in the presence of SHP-2 (src homology 2 domain-containing protein tyrosine phosphatase-2). This study aimed to examine the formerly reported association of G/A PTPN11 (protein-tyrosine phosphatase, nonreceptor-type 11) polymorphism (rs2301756) with gastric atrophy, as well as the association with gastric cancer in a Japanese population using a large sample size. Methods Study subjects were 583 histologically diagnosed patients with gastric cancer (429 males and 154 females) and age- and sex-frequency-matched 1,636 non-cancer outpatients (1,203 males and 433 females), who visited Aichi Cancer Center Hospital between 2001–2005. Serum anti-H. pylori IgG antibody and pepsinogens were measured to evaluate H. pylori infection and gastric atrophy, respectively. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by a logistic model. Results Among H. pylori seropositive non-cancer outpatients, the age- and sex-adjusted OR of gastric atrophy was 0.82 (95% CI 0.62–1.10, P = 0.194) for G/A, 0.84 (95% CI 0.39–1.81, P = 0.650) for A/A, and 0.83 (95% CI 0.62–1.09, P = 0.182) for G/A+A/A, relative to G/G genotype, and that of severe gastric atrophy was 0.70 (95% CI 0.47–1.04, P = 0.079), 0.56 (95% CI 0.17–1.91, P = 0.356), and 0.68 (95% CI 0.46–1.01, P = 0.057), respectively. Among H. pylori infected subjects (H. pylori seropositive subjects and seronegative subjects with gastric atrophy), the adjusted OR of severe gastric atrophy was further reduced; 0.62 (95% CI 0.42–0.90, P = 0.012) for G/A+A/A. The distribution of the genotype in patients with gastric cancer was not significantly different from that for H. pylori infected subjects without gastric atrophy. Conclusion Our study results revealed that those with the A/A genotype of PTPN11 rs2301756 polymorphism are at lower risk of severe gastric atrophy, but are not associated with a decreased risk of gastric cancer, which partially supported our previous finding that the polymorphism in the PTPN11 gene encoding SHP-2 was associated with the gastric atrophy risk in H. pylori infected Japanese. The biological roles of this PTPN11 polymorphism require further investigation.
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Affiliation(s)
- Asahi Hishida
- Department of Preventive Medicine/Biostatistics and Medical Decision Making, Nagoya University Graduate School of Medicine, Nagoya, Japan.
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Kabir S. Effect of Helicobacter pylori eradication on incidence of gastric cancer in human and animal models: underlying biochemical and molecular events. Helicobacter 2009; 14:159-71. [PMID: 19702845 DOI: 10.1111/j.1523-5378.2009.00677.x] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Gastric cancer remains one of the most common cancers worldwide. A strong association exists between Helicobacter pylori infection and the risk of developing noncardia gastric cancer. H. pylori eradication by antibiotic treatment is regarded as a primary chemoprevention strategy to reduce gastric cancer incidence. AIM To analyze the efficacy of H. pylori eradication in preventing gastric cancer in human and animal models, and to discuss whether biochemical, genetic, and epigenetic changes associated with H. pylori infection are reversible after curing the infection. RESULTS Several intervention trials have indicated that in some patients, H. pylori eradication leads to regression and prevents the progression of precancerous lesions. The eradication therapy reduces gastric cancer incidence in patients without any precancerous lesions at the baseline and is most effective before the development of atrophic gastritis. A few recent intervention studies in Japan have demonstrated significant prophylactic effects of eradication therapy on the development of gastric cancer, suggesting the use of eradication therapy in high-risk populations as a gastric cancer reduction strategy. However, gastric cancer may still develop despite successful eradication therapy. Studies in animal models have confirmed the use of eradication therapy at an early point of infection to prevent gastric cancer development. CONCLUSION H. pylori eradication may not completely abolish the risk of gastric cancer. However, eradication therapy may be used in high-risk populations to reduce gastric cancer incidence. It can reverse many biochemical, genetic, and epigenetic changes that H. pylori infection induces in the stomach.
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Affiliation(s)
- Shahjahan Kabir
- Academic Research and Information Management, Uppsala, Sweden.
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Wang G, Yu D, Tan W, Zhao D, Wu C, Lin D. Genetic polymorphism in chemokine CCL22 and susceptibility toHelicobacter pyloriinfection-related gastric carcinoma. Cancer 2009; 115:2430-7. [DOI: 10.1002/cncr.24255] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
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Persson C, Engstrand L, Nyrén O, Hansson LE, Enroth H, Ekström AM, Ye W. Interleukin 1-beta gene polymorphisms and risk of gastric cancer in Sweden. Scand J Gastroenterol 2009; 44:339-45. [PMID: 19031173 DOI: 10.1080/00365520802556015] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/09/2023]
Abstract
OBJECTIVE Helicobacter pylori (H. pylori) infection stimulates the production of interleukin (IL)-1 beta, a pro-inflammatory cytokine and suppressor of gastric acid secretion. As both inflammation and hypochlorhydria, which might facilitate proximal colonization of H. pylori and other bacterial species alike, have been implicated in gastric carcinogenesis, much attention has been directed to functional genetic polymorphisms that affect the production of IL-1 beta. The purpose of this study was to clarify the role of these polymorphisms. MATERIAL AND METHODS We analysed a population-based, case-control study in 5 Swedish counties and a hospital-based, case-control study conducted in 8 Swedish hospitals, with a total of 351 gastric cancer cases and 539 controls. The IL1B-31, IL1B-511 and IL1B+3954 biallelic polymorphisms were genotyped using pyrosequencing. The variable number of tandem repeats (VNTR) polymorphism of IL1-RN was analysed using polymerase chain reaction (PCR) followed by gel electrophoresis. Relative risks were estimated by odds ratios with 95% confidence intervals, derived from unconditional logistic regression. RESULTS The risk of gastric cancer was unrelated to genotype in all of the studied polymorphic loci, and the absence of any association was confirmed in both the population-based and hospital-based case-control studies. Analyses confined to histological subtypes (intestinal or diffuse) and site-specific tumours (cardia or distal stomach), as well as analyses stratified by H. pylori infection status and family history of gastric cancer, did not reveal any significant increases or decreases in risk. CONCLUSION Our results do not lend support to the hypothesis that human genetic polymorphisms related to the production of IL-1 beta are associated with the risk of gastric cancer.
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Affiliation(s)
- Christina Persson
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
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The effects of genetic polymorphisms of IL-6, IL-8, and IL-10 on Helicobacter pylori-induced gastroduodenal diseases in Korea. J Clin Gastroenterol 2009; 43:420-8. [PMID: 19077731 DOI: 10.1097/mcg.0b013e318178d1d3] [Citation(s) in RCA: 74] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND The genes that encode proinflammatory and anti-inflammatory cytokines are good candidate markers of host susceptibility to gastroduodenal disease. The present study was performed to evaluate whether or not the genetic polymorphisms of IL-6, IL-8, and IL-10 are associated with gastroduodenal disease in the Korean population. METHODS This study enrolled 1187 patients, including controls, those with gastric cancer (GC), benign gastric ulcer (BGU), and duodenal ulcer patients. Six polymorphisms were genotyped, 3 of IL-10 (at -592, -819, and -1082), 1 of IL-8 (at -251), and 2 of IL-6 (at -174 and -572), by polymerase chain reaction-restriction fragment length polymorphism analysis. RESULTS The frequency of IL-10-1082 G carriers was higher in cases of a diffuse type GC [odds ratio (OR) 1.8, 95% confidence interval (CI): 1.0-3.1, P=0.041] or BGU (OR 1.6, 95% CI: 1.0-2.5, P=0.040), than in the control group regardless of Helicobacter pylori infection. The IL-8-251 A/A genotype was more common in H. pylori-positive patients with GC (OR 2.0, 95% CI: 1.2-3.6, P=0.013) or BGU (OR 2.7, 95% CI: 1.5-4.8, P=0.001) than in H. pylori-positive controls. In addition, the frequencies of IL-6-572 G/G (OR 0.3, 95% CI: 0.1-0.9, P=0.027) and of G carriers (OR 0.5, 95% CI: 0.4-0.8, P=0.003) were lower in H. pylori-positive duodenal ulcer patients than in H. pylori-positive controls. IL-10-592 C/C (OR 0.4, 95% CI: 0.2-0.9, P=0.028) was an independent factor associated with a decreased risk of the intestinal type of GC by multivariate analysis. Furthermore, a synergistic effect was observed between IL-10-592 A/A and IL-8-251 A/A with respect to the development of GC or BGU. CONCLUSIONS These results suggest that the genetic polymorphisms of these 3 inflammation-related cytokines, IL-10, IL-8, and IL-6, are associated with the development of H. pylori-associated gastroduodenal disease.
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Chakravorty M, Datta De D, Choudhury A, Santra A, Roychoudhury S. Association of specific haplotype of TNFalpha with Helicobacter pylori-mediated duodenal ulcer in eastern Indian population. J Genet 2009; 87:299-304. [PMID: 19147919 DOI: 10.1007/s12041-008-0048-9] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Affiliation(s)
- Meenakshi Chakravorty
- Molecular and Human Genetics, Indian Institute of Chemical Biology, Kolkata 700 032, India
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The interleukin-8-251 A allele is associated with increased risk of noncardia gastric adenocarcinoma in Helicobacter pylori-infected Koreans. J Clin Gastroenterol 2009; 43:233-9. [PMID: 18542040 DOI: 10.1097/mcg.0b013e3181646701] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
BACKGROUND AND GOALS Chronic inflammation associated with Helicobacter pylori infection is a risk factor of gastric adenocarcinoma. Interleukin-8 (IL-8) plays an important role in gastric mucosal inflammation induced by H. pylori infection. Recently, studies on the association of genetic polymorphisms of various proinflammatory cytokines with gastric carcinogenesis showed varying results on the basis of the ethnicity. We conducted this study to investigate the association of IL-8-251 A/T polymorphism with gastric carcinogenesis in H. pylori-infected Koreans. STUDY The IL-8-251 A/T polymorphism was identified by polymerase chain reaction-restriction fragment length polymorphism using DNA from a total of 605 H. pylori-infected subjects; 206 controls, 149 chronic atrophic gastritis and/or intestinal metaplasia, 97 gastric dysplasia, and 153 gastric adenocarcinoma. Degrees of gastric mucosal inflammation and mucosal IL-8 level were also assessed. RESULTS The IL-8-251 A carriers showed a higher risk of gastric adenocarcinoma (adjusted odds ratio 2.06, 95% confidence interval 1.16-3.68) than IL-8-251 T/T genotypes. The IL-8-251 A allele was also significantly associated with the degree of neutrophil infiltration, atrophy, and intestinal metaplasia in a younger age group. Among the chronic atrophic gastritis and/or intestinal metaplasia group, mucosal IL-8 level was significantly higher in subjects with IL-8-251 A allele than those with IL-8-251 T/T genotypes (P=0.011). CONCLUSIONS The IL-8-251 A allele is associated with higher IL-8 production, more severe inflammation, mucosal atrophy, and intestinal metaplasia than IL-8-251 T/T genotype in H. pylori-infected hosts. The IL-8-251 A allele may also increase the risk of gastric adenocarcinoma through an enhanced inflammatory process in H. pylori-infected Koreans.
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Chang YW, Oh HC, Jang JY, Hwangbo Y, Lee JW, Lee HJ, Joo KR, Dong SH, Kim SS, Kim HJ, Kim BH, Chang R. IL-1beta and IL-8, matrix metalloproteinase 3, and pepsinogen secretion before and after H. pylori eradication in gastroduodenal phenotypes. Scand J Gastroenterol 2009; 43:1184-93. [PMID: 18609140 DOI: 10.1080/00365520802130209] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
OBJECTIVE Relations between host genetic factors and clinical outcomes of Helicobacter pylori infection are variable among ethnicities. The aim of this study was to examine gastric mucosal cytokines, matrix metalloproteinase 3 (MMP-3), and serum pepsinogen levels before and after eradication of H. pylori according to IL-1B genotypes and benign gastroduodenal phenotypes in a Korean population. MATERIAL AND METHODS A total of 349 Koreans including H. pylori-infected subjects (n=230) and H. pylori-negative controls (n=119) were enrolled. The former subjects were classified into groups according to the presence of non-atrophic gastritis (n=74), atrophic gastritis (n=56), gastric ulcer (n=37), and duodenal ulcer (n=63). IL-1B polymorphisms were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Gastric mucosal IL-1beta, IL-8, and MMP-3, and serum pepsinogen I and II levels were measured by ELISA and radioimmunoassay, respectively. RESULTS There were no significant differences between the IL-1B-31/-511 haplotype (TT/CC, CT/CT, and CC/TT) frequencies among the H. pylori-positive and -negative groups. The genotypes of IL-1B-31/-511 polymorphisms did not affect clinical phenotypes, inflammatory cytokines, MMP-3, and pepsinogen secretion. Subjects with H. pylori-infected atrophic gastritis exhibited significantly higher basal levels of cytokines and a lower pepsinogen I/II ratio than those of other groups. Following H. pylori eradication, inflammatory cytokines significantly decreased and the pepsinogen I/II ratio increased in all groups. CONCLUSIONS Mucosal inflammatory cytokines, MMP-3, and pepsinogen secretion are related to gastroduodenal phenotypes but not to IL-1B genotypes. Eradication of H. pylori can reduce mucosal inflammation and restore pepsinogen secretion.
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Affiliation(s)
- Young Woon Chang
- Department of Gastroenterology, Kyung Hee University College of Medicine, Seoul, Korea
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Erzin Y, Koksal V, Altun S, Dobrucali A, Aslan M, Erdamar S, Goksel S, Dirican A, Kocazeybek B. Role of host interleukin 1beta gene (IL-1B) and interleukin 1 receptor antagonist gene (IL-1RN) polymorphisms in clinical outcomes in Helicobacter pylori-positive Turkish patients with dyspepsia. J Gastroenterol 2009; 43:705-10. [PMID: 18807132 DOI: 10.1007/s00535-008-2220-7] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2007] [Accepted: 05/15/2008] [Indexed: 02/04/2023]
Abstract
BACKGROUND Helicobacter pylori infection leads to different clinical outcomes depending on both host and bacterial factors. In a recent study, we identified H. pylori cagE and babA2 genotypes as independent predictors of duodenal ulcer (DU) and gastric cancer (GC) in dyspepsia patients, but no previous studies have examined the role of host-related genetic factors in Turkey. This time our aim was to evaluate whether polymorphisms of the interleukin 1B (IL-1B) and the interleukin 1 receptor antagonist (IL-1RN) genes are important factors in the differential expression of gastroduodenal diseases in H. pylori-positive dyspepsia patients. METHODS Ninety-three H. pylori-positive patients, 30 with nonulcer dyspepsia (NUD), 30 with DU, and 33 with GC, were investigated. The IL-1B-511 and IL-1B-31 biallelic polymorphisms, and the IL-1RN intron 2 variable number tandem repeat were genotyped by polymerase chain reaction and single-strand confirmation polymorphism analysis. RESULTS The IL-1RN-1/1 genotype was significantly more prevalent among patients with NUD than among those with GC (chi(2) = 9.270; P = 0.002), and the IL-1RN-1/2 genotype was significantly more common in patients with GC (chi(2) = 6.01; P = 0.014). Multivariate regression analysis showed that cagE, babA2, and IL-1RN-1/2 genotypes were independent predictors of GC, but when patients with benign disorders were grouped together (NUD + DU) and compared with patients with GC, regression analysis disclosed that babA2 (P = 0.000) and IL-1B-31 gene polymorphisms (CC or CT) (P = 0.01) were the only independent markers of GC. CONCLUSIONS When analyzed together with host genetic factors, the well established bacterial risk factor babA2 seems to be the most important predictor of malignant disorders, and the presence of the IL-1B-31TT genotype emerges as a protective factor against them.
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Affiliation(s)
- Yusuf Erzin
- Department of Gastroenterology, Istanbul University, Cerrahpasa Medical Faculty, Istanbul, Turkey
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