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Qyi YZ, Aung HH, Aye SN, Tung WS, Naing C. Toll-like receptor 9 (-1237 T/C, -1486 T/C) and the risk of gastric cancer: a meta-analysis of genetic association studies. BMC Cancer 2023; 23:1027. [PMID: 37875868 PMCID: PMC10594725 DOI: 10.1186/s12885-023-11509-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Accepted: 10/10/2023] [Indexed: 10/26/2023] Open
Abstract
BACKGROUND Gastric cancer has a complex aetiology including genetic factors. Individual case-control studies of toll like receptor (TLR) 9 (-1237 T/C, -1486 T/C) polymorphisms in the gastric cancer risk were available, and they showed variation in the findings. Therefore, we performed a meta-analysis to synthesize the evidence on the association between polymorphisms of TLR 9 (-1237 T/C, -1486 T/C) and the risk of gastric cancer using data from eligible studies. METHODS This study followed the PRISMA 2020 Checklist. Studies were searched in health-related databases. The methodological quality of studies was evaluated with the use of Newcastle-Ottawa Scale criteria. The summary odds ratio (OR) and its 95% confidence interval (CI) were used to determine the strength of association between each polymorphism and the risk of gastric cancer using five genetic models. Stratification was done by ethnic groups. For the robustness of the analysis, a leave-one-out meta-analysis was performed. RESULTS Eight case-control studies with 3,644 participants (1914 cases, 1730 controls) were conducted across six countries. Half of the studies were conducted in China. In the NOS methodological quality assessment, only three studies received a high-quality rating (i.e., a score of ≥ 7). TLR 9 (-1486 T/C) polymorphism and the risk of gastric cancer were assessed in six studies, four of Asian ethnicity and two of non-Asian. Under the dominant model, only in the Asian ethnic group showed a marginally and significantly increased risk of gastric cancer (overall: OR = 1.22, 95%CI = 0.90-1.67, I2 = 56%; Asian: OR = 1.24, 95%CI = 1.00-1.54, I2 = 0%, non-Asian: OR = 1.25, 95%CI = 0.38-4.09, I2 = 89%). Under the recessive model in the absence of heterogeneity, only the Asian group had a significantly higher risk of developing gastric cancer (overall: OR = 1.4, 95% CI = 0.74-2.64, I2 = 85%; Asian: OR: 1.41, 95% CI = 1.07-1.86, I2 = 0%, non-Asian: OR = 1.18, 95% CI = 0.12-11.76, I2 = 97%). Under the heterozygous model, there was no significant association with the risk of gastric cancer overall or among any ethnic subgroup. Under the homozygous model in the absence of heterogeneity, only the Asian group had a significantly higher risk of gastric cancer (overall, OR = 1.47, 95% CI = 0.76-2.86, I2 = 82%; Asian: OR = 1.54, 95% CI = 1.13-2.1, I2 = 0%; non-Asian: OR = 1.19, 95% CI = 0.1-14.33, I2 = 96%). Under the allele model, a significantly increased risk of gastric cancer was observed only in the Asian group (overall: OR = 1.23, 95% CI = 0.89-1.71, I2 = 84%; Asian: OR = 1.22, 95% CI = 1.05-1.41, I2 = 0%; non-Asian: OR = 1.24, 95% CI = 0.34-4.59, I2 = 97%). Four studies investigated the association between TLR 9 (-1237 T/C) polymorphism and the risk of developing gastric cancer. Under any of the five genetic models, there was no association between TLR 9 (-1237 T/C) and the development of gastric cancer in overall or in any ethnic subgroup. Sensitivity analysis revealed that the effect was unstable. With a small number of studies with a small number of participants, we addressed the issue of insufficient power for drawing conclusions. CONCLUSIONS The findings suggested that TLR9 (-1486 T/C) may play a role in the risk of gastric cancer specific to the Asian ethnic group. To substantiate the findings on the association between these two polymorphisms (TLR9 -1237 T/C, -1486 T/C) and the risk of gastric cancer, future well-designed case-control studies with a sufficient number of participants in multi-ethnic groups are recommended.
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Affiliation(s)
- Yap Zi Qyi
- School of Medicine, International Medical University, Kuala Lumpur, Malaysia
- School of Humanities, Social Sciences and Law, University of Dundee, Dundee, Scotland, UK
| | - Htar Htar Aung
- School of Medicine, International Medical University, Kuala Lumpur, Malaysia.
| | - Saint-Nway Aye
- School of Medicine, International Medical University, Kuala Lumpur, Malaysia
| | - Wong Siew Tung
- School of Medicine, International Medical University, Kuala Lumpur, Malaysia
| | - Cho Naing
- Faculty of Tropical Health and Medicine, James Cook University, Queensland, Australia
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Gobert AP, Wilson KT. Induction and Regulation of the Innate Immune Response in Helicobacter pylori Infection. Cell Mol Gastroenterol Hepatol 2022; 13:1347-1363. [PMID: 35124288 PMCID: PMC8933844 DOI: 10.1016/j.jcmgh.2022.01.022] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Revised: 01/25/2022] [Accepted: 01/25/2022] [Indexed: 12/30/2022]
Abstract
Gastric cancer (GC) is the fifth most common cancer and the fourth most common cause of cancer-related death worldwide. The intestinal type of GC progresses from acute to chronic gastritis, multifocal atrophic gastritis, intestinal metaplasia, dysplasia, and carcinoma. Infection of the stomach by Helicobacter pylori, a Gram-negative bacterium that infects approximately 50% of the world's population, is the causal determinant that initiates the gastric inflammation and then disease progression. In this context, the induction of the innate immune response of gastric epithelial cells and myeloid cells by H. pylori effectors plays a critical role in the outcome of the infection. However, only 1% to 3% of infected patients develop gastric adenocarcinoma, emphasizing that other mechanisms regulate the localized non-specific response, including the gastric microbiota and genetic factors. This review summarizes studies describing the factors that induce and regulate the mucosal innate immune response during H. pylori infection.
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Affiliation(s)
- Alain P Gobert
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Nashville, Tennessee; Center for Mucosal Inflammation and Cancer, Nashville, Tennessee; Program in Cancer Biology, Nashville, Tennessee.
| | - Keith T Wilson
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Nashville, Tennessee; Center for Mucosal Inflammation and Cancer, Nashville, Tennessee; Program in Cancer Biology, Nashville, Tennessee; Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee; Veterans Affairs Tennessee Valley Healthcare System, Nashville, Tennessee.
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Meliț LE, Mărginean CO, Săsăran MO, Mocan S, Ghiga DV, Bogliş A, Duicu C. Innate immunity - the hallmark of Helicobacter pylori infection in pediatric chronic gastritis. World J Clin Cases 2021; 9:6686-6697. [PMID: 34447815 PMCID: PMC8362532 DOI: 10.12998/wjcc.v9.i23.6686] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Revised: 06/14/2021] [Accepted: 07/05/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Innate immunity was found to be associated with both persistence of Helicobacter pylori (H. pylori) infection and increased risk of gastric cancer. AIM To identify the risk factors associated with H. pylori infection and to establish the role of TLR9 rs352140 in suppressing or promoting inflammation related to this infection in children. METHODS We performed a study of 155 children with digestive symptoms, who were divided into two groups according to the histopathological exam: Group 1 - 48 children with H. pylori-induced chronic gastritis, and Group 2 - control group. RESULTS Rural area and poor living conditions were significantly associated with H. pylori chronic gastritis (P = 0.0042/P < 0.0001). Both positive immunoglobulin A anti H. pylori and the rapid urease test were significantly associated with H. pylori infection (P < 0.0001). Significantly higher values of leukocytes and neutrophils within the peripheral blood were found in children with H. pylori chronic gastritis (P = 0.111/P = 0.284). We found a significant positive correlation between the variant TT genotype of TLR9 rs352140 polymorphism and both leucocytes and neutrophils (P = 0.0225/P = 0.0292). CONCLUSION Variant TT genotype carriers of the TLR9 rs352140 gene polymorphism might have a more severe degree of inflammation.
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Affiliation(s)
- Lorena Elena Meliț
- Department of Pediatrics I, “George Emil Palade” University of Medicine, Pharmacy, Sciences and Technology Târgu Mureș, Târgu Mureș 540136, Romania
| | - Cristina Oana Mărginean
- Department of Pediatrics I, “George Emil Palade” University of Medicine, Pharmacy, Sciences and Technology Târgu Mureș, Târgu Mureș 540136, Romania
| | - Maria Oana Săsăran
- Department of Pediatrics III, “George Emil Palade” University of Medicine, Pharmacy, Sciences and Technology Târgu Mureș, Târgu Mureș 540136, Romania
| | - Simona Mocan
- Department of Pathology, Emergency County Hospital Târgu Mureș, Târgu Mureș 540139, Romania
| | - Dana Valentina Ghiga
- Scientific Medical Research Methodology, “George Emil Palade” University of Medicine, Pharmacy, Sciences and Technology Târgu Mureș, Târgu Mureș 540136, Romania
| | - Alina Bogliş
- Department of Genetics, Center for Advanced Medical and Pharmaceutical Research, “George Emil Palade” University of Medicine, Pharmacy, Sciences and Technology Târgu Mureș, Târgu Mureș 540136, Romania
| | - Carmen Duicu
- Department of Pediatrics I, “George Emil Palade” University of Medicine, Pharmacy, Sciences and Technology Târgu Mureș, Târgu Mureș 540136, Romania
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Kulmambetova G, Shtefanov I, Aitkulova A, Imanbekova M, Iskakova A, Makishev A, Ramankulov Y. Association of polymorphisms in TP53 and the promoter region of IL10 with gastric cancer in a Kazakh population. Bosn J Basic Med Sci 2020; 20:539-546. [PMID: 32651972 PMCID: PMC7664782 DOI: 10.17305/bjbms.2020.4761] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Accepted: 07/02/2020] [Indexed: 12/19/2022] Open
Abstract
The emerging evidence indicates that single nucleotide polymorphisms (SNPs) of the tumor necrosis factor (TNF), interleukin 10 (IL10), tumor protein p53 (TP53), and cluster of differentiation 14 (CD14) genes may determine individual susceptibility to gastric cancer (GC). We aimed to investigate the associations for polymorphisms of the TNF, IL10, TP53, and CD14 genes in a population of Kazakhs, to identify potential risk or protective associations of the SNPs with GC. A case group of 143 patients hospitalized for GC was enrolled. Controls were 355 volunteers with no history of any cancer and frequency matched with cases by age. Differences in proportions for categorical variables and the assessment of genotypic frequencies conforming to the Hardy-Weinberg equilibrium law were evaluated by the Chi-square test. Associations between genetic polymorphisms and the risk of GC were estimated by regression analysis. For genetic analysis, three genetic models (additive, dominant, and recessive) were used. Four significant associations were found. The SNPs rs1042522 of TP53 and rs1800896 of IL10 were risk factors for GC by the additive model. Two polymorphisms of IL10 were protective of GC, namely, rs1800872 by additive model and rs1800871 by recessive model. No significant associations were observed between the TNF and CD14 polymorphisms and GC. The polymorphisms TP53 rs1042522 and IL10 rs1800896 are associated with GC risk, while the polymorphisms IL10 rs1800872 and rs1800871 are protective of GC in the population of Kazakhs.
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Affiliation(s)
- Gulmira Kulmambetova
- Biotechnology Core Facility, National Center for Biotechnology, Nur-Sultan, Kazakhstan
| | - Ivan Shtefanov
- Department of Oncology, City Oncology Center, Nur-Sultan, Kazakhstan
| | - Akbota Aitkulova
- Biotechnology Core Facility, National Center for Biotechnology, Nur-Sultan, Kazakhstan
| | - Meruyert Imanbekova
- Biotechnology Core Facility, National Center for Biotechnology, Nur-Sultan, Kazakhstan
| | - Aisha Iskakova
- Biotechnology Core Facility, National Center for Biotechnology, Nur-Sultan, Kazakhstan
| | - Abay Makishev
- Department of Oncology, City Oncology Center, Nur-Sultan, Kazakhstan
| | - Yerlan Ramankulov
- Biotechnology Core Facility, National Center for Biotechnology, Nur-Sultan, Kazakhstan
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Qaradakhi T, Gadanec LK, McSweeney KR, Abraham JR, Apostolopoulos V, Zulli A. The Anti-Inflammatory Effect of Taurine on Cardiovascular Disease. Nutrients 2020; 12:E2847. [PMID: 32957558 PMCID: PMC7551180 DOI: 10.3390/nu12092847] [Citation(s) in RCA: 81] [Impact Index Per Article: 16.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Revised: 09/02/2020] [Accepted: 09/12/2020] [Indexed: 12/12/2022] Open
Abstract
Taurine is a non-protein amino acid that is expressed in the majority of animal tissues. With its unique sulfonic acid makeup, taurine influences cellular functions, including osmoregulation, antioxidation, ion movement modulation, and conjugation of bile acids. Taurine exerts anti-inflammatory effects that improve diabetes and has shown benefits to the cardiovascular system, possibly by inhibition of the renin angiotensin system. The beneficial effects of taurine are reviewed.
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Affiliation(s)
- Tawar Qaradakhi
- Institute for Health and Sport, Victoria University, Melbourne, VIC 8001, Australia; (L.K.G.); (K.R.M.); (J.R.A.); (V.A.); (A.Z.)
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Guan Y, Huang XF, Li PJ, Cao W, Gao XH, Guan X. Association of CD14 gene -260C>T and -561C>T polymorphisms with cancer susceptibility: A meta-analysis. J Gene Med 2020; 22:e3151. [PMID: 31826310 DOI: 10.1002/jgm.3151] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2019] [Revised: 11/12/2019] [Accepted: 12/07/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Two polymorphisms, -260C>T (rs2569190) and -561C>T (rs5744455), in the CD14 gene have been implicated in susceptibility to cancer. However, the results remain inconclusive. The current meta-analysis was carried out aiming to confirm the function of these two polymorphisms on the susceptibility of cancer. METHODS We collected eligible studies from databases, including PubMed, EMBASE, CNKI, Wanfang, and VIP (Weipu). We used logistic regression calculation to compute odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS After strict selection, 24 studies with 5854 cases and 10339 controls for -260C>T and seven studies with 1809 cases and 7289 controls for -561C>T were finally enlisted into our analysis reference material. Pool results revealed that neither -260C>T, nor -561C>T was found to have any association with overall cancer susceptibility. Nevertheless, when stratified by cancer type, we detected a decreased risk associated with other cancers in a heterozygous model (OR = 0.69, 95% CI = 0.51-0.93, p = 0.014) and a dominant model (OR = 0.70, 95% CI = 0.53-0.93, p = 0.012) for -561C>T. An increased risk was found in other cancers under an allele model (OR = 1.29, 95% CI = 1.03-1.62, p = 0.026), in laryngeal cancer under a dominant model (OR = 1.38, 95% CI = 1.11-1.71, p = 0.003) and for a score ≤ 9 under a recessive model (OR = 1.45, 95% CI = 1.09-1.91, p = 0.009) for -561C>T. CONCLUSIONS In the present study, we conclude that the CD14 -260C>T and -561C>T polymorphisms might not be associated with overall cancer risk. Further studies are encouraged to confirm this conclusion.
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Affiliation(s)
- Yin Guan
- Intensive Critical Care Unit, Lanzhou University Second Hospital, Lanzhou, Gansu, China
| | - Xiao-Feng Huang
- Intensive Critical Care Unit, Lanzhou University Second Hospital, Lanzhou, Gansu, China
| | - Pei-Jie Li
- Intensive Critical Care Unit, Lanzhou University Second Hospital, Lanzhou, Gansu, China
| | - Wen Cao
- Intensive Critical Care Unit, Lanzhou University Second Hospital, Lanzhou, Gansu, China
| | - Xue-Hua Gao
- Department of Anethesiology, Gansu Provincial Cancer Hospital, Lanzhou, Gansu, China
| | - Xia Guan
- Digestive Endoscopy Center, The Second Peoples Hospital of Lanzhou, Lanzhou, Gansu, China
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Semlali A, Almutairi M, Pathan AAK, Azzi A, Parine NR, AlAmri A, Arafah M, Aljebreen AM, alharbi O, Almadi MA, Azzam NA, Alanazi M, Rouabhia M. Toll-like receptor 6 expression, sequence variants, and their association with colorectal cancer risk. J Cancer 2019; 10:2969-2981. [PMID: 31281474 PMCID: PMC6590037 DOI: 10.7150/jca.31011] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2018] [Accepted: 04/25/2019] [Indexed: 12/13/2022] Open
Abstract
This is the first study to examine the potential correlation of the rs3796508 and rs5743810 SNPs of the TLR6 gene in patients with colorectal cancer (CRC) in a subset of the Saudi population. TLR6 gene expression was studied by real-time PCR assaysin 10 matching normal and cancer colon tissues. TLR6 expression at the protein level was determined by immunohistochemistry. A case-control search was conductedon 115 case patients and 102 controls. All samples were genotyped with the TaqMan assay for the TLR6 gene. Odds ratios and 95% confidence interval were computed from logistic regression models after adjusting for age, sex, and tumor localization. Our findings showed a decrease in TLR6 expression (p <0.001) in colon cancer tissues when compared to normal colon tissues. Global analysis revealed no significant association between the TLR6 rs3796508 and rs5743810 and CRC in this population. However, the Val/Met genotype of rs3796508 had a significantly higher frequency in the control group than in the cases for the male group (OR= 0.095, and p= 0.03385) or the volunteers aged more than 57 years OR= 0.152; and p= 0.04069, respectively). Two non-synonymous single nucleotide polymorphisms (SNP; S249P and V327M) were common in a few patients and were predicted as damaging by SIFT and Polyphen and were further analyzed for their protein stability and function using advanced bioinformatics tools. The results suggest that TLR6 rs3796508 has a crucial role as a protective factor against colorectal cancer in the older Saudi male population.
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Affiliation(s)
- Abdelhabib Semlali
- Groupe de Recherche en Écologie Buccale, Département de stomatologie, Faculté de Médecine Dentaire, Université Laval, Québec, Québec, Canada
- Department of Biochemistry, College of Science King Saud University, Riyadh, Kingdom of Saudi Arabia
| | - Mikhlid Almutairi
- Zoology Department, College of Science, King Saud University, Riyadh, Kingdom of Saudi Arabia
| | - Akbar Ali Khan Pathan
- Department of Biochemistry, College of Science King Saud University, Riyadh, Kingdom of Saudi Arabia
- Integrated Gulf Biosystems (IGB), Riyadh, Kingdom of Saudi Arabia
| | - Arezki Azzi
- Pharmacology department, College of Medicine, Imam Mohammed Ibn Saud Islamic University (IMSIU), Riyadh, Kingdom of Saudi Arabia
| | - Narasimha Reddy Parine
- Department of Biochemistry, College of Science King Saud University, Riyadh, Kingdom of Saudi Arabia
| | - Abdullah AlAmri
- Department of Biochemistry, College of Science King Saud University, Riyadh, Kingdom of Saudi Arabia
| | - Maha Arafah
- College of Medicine, King Saud University, Riyadh, Kingdom of Saudi Arabia
| | - Abdulrahman M Aljebreen
- Division of Gastroenterology, King Khalid University Hospital, King Saud University, Riyadh, Saudi Arabia
| | - Othman alharbi
- Division of Gastroenterology, King Khalid University Hospital, King Saud University, Riyadh, Saudi Arabia
| | - Majid A Almadi
- Division of Gastroenterology, King Khalid University Hospital, King Saud University, Riyadh, Saudi Arabia
| | - Nahla Ali Azzam
- Division of Gastroenterology, King Khalid University Hospital, King Saud University, Riyadh, Saudi Arabia
| | - Mohammad Alanazi
- Department of Biochemistry, College of Science King Saud University, Riyadh, Kingdom of Saudi Arabia
| | - Mahmoud Rouabhia
- Groupe de Recherche en Écologie Buccale, Département de stomatologie, Faculté de Médecine Dentaire, Université Laval, Québec, Québec, Canada
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The Relationship between Toll-like Receptors and Helicobacter pylori-Related Gastropathies: Still a Controversial Topic. J Immunol Res 2019; 2019:8197048. [PMID: 30863783 PMCID: PMC6378784 DOI: 10.1155/2019/8197048] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2018] [Accepted: 01/02/2019] [Indexed: 12/13/2022] Open
Abstract
Innate immunity represents the first barrier against bacterial invasion. Toll-like receptors (TLRs) belong to the large family of pattern recognition receptors (PRRs), and their activation leads to the induction of inflammatory cytokines, chemokines, antigen-presenting molecules, and costimulatory molecules. Recent studies have focused on identifying the association between TLRs and Helicobacter pylori- (H. pylori-) related diseases. Therefore, this minireview focuses on assessing the role of these TLRs in the development of H. pylori-related gastropathies. Both TLR2 and TLR were found to be involved in H. pylori LPS recognition, with contradictory results most likely due to both the inability to obtain pure LPS in experimental studies and the heterogeneity of the bacterial LPS. In addition, TLR2 was found to be the most extensively expressed gene among all the TLRs in gastric tumors. High levels of TLR4 were also associated with a higher risk of gastric cancer. TLR5 was initially associated with the recognition of H. pylori flagellin, but it seems that this bacterium has developed mechanisms to escape this recognition representing an important factor involved in the persistence of this infection and subsequent carcinogenesis. TLR9, the only TLR with both anti- and proinflammatory roles, was involved in the recognition of H. pylori DNA. The dichotomous role of TLR9, promoting or suppressing the infection, depends on the gastric environment. Recently, TLR7 and TLR8 were shown to recognize purified H. pylori RNA, thereby inducing proinflammatory cytokines. TLR1 and TLR10 gene polymorphisms were associated with a higher risk for gastric cancer in H. pylori-infected individuals. Different gene polymorphisms of these TLRs were found to be associated with gastric cancer depending mostly on ethnicity. Further studies are required in order to develop preventive and therapeutic strategies against H. pylori infections based on the functions of TLRs.
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Hamdy S, Osman AM, Zakaria ZA, Galal I, Sobhy M, Hashem M, Allam WR, Abdel-Samiee M, Rewisha E, Waked I, Abdelwahab SF. Association of Toll-like receptor 3 and Toll-like receptor 9 single-nucleotide polymorphisms with hepatitis C virus persistence among Egyptians. Arch Virol 2018; 163:2433-2442. [PMID: 29860675 DOI: 10.1007/s00705-018-3893-8] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2017] [Accepted: 05/15/2018] [Indexed: 02/05/2023]
Abstract
Toll-like receptors (TLRs) give the innate immune system a considerable specificity for a large range of pathogens. TLR3 detects dsRNA of viruses while TLR9 recognizes bacterial and viral unmethylated CpG motifs. This study examined whether there is a potential association between single-nucleotide polymorphisms (SNPs) in the TLR3.rs3775290 (c.1377C/T), TLR9.rs5743836 (-1237T→C) and TLR9.rs352140 (G2848A) genes and HCV infection among Egyptian patients and healthcare workers (HCWs). We enrolled 546 subjects (409 HCWs and 137 patients) divided into four groups: group 1 included 265 seronegative, aviremic subjects; group 2 included 25 seronegative, viremic subjects; group 3 included 87 subjects with spontaneously resolved HCV infection; and group 4 included 169 chronic HCV patients. All subjects were genotyped for TLR3.rs3775290, TLR9.rs5743836 and TLR9.rs352140 SNPs by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) analysis. TLR3.rs3775290 "CC" genotype was associated with chronic HCV infection, where there was a significantly greater frequency of this genotype among chronic patients when compared to subjects with spontaneously resolved infection (63.9% vs. 51.9%; p = 0.033; OR = 1.639 and 95% CI = 0.94-2.84). However, this SNP did not correlate with the HCV RNA load among the chronic subjects (p > 0.05). There was no significant difference in TLR9.rs5743836 and TLR9.rs352140 genotype distribution between groups (p > 0.05). Lack of association between the three SNPs was found, as the three SNPs are located on two different chromosomes. In conclusion, the TLR3.rs3775290 "CC" genotype was associated with HCV chronicity, while the TLR9 gene may not play a major role in HCV infection.
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Affiliation(s)
- Shaimaa Hamdy
- The Holding Company for Biological Products and Vaccines (VACSERA), 51 Wizaret El-Zeraa St., Agouza, Giza, 22311, Egypt
| | - Ahmed M Osman
- Department of Zoology, Faculty of Science, Cairo University, Giza, 12613, Egypt
| | - Zainab A Zakaria
- The Holding Company for Biological Products and Vaccines (VACSERA), 51 Wizaret El-Zeraa St., Agouza, Giza, 22311, Egypt
- Biomedical Research Laboratory, Faculty of Pharmacy, Heliopolis University for Sustainable Development, Cairo, Egypt
| | - Iman Galal
- The Holding Company for Biological Products and Vaccines (VACSERA), 51 Wizaret El-Zeraa St., Agouza, Giza, 22311, Egypt
| | - Maha Sobhy
- The Holding Company for Biological Products and Vaccines (VACSERA), 51 Wizaret El-Zeraa St., Agouza, Giza, 22311, Egypt
| | - Mohamed Hashem
- The Holding Company for Biological Products and Vaccines (VACSERA), 51 Wizaret El-Zeraa St., Agouza, Giza, 22311, Egypt
- Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Walaa R Allam
- The Holding Company for Biological Products and Vaccines (VACSERA), 51 Wizaret El-Zeraa St., Agouza, Giza, 22311, Egypt
- Centre for Genomics, University of Science and Technology, Zewail City of Science and Technology, Giza, Egypt
| | - Mohamed Abdel-Samiee
- Department of Hepatology and Gastroenterology, National Liver Institute, Menoufia University, Menoufia, 32511, Egypt
| | - Eman Rewisha
- Department of Hepatology and Gastroenterology, National Liver Institute, Menoufia University, Menoufia, 32511, Egypt
| | - Imam Waked
- Department of Hepatology and Gastroenterology, National Liver Institute, Menoufia University, Menoufia, 32511, Egypt
| | - Sayed F Abdelwahab
- The Holding Company for Biological Products and Vaccines (VACSERA), 51 Wizaret El-Zeraa St., Agouza, Giza, 22311, Egypt.
- Department of Microbiology and Immunology, Faculty of Medicine, Minia University, Minia, 61511, Egypt.
- Department of Microbiology, Taif Faculty of Pharmacy, Al-Haweiah, PO Box 888, Taif, 21974, Kingdom of Saudi Arabia.
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Zhang F, Wang D, Chen F. Toll-like receptor-9 in hypoxic nasopharyngeal carcinoma cells and its correlation with cell proliferation and apoptosis. Oncol Lett 2017; 14:7829-7832. [PMID: 29250178 DOI: 10.3892/ol.2017.7235] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2017] [Accepted: 10/10/2017] [Indexed: 11/05/2022] Open
Abstract
The purpose of this study was to investigate the correlation between the expression of Toll-like receptor-9 (TLR-9) and cell proliferation and apoptosis in hypoxic nasopharyngeal carcinoma cells. Human nasopharyngeal carcinoma cell line HNE-1 (EBV positive) and CNE-1 (EBV negative) were used. Cells were divided into normal control group, hypoxia group and hyperoxia group. Hypoxic conditions were 5% CO2 and 0.01% partial pressure of oxygen, hyperoxia conditions were 5% CO2 and 10% partial pressure of oxygen. Reverse transcription-PCR (RT-PCR) and western blot analysis were used to detect the expression of TLR-9 mRNA and protein at 6, 12 and 24 h after the beginning of cell culture. MTT assay was used to detect the cell proliferation rate and flow cytometry was used to detect cell apoptosis rate. Expression levels of TLR-9 mRNA and protein in hypoxia group reached the peak at 12 h after the beginning of cell culture, and were significantly higher than those of hyperoxia group at all time-points, expression levels of TLR-9 mRNA and protein of control group were the lowest, difference between groups were all statistically significant (P<0.05). No significant changes in expression levels of TLR-9 mRNA and protein were found in control group and hyperoxia group between different time-points (P>0.05). Compared with the other two groups, cell proliferation rate was gradually decreased and apoptotic rate was gradually decreased in hypoxia group, significant differences were found between hypoxia group, and control group and hyperoxia group (P<0.05), no significant differences were found between control group and hyperoxia group (P>0.05). In conclusion, TLR-9 was highly expressed in hypoxic nasopharyngeal carcinoma cells regulating cell proliferation and apoptosis, which may be an important mechanism of tumorigenesis and a potential target for intervention therapy.
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Affiliation(s)
- Feng Zhang
- Department of Otorhinolaryngology, The Second People's Hospital of Liaocheng, Linqing, Shandong 252601, P.R. China
| | - Deli Wang
- Department of Otorhinolaryngology, The Affiliated Hospital of Taishan Medical University, Tai'an, Shandong 271200, P.R. China
| | - Fasheng Chen
- Department of Otolaryngology Head and Neck Surgery, Central Hospital of Enshi Autonomous Prefecture, Enshi, Hubei 445000, P.R. China
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Abstract
Helicobacter pylori is the most common bacterial infection worldwide, and virtually all infected persons develop co-existing gastritis. H. pylori is able to send and receive signals from the gastric mucosa, which enables both host and microbe to engage in a dynamic equilibrium. In order to persist within the human host, H. pylori has adopted dichotomous strategies to both induce inflammation as a means of liberating nutrients while simultaneously tempering the immune response to augment its survival. Toll-like receptors (TLRs) and Nod proteins are innate immune receptors that are present in epithelial cells and represent the first line of defense against pathogens. To ensure persistence, H. pylori manipulates TLR-mediated defenses using strategies that include rendering its LPS and flagellin to be non-stimulatory to TLR4 and TLR5, respectively; translocating peptidoglycan into host cells to induce NOD1-mediated anti-inflammatory responses; and translocating DNA into host cells to induce TLR9 activation.
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12
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Wifi MNA, Assem M, Elsherif RH, El-Azab HAF, Saif A. Toll-like receptors-2 and -9 (TLR2 and TLR9) gene polymorphism in patients with type 2 diabetes and diabetic foot. Medicine (Baltimore) 2017; 96:e6760. [PMID: 28445304 PMCID: PMC5413269 DOI: 10.1097/md.0000000000006760] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Toll-like receptors (TLRs) are innate immune receptors that mediate the inflammatory response in diabetes mellitus (DM). The aim of this study is to evaluate the association of TLR2 and TLR9 gene polymorphism in patients with type 2 DM (T2DM) and diabetic foot (DF).The study included 90 subjects divided into group I (30 patients with T2DM and DF), group II (30 patients with T2DM and no evidence of DF), and group III (normal control subjects). TLR2 (1350 T/C, rs3804100) and TLR9 (1237 T/C, rs5743836) genotyping was performed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique for all subjects.There was a statistically significant difference in the distribution of TLR9-1237 T/C genotypes between groups I and II (P < .029) as well as between groups I and III (P < .001). Calculated risk estimation revealed that TLR9-1237 polymorphism conferred almost 20 times increased risk of DF disorders in T2DM (OR = 20, 95% CI = 5.38-74.30). There was no statistical difference in the distribution of TLR2-1350T/C genotypes between the 3 groups.TLR9-1237 T/C gene polymorphism may be considered as a molecular risk for DF among patients with T2DM.
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Affiliation(s)
| | | | - Rasha Hamed Elsherif
- Department of Clinical and Chemical Pathology, Faculty of Medicine, Cairo Univeristy, Cairo, Egypt
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13
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Semlali A, Parine NR, Al Amri A, Azzi A, Arafah M, Kohailan M, Shaik JP, Almadi MA, Aljebreen AM, Alharbi O, Ali Azzam N, Rouabhia M, Alanazi MS. Association between TLR-9 polymorphisms and colon cancer susceptibility in Saudi Arabian female patients. Onco Targets Ther 2016; 10:1-11. [PMID: 28031717 PMCID: PMC5179201 DOI: 10.2147/ott.s106024] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
Abstract
Objective The authors aimed to explore the relationship between the expression/polymorphisms of TLR-9 and susceptibility to colon cancer development in the Saudi Arabian population. Methods In total, blood samples from 115 patients with colon cancer and 102 participants without colon cancer were analyzed in this study. Three single-nucleotide polymorphisms (SNPs) were selected from the TLR-9 gene, including two sites within the TLR-9 gene’s promoter region (rs352144 and rs187084) and one site in a TLR-9 intron region (rs5743839). Odds ratios (ORs) and 95% confidence intervals (CIs) were computed from logistic regression models after adjusting for age, gender, and tumor localization. To investigate the differential expression of TLR-9 in colon cancer, TLR-9 expression was evaluated using quantitative real-time reverse transcription polymerase chain reaction on 40 matched normal and colon tissues. Results The authors found that TLR-9 expression was decreased in colon cancer tissues as compared with that in normal tissues. Moreover, significant associations between the TLR-9 rs187084 SNP and colon cancer risk were observed in female patients only. In rs187084, the T allele had a significantly lower frequency (2.8 times) in female cancer patients than in controls (0.27 vs 0.41). The TLR-9 rs352139 and rs352144 SNPs were significantly associated with colon cancer development when the tumor was located in the rectal area. Conclusion The findings support the hypothesis that TLR-9 has an anticancer role in colon cancer development. Furthermore, genetic variation may influence colon cancer development, and SNPs in TLR-9 could serve as biomarkers for decision making in the treatment of females with rectal cancer.
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Affiliation(s)
- Abdelhabib Semlali
- Genome Research, Department of Biochemistry, College of Sciences, King Saud University
| | | | - Abdullah Al Amri
- Genome Research, Department of Biochemistry, College of Sciences, King Saud University
| | - Arezki Azzi
- College of Medicine, Al Imam Muhammad Ibn Saud Islamic University
| | | | - Muhammad Kohailan
- Genome Research, Department of Biochemistry, College of Sciences, King Saud University
| | - Jilani P Shaik
- Genome Research, Department of Biochemistry, College of Sciences, King Saud University
| | - Majid Abdulrahman Almadi
- Division of Gastroenterology, King Khalid University Hospital, King Saud University, Riyadh, Kingdom of Saudi Arabia; Division of Gastroenterology, McGill University Health Center, Montreal General Hospital, Montreal
| | - Abdulrahman M Aljebreen
- College of Medicine, King Saud University; Division of Gastroenterology, King Khalid University Hospital, King Saud University, Riyadh, Kingdom of Saudi Arabia
| | - Othman Alharbi
- College of Medicine, King Saud University; Division of Gastroenterology, King Khalid University Hospital, King Saud University, Riyadh, Kingdom of Saudi Arabia
| | - Nahla Ali Azzam
- College of Medicine, King Saud University; Division of Gastroenterology, King Khalid University Hospital, King Saud University, Riyadh, Kingdom of Saudi Arabia
| | - Mahmoud Rouabhia
- Groupe de Recherche en Écologie Buccale, Département de Stomatologie, Faculté de Médecine Dentaire, Université Laval, Québec City, QC, Canada
| | - Mohammad Saud Alanazi
- Genome Research, Department of Biochemistry, College of Sciences, King Saud University
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Hu Y, Liu JP, Zhu Y, Lu NH. The Importance of Toll-like Receptors in NF-κB Signaling Pathway Activation by Helicobacter pylori Infection and the Regulators of this Response. Helicobacter 2016; 21:428-40. [PMID: 26763943 DOI: 10.1111/hel.12292] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Helicobacter pylori (H. pylori) is a common pathogenic bacterium in the stomach that infects almost half of the population worldwide and is closely related to gastric diseases and some extragastric diseases, including iron-deficiency anemia and idiopathic thrombocytopenic purpura. Both the Maastricht IV/Florence consensus report and the Kyoto global consensus report have proposed the eradication of H. pylori to prevent gastric cancer as H.pylori has been shown to be a major cause of gastric carcinogenesis. The interactions between H. pylori and host receptors induce the release of the proinflammatory cytokines by activating proinflammatory signaling pathways such as nuclear factor kappa B (NF-κB), which plays a central role in inflammation, immune response, and carcinogenesis. Among these receptors, Toll-like receptors (TLRs) are classical pattern recognition receptors in the recognition of H. pylori and the mediation of the host inflammatory and immune responses to H. pylori. TLR polymorphisms also contribute to the clinical consequences of H. pylori infection. In this review, we focus on the functions of TLRs in the NF-κB signaling pathway activated by H. pylori, the regulators modulating this response, and the functions of TLR polymorphisms in H.pylori-related diseases.
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Affiliation(s)
- Yi Hu
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Jian-Ping Liu
- Department of Biosciences and Nutrition, Karolinska Institute, Huddinge, Sweden
| | - Yin Zhu
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China.
| | - Nong-Hua Lu
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China.
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15
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Gong AM, Li XY, Xie YQ, Jia ZD, Li YX, Zou YY, Xu CQ, Wang ZY. Association between CD14 SNP -159 C/T and gastric cancer: an independent case-control study and an updated meta-analysis. Onco Targets Ther 2016; 9:4337-42. [PMID: 27486336 PMCID: PMC4958350 DOI: 10.2147/ott.s95807] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
PURPOSE The association between CD14 -159C/T polymorphism and the susceptibility to gastric cancer (GC) has been reported. However, the results were inconclusive. In the present study, a case-control study and a meta-analysis were performed to assess the possible association between -159C/T in the CD14 gene and GC risk. PATIENTS AND METHODS Relevant studies were searched in several databases including PubMed, Web of Science, EMBASE, Chinese National Knowledge Infrastructure database, and Wanfang database (last search was performed on December 30, 2015). In addition, a case-control study involving 164 GC cases and 169 controls was also performed in the analysis. Statistical analysis was performed by the software Revman5.3. RESULTS A total of ten published studies and the present case-control study involving 2,844 GC and 3,983 controls were included for the meta-analysis. The analysis result indicated that the T allele of CD14 -159C/T polymorphism did not confer risk for GC (in our study: [P=0.93]; in the meta-analysis: T vs 2N odds ratio =1.28 and 95% confidence interval (CI) =0.95-1.24, [P=0.24]). However, we found a significant association in the recessive model (in our study: TT vs TC+CC [P=0.04]; in the meta-analysis: TT vs TC+CC odds ratio =1.12 and 95% CI =1.01-1.26, [P=0.04]). Furthermore, a subgroup analysis by ethnicity showed that TT genotype was significantly associated with GC in Asian (odds ratio =1.17 and 95% CI =1.02-1.34, [P=0.02]) but not in Caucasian. CONCLUSION Our results highlight the TT genotype of CD14 -159C/T as a genetic susceptibility factor for gastric cancer, particularly, in Asians and population-based controls.
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Affiliation(s)
- Ai-Min Gong
- Department of Internal Medicine of Traditional Chinese Medicine, Hainan Medical University, Hainan; Department of Pathophysiology, Harbin Medical University, Harbin
| | - Xin-Yuan Li
- Department of Pathophysiology, Harbin Medical University, Harbin
| | - Yi-Qiang Xie
- Department of Internal Medicine of Traditional Chinese Medicine, Hainan Medical University, Hainan
| | - Zhan-Dong Jia
- Department of Nephrology, Ningbo Tradition Chinese Medicine Hospital affiliated to Zhejiang Chinese Medical University, Ningbo
| | | | - Yong-Yan Zou
- Department of Nephrology, Jining Tradition Chinese Medicine Hospital, Jining, People's Republic of China
| | - Chang-Qing Xu
- Department of Pathophysiology, Harbin Medical University, Harbin
| | - Zhen-Yu Wang
- Department of Pathophysiology, Harbin Medical University, Harbin
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16
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Wan GX, Cao YW, Li WQ, Li YC, Zhang WJ, Li F. Associations between TLR9 polymorphisms and cancer risk: evidence from an updated meta-analysis of 25,685 subjects. Asian Pac J Cancer Prev 2015; 15:8279-85. [PMID: 25339018 DOI: 10.7314/apjcp.2014.15.19.8279] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
A meta-analysis incorporating 34 case-control studies from 19 articles involving 12,197 cases and 13,488 controls was conducted to assess the effects of three genetic variants of Toll-like receptor 9 (TLR9): rs187084, rs352140, and rs5743836. Studies on associations between TLR9 polymorphisms and cancer risk were systematically searched in electronic databases. The reported odds ratios (OR) and 95% confidence intervals (CI) were pooled to assess the strength of any associations. The results showed that the rs187084 polymorphism was significantly associated with an increased risk of cancer (CC vs TC+TT: OR=1.14, 95% CI=1.02-1.28), specifically cervical cancer (C vs T: OR=1.19, 95% CI=1.05-1.34; TC vs TT: OR=1.32, 95% CI=1.10-1.58; CC vs TT: OR=1.31, 95% CI= 1.03-1.68; CC+TC vs TT: OR=1.32, 95% CI=1.11-1.56), and that this association was significantly positive in Caucasians (CC vs. TC+TT: OR=1.18, 95% CI=1.01-1.38). The rs352140 polymorphism had a protective effect on breast cancer (GA vs GG: OR=0.77, 95% CI=0.66-0.89), whereas the rs5743836 polymorphism was likely protective for digestive system cancers (CC+TC vs TT: OR=0.81, 95% CI=0.66-0.98). In conclusion, our results suggest that the rs187084 polymorphism may be associated with an elevated cancer risk, whereas polymorphisms of rs352140 and rs5743836 may play protective roles in the development of breast and digestive system cancers, respectively. From the results of this meta-analysis further large-scale case-control studies are warranted to verify associations between TLR9 polymorphisms and cancer.
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Affiliation(s)
- Guo-Xing Wan
- Department of Pathology and the Key Laboratories for Xinjiang Endemic and Ethnic Diseases (a joint venture with the Chinese Ministry of Education), Shihezi University School of Medicine, Shihezi, Xinjiang, China E-mail :
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17
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Trejo-de la O A, Torres J, Sánchez-Zauco N, Pérez-Rodríguez M, Camorlinga-Ponce M, Flores-Luna L, Lazcano-Ponce E, Maldonado-Bernal C. Polymorphisms in TLR9 but not in TLR5 increase the risk for duodenal ulcer and alter cytokine expression in the gastric mucosa. Innate Immun 2015; 21:706-13. [PMID: 25995217 DOI: 10.1177/1753425915587130] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2014] [Accepted: 04/22/2015] [Indexed: 02/06/2023] Open
Abstract
Colonization of the gastric mucosa by Helicobacter pylori can lead to peptic ulcer and gastric adenocarcinoma. TLRs are signaling receptors involved in the recognition of microorganisms, and polymorphisms in their genes may influence the innate and adaptive immune response to H. pylori, affecting the clinical outcomes of the infection. We assessed the association between single nucleotide polymorphisms in TLR9 and TLR5 and gastroduodenal diseases. All patients were genotyped by allelic discrimination in regions 1174C>T and 1775A>G of TLR5 and -1237T>C and 2848G>A of TLR9. The 2848A allele of TLR9 was more frequent in duodenal ulcer and showed an association of risk with this pathology. Polymorphisms in TLR5 were not found to be associated with disease. Patients with polymorphisms in TLR9 and TLR5 expressed significantly lower levels of IL-1β and TNF-α, whereas polymorphisms in TLR5 also decreased the expression of IL-6 and IL-10. Our findings suggest that 2848G>A polymorphism in TLR9 increases the risk for the development of duodenal ulcer probably by modifying the inflammatory response to H. pylori infection. This is the first study to show an association of 2848A allele of TLR9 with duodenal ulcer and with altered expression of inflammatory cytokines in the gastric mucosa.
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Affiliation(s)
| | - Javier Torres
- Unidad de Investigación en Enfermedades Infecciosas, Hospital de Pediatría, Centro Médico Nacional Siglo XXI, IMSS, Mexico City, Mexico
| | - Norma Sánchez-Zauco
- Unidad de Investigación en Enfermedades Infecciosas, Hospital de Pediatría, Centro Médico Nacional Siglo XXI, IMSS, Mexico City, Mexico Laboratorio de Investigación en Inmunología y Proteómica, Hospital Infantil de México Federico Gómez, SS, Mexico City, Mexico Laboratorio de Bacteriología Médica, Escuela Nacional de Ciencias Biológicas-IPN, Mexico City, Mexico
| | | | - Margarita Camorlinga-Ponce
- Unidad de Investigación en Enfermedades Infecciosas, Hospital de Pediatría, Centro Médico Nacional Siglo XXI, IMSS, Mexico City, Mexico
| | - Lourdes Flores-Luna
- Centro de Investigación en Salud Poblacional, Instituto Nacional de Salud Pública, Cuernavaca, Mor., México
| | - Eduardo Lazcano-Ponce
- Centro de Investigación en Salud Poblacional, Instituto Nacional de Salud Pública, Cuernavaca, Mor., México
| | - Carmen Maldonado-Bernal
- Laboratorio de Investigación en Inmunología y Proteómica, Hospital Infantil de México Federico Gómez, SS, Mexico City, Mexico
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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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Zhang T, Cao HL, Luo SJ, Zheng DL, Chen YN. Construction of a gastric cancer cell line with stably silenced expression of CD14. Shijie Huaren Xiaohua Zazhi 2014; 22:3194-3200. [DOI: 10.11569/wcjd.v22.i22.3194] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To develop a SGC-7901 cell line with stably silenced expression of CD14 to provide an experimental basis for the study of the pathogenesis of gastric cancer.
METHODS: A CD14-shRNA lentiviral vector was constructed to transfect gastric cancer SGC-7901 cells. RT-PCR and Western blot were used to detect the CD14 mRNA and protein levels in untreated SGC-7901 cells (blank control group), SGC-7901 cells transfected with NC-CD14 shRNA (NC-CD14 shRNA control group) and SGC-7901 cells transfected with the CD14-shRNA lentiviral vector (CD14-shRNA lentiviral vector group).
RESULTS: CD14-shRNA expression vector was successfully constructed and transfected into gastric cancer cells. RT-PCR showed that the Ct value for the CD14-shRNA lentiviral vector group was significantly higher than those for the NC-CD14 shRNA control group and blank control group (P = 0.000; P < 0.001), and the 2Ct value for the CD14-shRNA lentiviral vector group (1±0.08) was significantly lower than those for the NC-CD14 shRNA control group and blank control group (P = 0.0001; P < 0.001). Western blot analysis showed that the relative expression of CD14 protein in the CD14-shRNA lentiviral vector group (0.01) was significantly less than that in the blank control group (1.0) and NC-CD14 shRNA control group (0.83).
CONCLUSION: A CD14-shRNA lentiviral vector has been successfully transfected into gastric cancer SGC-7901 cells, which can inhibit the expression of CD14 mRNA and protein in SGC-7901 cells.
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20
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Castaño-Rodríguez N, Kaakoush NO, Mitchell HM. Pattern-recognition receptors and gastric cancer. Front Immunol 2014; 5:336. [PMID: 25101079 PMCID: PMC4105827 DOI: 10.3389/fimmu.2014.00336] [Citation(s) in RCA: 71] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2014] [Accepted: 07/03/2014] [Indexed: 12/12/2022] Open
Abstract
Chronic inflammation has been associated with an increased risk of several human malignancies, a classic example being gastric adenocarcinoma (GC). Development of GC is known to result from infection of the gastric mucosa by Helicobacter pylori, which initially induces acute inflammation and, in a subset of patients, progresses over time to chronic inflammation, gastric atrophy, intestinal metaplasia, dysplasia, and finally intestinal-type GC. Germ-line encoded receptors known as pattern-recognition receptors (PRRs) are critical for generating mature pro-inflammatory cytokines that are crucial for both Th1 and Th2 responses. Given that H. pylori is initially targeted by PRRs, it is conceivable that dysfunction within genes of this arm of the immune system could modulate the host response against H. pylori infection, and subsequently influence the emergence of GC. Current evidence suggests that Toll-like receptors (TLRs) (TLR2, TLR3, TLR4, TLR5, and TLR9), nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) (NOD1, NOD2, and NLRP3), a C-type lectin receptor (DC-SIGN), and retinoic acid-inducible gene (RIG)-I-like receptors (RIG-I and MDA-5), are involved in both the recognition of H. pylori and gastric carcinogenesis. In addition, polymorphisms in genes involved in the TLR (TLR1, TLR2, TLR4, TLR5, TLR9, and CD14) and NLR (NOD1, NOD2, NLRP3, NLRP12, NLRX1, CASP1, ASC, and CARD8) signaling pathways have been shown to modulate the risk of H. pylori infection, gastric precancerous lesions, and/or GC. Further, the modulation of PRRs has been suggested to suppress H. pylori-induced inflammation and enhance GC cell apoptosis, highlighting their potential relevance in GC therapeutics. In this review, we present current advances in our understanding of the role of the TLR and NLR signaling pathways in the pathogenesis of GC, address the involvement of other recently identified PRRs in GC, and discuss the potential implications of PRRs in GC immunotherapy.
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Affiliation(s)
- Natalia Castaño-Rodríguez
- School of Biotechnology and Biomolecular Sciences, The University of New South Wales , Sydney, NSW , Australia
| | - Nadeem O Kaakoush
- School of Biotechnology and Biomolecular Sciences, The University of New South Wales , Sydney, NSW , Australia
| | - Hazel M Mitchell
- School of Biotechnology and Biomolecular Sciences, The University of New South Wales , Sydney, NSW , Australia
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Association between CD14 gene polymorphisms and cancer risk: a meta-analysis. PLoS One 2014; 9:e100122. [PMID: 24978812 PMCID: PMC4076245 DOI: 10.1371/journal.pone.0100122] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2014] [Accepted: 05/21/2014] [Indexed: 12/12/2022] Open
Abstract
Background Two polymorphisms, -260C/T and -651C/T, in the CD14 gene have been implicated in susceptibility to cancer. However, the results remain inconclusive. This meta-analysis aimed to investigate the association between the two polymorphisms and risk of cancer. Methods All eligible case-control studies published up to March 2014 were identified by searching PubMed, Web of Science, CNKI and WanFang database. Pooled odds ratio (OR) with 95% confidence interval (CI) were used to access the strength of this association in fixed- or random-effects model. Results 17 case-control studies from fourteen articles were included. Of those, there were 17 studies (4198 cases and 4194 controls) for -260C/T polymorphism and three studies (832 cases and 1190 controls) for -651C/T polymorphism. Overall, no significant associations between the two polymorphisms of CD14 gene and cancer risk were found. When stratified by ethnicity, cancer type and source of control, similar results were observed among them. In addition, in further subgroups analysis by Helicobacter pylori (H. pylori) infection status and tumor location in gastric cancer subgroup, we found that the CD14 -260C/T polymorphism may increase the risk of gastric cancer in H. pylori-infected individuals. Conclusions This meta-analysis suggests that the CD14 -260C/T polymorphism may increase the risk of gastric cancer in H. pylori-infected individuals. However, large and well-designed studies are warranted to validate our findings.
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Tong X, Li Z, Fu X, Zhou K, Wu Y, Zhang Y, Fan H. The association between CD14-260C/T polymorphism and malignant tumor risk: a meta-analysis of 5,603 participants. Tumour Biol 2014; 35:8707-13. [PMID: 24870592 DOI: 10.1007/s13277-014-2040-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2013] [Accepted: 04/29/2014] [Indexed: 02/05/2023] Open
Abstract
The CD14-260C/T polymorphism has been implicated to be in association with malignant tumor. However, a number of studies have reported inconclusive results. The aim of this study was to investigate the relationship of CD14-260C/T polymorphism and malignant tumor risk by meta-analysis. A search was performed in PubMed, Embase, the Chinese Journals Full-text Database (CNKI), and Wanfang databases up to August 2013. Odds ratio (OR) and 95 % confidence interval (95 % CI) were used to assess the association. Statistical analysis was calculated by STATA 11.0 software. The polymorphism was identified from 11 articles (12 case-control studies), involving 2,660 cases and 2,943 controls. Overall, no significant association between CD14-260C/T polymorphism and malignant tumor risk was found in the dominant model (TT + TC vs. CC: OR = 0.86, 95 % CI = 0.67-1.11). In the subgroup analysis by malignant tumor types, we found that the heterozygote model (TC vs. CC) might reduce the risk of malignant tumor, especially hematological malignance and prostate cancer (OR = 0.67, 95 % CI = 0.47-0.95), but not associated with gastrointestinal cancer susceptibility. In the subgroup analysis by ethnicity, no significant associations were found among different ethnicities. The study suggested that CD14-260C/T polymorphism might be a protective factor for hematological malignance and prostate tumor susceptibility but not an independent risk factor for gastrointestinal cancer susceptibility. To further evaluate the association between the polymorphism and malignant tumor susceptibility, more studies involving thousands of patients are required.
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Affiliation(s)
- Xiang Tong
- West China School of Medicine/West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China
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Uno K, Kato K, Shimosegawa T. Novel role of toll-like receptors in Helicobacter pylori - induced gastric malignancy. World J Gastroenterol 2014; 20:5244-51. [PMID: 24833854 PMCID: PMC4017039 DOI: 10.3748/wjg.v20.i18.5244] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2013] [Revised: 12/13/2013] [Accepted: 01/06/2014] [Indexed: 02/06/2023] Open
Abstract
Helicobacter pylori (H. pylori) infects the human stomach during infancy and develops into chronic active inflammation. The majority of H. pylori tend to colonize within the mucous gel layer of the stomach. The stomach lacks its own immune function, thus innate immunity as the first line of defense is vital for specific immunity against H. pylori. We review recent discoveries in the pathophysiologic roles of toll-like receptors (TLRs), mainly TLR2 and TLR4, in H. pylori-induced inflammation. In addition, the TLR pathways activated by H. pylori-induced inflammation have been shown to be closely associated not only with gastric carcinogenesis, but also with formation of the tumor microenvironment through the production of pro-inflammatory cytokines, chemokines, and reactive oxygen species. Although the correlation between single nucleotide polymorphisms of TLRs and gastric cancer risk remains unclear, a recent study demonstrated that STAT3-driven up-regulation of TLR2 might promote gastric tumorigenesis independent of inflammation. Further research on the regulation of TLRs in H. pylori-associated gastric carcinogenesis will uncover diagnostic/predictive biomarkers and therapeutic targets for gastric cancer.
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Kauppila JH, Selander KS. Toll-like receptors in esophageal cancer. Front Immunol 2014; 5:200. [PMID: 24847326 PMCID: PMC4019875 DOI: 10.3389/fimmu.2014.00200] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2014] [Accepted: 04/23/2014] [Indexed: 12/13/2022] Open
Abstract
Esophageal squamous cell carcinoma and esophageal adenocarcinoma are cancers of high mortality. EAC develops through Barrett’s esophagus (BE) and columnar dysplasia, preceded by gastro-esophageal reflux disease. The risk of esophageal squamous cell carcinoma is increased by smoking and alcohol consumption. New treatment options for esophageal cancer are desperately needed. Toll-like receptors (TLRs) play a central role in mammalian immunity and cancer. TLRs are activated by microbial components, such as lipopolysaccharide, flagellin, DNA, and RNA, as well as endogenous ligands, including heat-shock proteins and endogenous DNA. This review summarizes the studies on TLRs in esophageal squamous cell carcinoma and EAC. It has been shown that TLRs 1–10 are expressed in the normal esophagus. In esophageal squamous cell carcinoma, TLRs3, 4, 7, and 9 have been studied, showing associations to aggressive disease properties. In BE and EAC, only TLRs4, 5, and 9 have been studied. In the review, we discuss the implications of TLRs in esophageal cancer.
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Affiliation(s)
- Joonas H Kauppila
- Department of Pathology, University of Oulu , Oulu , Finland ; Department of Surgery, University of Oulu , Oulu , Finland ; Medical Research Center Oulu , Oulu , Finland ; Oulu University Hospital , Oulu , Finland
| | - Katri S Selander
- Department of Hematology-Oncology, University of Alabama at Birmingham , Birmingham, AL , USA ; Department of Pathology, Lapland Central Hospital , Rovaniemi , Finland
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25
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Dai Q, Li XP, Chai L, Long HA, Yang ZH. Polymorphisms of Toll-like receptor 9 are associated with nasopharyngeal carcinoma susceptibility. Tumour Biol 2014; 35:3247-3253. [PMID: 24504675 DOI: 10.1007/s13277-013-1424-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2013] [Accepted: 11/13/2013] [Indexed: 12/12/2022] Open
Abstract
Toll-like receptor 9 (TLR9) plays a pivotal role in sensing a wide range of pathogens, including bacteria, fungi, and viruses. A dysregulation of TLR9 signaling may contribute to a higher risk of developing cancers. A hospital-based case-control study, including 356 nasopharyngeal carcinoma (NPC) cases and 356 controls, was conducted to assess the relationship between TLR9 -1237T/C, -1486T/C, and 2848G/A polymorphisms and NPC risk as well as clinical characteristics. The genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Protein level of transforming growth factor-β1 (TGF-β1), vascular endothelial growth factor (VEGF), and interleukin-6 (IL-6) in NPC biopsies was measured by enzyme-linked immunosorbent assay (ELISA). We found that -1486T/C CC genotype had an increased NPC risk at odds ratio (OR) = 1.808 with 95% confidence interval (CI) 1.169 ∼ 2.798 (P = 0.008). The patients with -1486 CC genotype are inclined to advanced tumor stage and lymph node metastasis. In addition, protein concentration of VEGF in NPC biopsies with -1486 CC genotype was significantly increased compared patients with -1486 TT genotype. For the first time, our data suggested that TLR9 -1486T/C may be a risk biomarker of NPC.
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Affiliation(s)
- Qiong Dai
- Department of Human Anatomy, Luzhou Medical College, Luzhou, 646000, Sichuan, People's Republic of China
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Companioni O, Bonet C, Muñoz X, Weiderpass E, Panico S, Tumino R, Palli D, Agnoli C, Vineis P, Boutron-Ruault MC, Racine A, Clavel-Chapelon F, Travis RC, Khaw KT, Riboli E, Murphy N, Vergnaud AC, Trichopoulou A, Benetou V, Trichopoulos D, Lund E, Johansen D, Lindkvist B, Johansson M, Sund M, Ardanaz E, Sánchez-Cantalejo E, Huerta JM, Dorronsoro M, Ramón Quirós J, Tjonneland A, Mortensen LM, Overvad K, Chang-Claude J, Rizzato C, Boeing H, Bueno-de-Mesquita HB, Bueno de Mesquita HB, Siersema P, Peeters PHM, Numans ME, Carneiro F, Licaj I, Freisling H, Sala N, González CA. Polymorphisms of Helicobacter pylori signaling pathway genes and gastric cancer risk in the European Prospective Investigation into Cancer-Eurgast cohort. Int J Cancer 2014; 134:92-101. [PMID: 23824692 DOI: 10.1002/ijc.28357] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2013] [Accepted: 04/16/2013] [Indexed: 02/06/2023]
Abstract
Helicobacter pylori is a recognized causal factor of noncardia gastric cancer (GC). Lipopolysaccharide and peptidoglycan of this bacterium are recognized by CD14, TLR4 and NOD2 human proteins, while NFKB1 activates the transcription of pro-inflammatory cytokines to elicit an immune response. Single nucleotide polymorphisms (SNPs) in these genes have been associated with GC in different populations. We genotyped 30 SNPs of these genes, in 365 gastric adenocarcinomas and 1,284 matched controls from the European Prospective Investigation into Cancer cohort. The association with GC and its histological and anatomical subtypes was analyzed by logistic regression and corrected for multiple comparisons. Using a log-additive model, we found a significant association between SNPs in CD14, NOD2 and TLR4 with GC risk. However, after applying the multiple comparisons tests only the NOD2 region remained significant (p = 0.009). Analysis according to anatomical subtypes revealed NOD2 and NFKB1 SNPs associated with noncardia GC and CD14 SNPs associated with cardia GC, while analysis according to histological subtypes showed that CD14 was associated with intestinal but not diffuse GC. The multiple comparisons tests confirmed the association of NOD2 with noncardia GC (p = 0.0003) and CD14 with cardia GC (p = 0.01). Haplotype analysis was in agreement with single SNP results for NOD2 and CD14 genes. From these results, we conclude that genetic variation in NOD2 associates with noncardia GC while variation in CD14 is associated with cardia GC.
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Affiliation(s)
- Osmel Companioni
- Unit of Nutrition, Environment and Cancer, Cancer Epidemiology Research Program, Catalan Institute of Oncology-IDIBELL, Barcelona, 08908, Spain
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27
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Zhou W, Jia L, Guo S, Hu Q, Shen Y, Li N. The -159C/T polymorphism in the CD14 gene and cancer risk: a meta-analysis. Onco Targets Ther 2013; 7:5-12. [PMID: 24376358 PMCID: PMC3865088 DOI: 10.2147/ott.s54547] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
Purpose The -159C/T polymorphism in the cluster of differentiation (CD)14 gene has been extensively studied for an association with cancer; however, results from replication studies have been inconclusive. The aim of this study was to perform a comprehensive assessment of the possible association between the -159C/T polymorphism in the CD14 gene and cancer risk, by meta-analysis. Methods We searched in PubMed, Embase, and other databases, covering all case-control studies on the possible association between CD14 -159C/T gene polymorphism and cancer risk. Data were extracted and statistical analyses were performed using RevMan 5.0 and STATA 12.0 software. Results A total of 12 case-control studies met our inclusion criteria, including 2,498 cases and 2,696 controls. The combined analysis indicated that the CD14 -159C/T gene polymorphism didn’t confer risk for cancer – the recessive model (TT versus (vs) CT + CC), showed odds ratio (OR) =1.01, 95% confidence interval (CI) =0.82–1.23 (P=0.94), while the dominant model (TT + TC vs CC) showed OR =0.81, 95% CI =0.66–1.00 (P=0.05). A subgroup analysis by ethnicity showed that the cancer risk associated with CD14 -159C/T gene polymorphism was significantly decreased among Caucasians for the TC + TT vs CC comparison (OR =0.83, 95% CI =0.70–0.98 [P=0.03]). The subgroup analysis by cancer type suggested that the CD14 -159C/T gene polymorphism was not associated with gastric cancer risk. Conclusion The evidence from the present meta-analysis did not support the CD14 -159C/T gene polymorphism as a genetic risk factor for cancer. Further studies on different cancer types and ethnicities are needed to validate our findings.
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Affiliation(s)
- Wei Zhou
- West China School of Public Health, Sichuan University, Chengdu, People's Republic of China ; Human Body Function Laboratory, Chengdu University of Technology, Chengdu, People's Republic of China
| | - Liuqun Jia
- Division of Pulmonary Diseases, State Key Laboratory of Biotherapy of China and Department of Respiratory Medicine, West China Hospital of Sichuan University, Chengdu, People's Republic of China
| | - Shujin Guo
- Division of Pulmonary Diseases, State Key Laboratory of Biotherapy of China and Department of Respiratory Medicine, West China Hospital of Sichuan University, Chengdu, People's Republic of China
| | - Qianjin Hu
- Division of Pulmonary Diseases, State Key Laboratory of Biotherapy of China and Department of Respiratory Medicine, West China Hospital of Sichuan University, Chengdu, People's Republic of China
| | - Yongchun Shen
- Division of Pulmonary Diseases, State Key Laboratory of Biotherapy of China and Department of Respiratory Medicine, West China Hospital of Sichuan University, Chengdu, People's Republic of China
| | - Ningxiu Li
- West China School of Public Health, Sichuan University, Chengdu, People's Republic of China
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Risk of Atherosclerosis and Helicobacter pylori Infection according to CD14 Promotor Polymorphism in Healthy Korean Population. Gastroenterol Res Pract 2013; 2013:570597. [PMID: 24228026 PMCID: PMC3818843 DOI: 10.1155/2013/570597] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2013] [Accepted: 08/28/2013] [Indexed: 12/20/2022] Open
Abstract
Background and Aim. We aim to elucidate the association of risk factors for atherosclerosis and H. pylori infection according to the promotor polymorphism of the CD14 gene in healthy Korean population. Methods. The patients who visited our hospital for routine health examinations and 266 healthy adults (170 males and 96 females) were enrolled in this study. The promotor polymorphism at -159C/T of the CD14 gene was determined by PCR-restriction fragment length polymorphism analysis. According to genetic polymorphism and H. pylori infection, we analyzed the risk of atherosclerosis. Results. The genotype frequencies were CC 7.9%, CT 45.1%, and TT 47.0%, respectively. There were no differences between specific genotypes of CD14 gene and H. pylori infection rate. As for HDL cholesterol level, there were significant differences among the three genotypes (P < 0.01). In subjects with H. pylori infection, no significant differences were observed between specific genotypes of CD14 gene and the risk factors of atherosclerosis. Conclusion. The promotor polymorphism at -159C/T of the CD14 gene was associated with the risk factor of atherosclerosis in healthy Korean population. However, it was not associated with the rate of H. pylori infection and H. pylori induced atherosclerotic risk.
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Pothlichet J, Quintana-Murci L. The genetics of innate immunity sensors and human disease. Int Rev Immunol 2013; 32:157-208. [PMID: 23570315 DOI: 10.3109/08830185.2013.777064] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Since their discovery, innate immunity microbial sensors have been increasingly studied and shown to play a critical role in innate responses to microbes in several experimental in vitro, ex vivo, and animal models. However, their role in the human response to infection in natural conditions has just started to be deciphered, by means of clinical studies of primary immunodeficiencies and epidemiological genetic studies. Here, we summarize the major findings concerning the genetic diversity of the various families of microbial sensors in humans, and of other molecules involved in the signaling pathways they trigger. Specifically, we review the genetic associations, revealed by both clinical and epidemiological genetics studies, of microbial sensors from five different families: Toll-like receptors, C-type lectin receptors, NOD-like receptors, RIG-I-like receptors, and cytosolic DNA sensors. In particular, we consider the relationships between variation at the genes encoding these molecules and susceptibility to and the severity of infectious diseases and other clinical conditions associated with immune dysfunction, including autoimmunity, inflammation, allergy, and cancer. Despite the fact that the genetic links between innate immunity sensors and human disorders remain still limited, human genetics studies are increasingly improving our understanding of the genuine functions of microbial sensors and downstream signaling molecules in the natural setting.
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Affiliation(s)
- Julien Pothlichet
- Institut Pasteur, Unit of Human Evolutionary Genetics, Paris, France
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30
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The TLR9 gene polymorphisms and the risk of cancer: evidence from a meta-analysis. PLoS One 2013; 8:e71785. [PMID: 23990988 PMCID: PMC3747197 DOI: 10.1371/journal.pone.0071785] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2013] [Accepted: 07/02/2013] [Indexed: 12/16/2022] Open
Abstract
Background Growing studies have revealed the association between polymorphisms in the Toll-like receptor 9 (TLR9) and susceptibility to cancer, however, the results remained inconsistent. Methodology/Principal Findings To assess the effect of three selected SNPs (rs352140, rs5743836 and rs187084) in TLR9 on cancer, we performed a meta-analysis based on 11 case-control studies, including a total of 6,585 cancer cases and 7,506 controls. Summary odds ratios (OR) and corresponding 95% confidence intervals (CIs) for polymorphisms in TLR9 and cancer risk were estimated. Our meta-analysis indicated that rs352140 was associated with an increased cancer risk, especially in Caucasian. However, no significantly increased cancer risk was detected to be associated with rs187084 and rs5743836 either the overall or subgroup estimation. Conclusions These meta-analysis results indicate that polymorphisms in TLR9 may play a role in cancer development.
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Stanimirovic D, Zeljic K, Jankovic L, Magic M, Hadzi-Mihajlovic M, Magic Z. TLR2,TLR3,TLR4andCD14gene polymorphisms associated with oral lichen planus risk. Eur J Oral Sci 2013; 121:421-6. [DOI: 10.1111/eos.12074] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/28/2013] [Indexed: 01/01/2023]
Affiliation(s)
- Dragan Stanimirovic
- School of Dental Medicine; Clinic of Periodontology and Oral Medicine; University of Belgrade; Belgrade; Serbia
| | | | - Ljiljana Jankovic
- School of Dental Medicine; Clinic of Periodontology and Oral Medicine; University of Belgrade; Belgrade; Serbia
| | - Marko Magic
- School of Dental Medicine; Clinic of Periodontology and Oral Medicine; University of Belgrade; Belgrade; Serbia
| | - Milos Hadzi-Mihajlovic
- School of Dental Medicine; Clinic of Periodontology and Oral Medicine; University of Belgrade; Belgrade; Serbia
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Zeljic K, Supic G, Jovic N, Kozomara R, Brankovic‐Magic M, Obrenovic M, Magic Z. Association of TLR2, TLR3, TLR4 and CD14 genes polymorphisms with oral cancer risk and survival. Oral Dis 2013; 20:416-24. [DOI: 10.1111/odi.12144] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2013] [Revised: 05/12/2013] [Accepted: 05/27/2013] [Indexed: 12/13/2022]
Affiliation(s)
- K Zeljic
- Institute for Medical Research Military Medical Academy BelgradeSerbia
- Faculty of Biology University of Belgrade BelgradeSerbia
| | - G Supic
- Institute for Medical Research Military Medical Academy BelgradeSerbia
- Faculty of Medicine Military Medical Academy University of Defence BelgradeSerbia
| | - N Jovic
- Faculty of Medicine Military Medical Academy University of Defence BelgradeSerbia
- Clinic for Maxillofacial Surgery Military Medical Academy BelgradeSerbia
| | - R Kozomara
- Faculty of Medicine Military Medical Academy University of Defence BelgradeSerbia
- Clinic for Maxillofacial Surgery Military Medical Academy BelgradeSerbia
| | | | - M Obrenovic
- Faculty of Medicine University of East Sarajevo Foca Bosnia and Herzegovina
| | - Z Magic
- Institute for Medical Research Military Medical Academy BelgradeSerbia
- Faculty of Medicine Military Medical Academy University of Defence BelgradeSerbia
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Kim EJ, Chung WC, Lee KM, Paik CN, Kim SB, Oh YS, Lee YW, Kang SG, Noh SJ. Helicobacter pylori Infection Enhances Gastric Mucosal Inflammation in Individuals Carrying the 260-T Allele of the CD14 Gene. Gut Liver 2013; 7:317-22. [PMID: 23710313 PMCID: PMC3661964 DOI: 10.5009/gnl.2013.7.3.317] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2012] [Revised: 09/19/2012] [Accepted: 10/05/2012] [Indexed: 12/27/2022] Open
Abstract
BACKGROUND/AIMS We aim to evaluate the association between promoter polymorphism of the clusters of differentiation 14 (CD14) gene and Helicobacter pylori-induced gastric mucosal inflammation in a healthy Korean population. METHODS The study population consisted of 267 healthy subjects who visited our hospital for free nationwide gastric cancer screening. Promoter polymorphism at -260 C/T of the CD14 gene was determined by polymerase chain reaction and restriction fragment length polymorphism analysis. The severity of gastric mucosal inflammation was estimated by a gastritis score based on the sum of the values of the grade and activity of the gastritis. Expression of soluble CD14 (sCD14) was assessed by quantitative sandwich ELISA. RESULTS CD14 polymorphism was not associated with H. pylori infection. There were no significant differences in gastritis scores among the genotype subgroups, but subjects carrying the CD14 -260 CT/TT genotype had significantly higher sCD14 levels than those carrying the CC genotype. Subjects with the 260-T allele of the CD14 gene and H. pylori infection had significantly higher sCD14 levels than those with the same genotype but without infection. CONCLUSIONS In individuals with the T allele at the -260 site of the promoter region of the CD14 gene, H. pylori infection accentuates gastric mucosal inflammation.
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Affiliation(s)
- Eun Jung Kim
- Department of Internal Medicine, St. Vincent's Hospital, The Catholic University of Korea College of Medicine, Suwon, Korea
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Castaño-Rodríguez N, Kaakoush NO, Goh KL, Fock KM, Mitchell HM. The role of TLR2, TLR4 and CD14 genetic polymorphisms in gastric carcinogenesis: a case-control study and meta-analysis. PLoS One 2013; 8:e60327. [PMID: 23565226 PMCID: PMC3614925 DOI: 10.1371/journal.pone.0060327] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2012] [Accepted: 02/25/2013] [Indexed: 12/16/2022] Open
Abstract
Background In addition to Helicobacter pylori infection, host genetic factors contribute to gastric cancer (GC). Recognition of H. pylori is known to involve Toll-like receptors (TLR), which subsequently leads to activation of NF-κB. Thus, the overall aim of this study was to estimate for the first time the pooled effect size of polymorphisms in TLR2, TLR4 and CD14 on GC development through a meta-analysis. Methods A case-control study comprising 284 ethnic Chinese individuals (70 non-cardia GC cases and 214 functional dyspepsia controls) was conducted for the genotyping of TLR2 -196 to -174del, CD14 -260 C/T and TLR4 rs11536889 using PCR, RT-PCR and mass spectrometry. Case-control studies of TLR2, TLR4 and CD14 polymorphisms and GC were searched up to June 2012. Pooled odds ratios and 95% confidence intervals were obtained by means of the random effects model. Results In our ethnic Chinese case-control study, the TLR4 rs11536889 C allele increased the risk of GC (OR: 1.89, 95%CI: 1.23–2.92) while the CD14 -260 T allele was protective (OR: 0.62, 95%CI: 0.42–0.91). TLR2 -196 to -174 increased the risk of GC only in H. pylori-infected individuals (OR: 3.10, 95%CI: 1.27–7.60). In the meta-analysis, TLR4 Asp299Gly showed borderline results in the general analysis (pooled OR: 1.58, 95%CI: 0.98–2.60), nevertheless, stratified analysis by ethnicity showed that the mutant allele was a definitive risk factor for GC in Western populations (pooled OR: 1.87, 95%CI: 1.31–2.65). There was a potential association between the TLR2 -196 to -174 deletion allele and GC in Japanese (pooled OR: 1.18, 95%CI: 0.96–1.45). TLR4 Thr399Ile did not provide significant results. Conclusions TLR4 rs11536889 and CD14 -260 C/T are associated with non-cardia GC in Chinese. Based on our meta-analysis, the TLR signalling pathway is involved in gastric carcinogenesis, TLR4 Asp299Gly and TLR2 -196 to -174del showing associations with GC in an ethnic-specific manner.
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Affiliation(s)
- Natalia Castaño-Rodríguez
- School of Biotechnology and Biomolecular Sciences, The University of New South Wales, Sydney, Australia
| | - Nadeem O. Kaakoush
- School of Biotechnology and Biomolecular Sciences, The University of New South Wales, Sydney, Australia
| | - Khean-Lee Goh
- Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Kwong Ming Fock
- Division of Gastroenterology, Department of Medicine, Changi General Hospital, Singapore, Singapore
| | - Hazel M. Mitchell
- School of Biotechnology and Biomolecular Sciences, The University of New South Wales, Sydney, Australia
- * E-mail:
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Kim EJ, Lee JR, Chung WC, Jung SH, Sung HJ, Lee YW, Oh YS, Kim SB, Paik CN, Lee KM, Noh SJ. Association between genetic polymorphisms of NOD 1 and Helicobacter pylori-induced gastric mucosal inflammation in healthy Korean population. Helicobacter 2013; 18:143-50. [PMID: 23136938 DOI: 10.1111/hel.12020] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Gastric cancer is supposed to be a result of inflammation induced by Helicobacter pylori (H. pylori) infection. Nucleotide-binding oligomerization domain 1 (NOD 1) is required for the innate immune response to H. pylori. We aim to investigate whether single nucleotide polymorphism (SNP) in NOD 1 gene is associated with H. pylori-induced gastric mucosal inflammation in a healthy Korean population. METHODS The study was conducted on 412 adults who visited two different healthcare centers for health examinations. The G796A (E266K) NOD 1 SNP was detected by using polymerase chain reaction/restriction fragment length polymorphism. A gastritis score was calculated by the summed values of the grade and the activity of gastritis scored according to the updated Sydney system. The expression of IL-8 and COX-2 mRNA was assessed by quantitative reverse transcription polymerase chain reaction. In the group with H. pylori infection, the complete screening of the genes comprising the cag PAI was performed. RESULTS The genotype frequencies were 26.7% (AA type), 58.3% (GA), and 15.0% (GG). In H. pylori-positive patients, gastritis score of the AA genotype was significantly higher than those of the others (p = .04). Also, the IL-8 and COX-2 mRNA levels increased in the AA genotype. In the group with H. pylori infection, 31.9% were found to carry the complete cag PAI. When the subjects were infected with intact cag PAI, the IL-8 and COX-2 mRNA levels were significantly high in AA genotype. CONCLUSION G796A (E266K) NOD 1 polymorphism is closely correlated with H. pylori-associated gastric mucosal inflammation in the Korean population.
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Affiliation(s)
- Eun Jung Kim
- Internal Medicine, The Catholic University of Korea, Suwon, Korea
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CD14 overexpression upregulates TNF-α-mediated inflammatory responses and suppresses the malignancy of gastric carcinoma cells. Mol Cell Biochem 2013; 376:137-43. [PMID: 23338226 PMCID: PMC3576562 DOI: 10.1007/s11010-013-1559-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2012] [Accepted: 01/09/2013] [Indexed: 01/07/2023]
Abstract
CD14 mediates the inflammatory response via recognition of lipopolysaccharide, which has been implicated in Helicobacter pylori (H. pylori) infections. Increasing evidence has suggested that CD14 status significantly influences the clinical outcome of H. pylori infection, which can result in gastric carcinoma. However, there is little evidence regarding the cellular impact and associated molecular basis of CD14 on gastric carcinoma cells. To address this question, we generated a CD14-overexpressing SGC-7901 gastric carcinoma cell line and analyzed the impact of CD14 expression. Our results revealed that cells overexpressing CD14 exhibited antitumor potential, including significantly decreased clonogenic ability, proliferation, metastatic invasion, as well as enhanced apoptosis, suggesting a tumor-suppressive role of CD14 in the cells. Intriguingly, we further discovered that CD14 overexpression activated NF-κB via upregulating its expression and simultaneously stimulating DNA binding activity. Upregulated NF-κB transcriptionally elevated a series of pro-inflammatory cytokines, including TNF-α, IL-1β, IL-6, and IL-12. Together, the current study utilized a CD14-overexpressing gastric cell model to determine the impacts of CD14 upregulation on cell viability, apoptosis, and migration and NF-κB-mediated inflammation.
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Frequency of TLR 2, 4, and 9 gene polymorphisms in Chinese population and their susceptibility to type 2 diabetes and coronary artery disease. J Biomed Biotechnol 2012; 2012:373945. [PMID: 23091345 PMCID: PMC3469311 DOI: 10.1155/2012/373945] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2012] [Accepted: 07/27/2012] [Indexed: 02/06/2023] Open
Abstract
Toll-like receptors (TLRs) are pivotal components of the innate immune response. Activation of the innate immune system and subsequent chronic low-grade inflammation are thought to be involved in the pathogenesis of atherosclerosis and type 2 diabetes. In the study, we genotyped TLRs gene polymorphisms, including TLR2 Arg677Trp and Arg753Gln, TLR4 Asp299Gly and Thr399Ile, TLR9-1486T/C and -1237T/C. The frequencies of TT, TC and CC genotype of TLR9-1486T/C mutation were 39.6%, 45.8% and 14.6%, respectively; the frequencies of T allele and C allele were 62.5% and 37.5%. However, neither of these parameters was statistically significant among study groups. In addition, we were surprised to find that the commonly reported TLR SNPs in the Western countries, like TLR2 Arg677Trp or Arg753Gln, TLR4 Asp299Gly or Thr399Ile and TLR9-1237T/C, were not polymorphic at all in all study subjects. In conclusion, our data suggests that TLR2 Arg677Trp or Arg753Gln, TLR4 Asp299Gly or Thr399Ile and TLR9-1237T/C polymorphisms have low frequency and TLR9-1486T/C polymorphism may not be a suitable marker in predicting the susceptibility to type 2 diabetes or coronary artery disease in the Chinese Han population.
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Junjie X, Songyao J, Minmin S, Yanyan S, Baiyong S, Xiaxing D, Jiabin J, Xi Z, Hao C. The association between Toll-like receptor 2 single-nucleotide polymorphisms and hepatocellular carcinoma susceptibility. BMC Cancer 2012; 12:57. [PMID: 22309608 PMCID: PMC3311588 DOI: 10.1186/1471-2407-12-57] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2011] [Accepted: 02/07/2012] [Indexed: 01/16/2023] Open
Abstract
Background Toll-like receptors (TLR) are key innate immunity receptors participating in an immune response. Growing evidence suggests that mutations of TLR2/TLR9 gene are associated with the progress of cancers. The present study aimed to investigate the temporal relationship of single nucleotide polymorphisms (SNP) of TLR2/TLR9 and the risk of hepatocellular carcinoma (HCC). Methods In this single center-based case-control study, SNaPshot method was used to genotype sequence variants of TLR2 and TLR9 in 211 patients with HCC and 232 subjects as controls. Results Two synonymous SNPs in the exon of TLR2 were closely associated with risk of HCC. Compared with those carrying wild-type homozygous genotypes (T/T), risk of HCC decreased significantly in individuals carrying the heterozygous genotypes (C/T) of the rs3804099 (adjusted odds ratio (OR), 0.493, 95% CI 0.331 - 0.736, P < 0.01) and rs3804100 (adjusted OR, 0.509, 95% CI 0.342 - 0.759, P < 0.01). There was no significant association found in two TLR9 SNPs concerning the risk of HCC. The haplotype TT for TLR2 was associated significantly with the decreased risk of HCC (OR 0.524, 95% CI 0.394 - 0.697, P = 0.000). Inversely, the risk of HCC increased significantly in patients with the haplotype CC (OR 2.743, 95% CI 1.915 - 3.930, P = 0.000). Conclusions These results suggested that TLR2 rs3804099 C/T and rs3804100 C/T polymorphisms were closely associated with HCC. In addition, the haplotypes composed of these two TLR2 synonymous SNPs have stronger effects on the susceptibility of HCC.
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Affiliation(s)
- Xie Junjie
- Department of Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, PR China
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Association of Toll-like receptor (TLR) 2, 3 and 9 genes polymorphism with prostate cancer risk in North Indian population. Mol Biol Rep 2012; 39:7263-9. [PMID: 22311043 DOI: 10.1007/s11033-012-1556-5] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2011] [Accepted: 01/24/2012] [Indexed: 12/17/2022]
Abstract
Prostate cancer (PCa) is the most common cancer among men. It has been suggested that toll like receptors (TLRs) may contribute to PCa pathogenesis by stimulating prostate epithelial cell proliferation in response to infectious stimuli. We performed case control study to analyze the genetic variants of TLR2, 3 and 9 gene polymorphisms with PCa risk in a North Indian population. For this study we genotyped age matched, unrelated 195 PCa patients and 250 healthy controls of similar ethnicity in a case-control study. They were genotyped for TLR2 (-196 to -174 Del), TLR3 (c.1377C/T) [rs3775290] and TLR9 (G2848A) [rs352140] gene polymorphisms using polymerase chain reaction and restriction fragment length polymorphism method. Variant allele Del (D) carriers i.e. (ID + DD) of TLR2 (-196 to -174 Del) SNP, demonstrated 1.57 fold increased risk (p = 0.040; OR = 1.57, 95% CI = 1.02-2.24) as compared to Ins (I) allele, suggesting a dominant effect model involved in the risk of this polymorphism in PCa. However, variants of TLR3 and 9 gene polymorphisms were not associated with PCa risk. Our results suggested the low penetrance variant of TLR2 (-196 to -174 Del) to be at increased PCa risk in North Indian population. Functional studies in ethnically diverse populations may provide a more comprehensive involvement of innate immunity in identifying the disease-associated variants for PCa etiology.
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Pandey S, Mittal B, Srivastava M, Singh S, Srivastava K, Lal P, Mittal RD. Evaluation of Toll-like receptors 3 (c.1377C/T) and 9 (G2848A) gene polymorphisms in cervical cancer susceptibility. Mol Biol Rep 2011; 38:4715-4721. [PMID: 21132533 DOI: 10.1007/s11033-010-0607-z] [Citation(s) in RCA: 69] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2010] [Accepted: 11/25/2010] [Indexed: 12/13/2022]
Abstract
Cervical cancer is emerging as a leading cause of morbidity and mortality in women worldwide. Toll-like Receptor (TLR) gene polymorphisms may contribute to subsequent inter-individual variability in cancer susceptibility. The present study aimed to identify the role of TLR 3 (c.1377C/T) [rs3775290] and TLR 9 (G2848A) [rs352140] gene polymorphisms in the risk of developing cervical cancer in North India. Peripheral blood samples were collected from 200 histopathologically confirmed cervical cancer patients from North India and 200 unrelated, cancer-free, age-matched healthy female controls of similar ethnicity. Genomic DNA was extracted using the salting-out method, and genotyped for TLR 3 and TLR 9 using polymerase chain reaction-based restriction fragment length polymorphism (PCR-RFLP). Our data demonstrated a lack of association between TLR 3 (c.1377C/T) and TLR 9 (G2848A) gene polymorphisms and the risk of developing cervical cancer. TLR 3 CT + TT was marginally associated (P = 0.061; age-adjusted OR = 1.46; 95% CI = 0.98-2.16) with cervical cancer susceptibility. The AA genotype of TLR 9 showed borderline significance (P = 0.053) conferring a marginal increased risk (OR = 2.63, 95%CI = 0.99-7.01) for advanced cancer stages (III + IV). Further, TLR 3 and 9 polymorphisms did not have a significant role in modulation of risk due to tobacco usage in cervical cancer patients. Our study suggests only marginal role of TLR 3 and 9 gene polymorphisms in cervical cancer susceptibility in North India; however, future studies in ethnically diverse populations may provide a more comprehensive involvement of innate immunity in cervical cancer etiology in women worldwide.
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Affiliation(s)
- Saumya Pandey
- Department of Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India
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Kutikhin AG. Association of polymorphisms in TLR genes and in genes of the Toll-like receptor signaling pathway with cancer risk. Hum Immunol 2011; 72:1095-116. [PMID: 21872627 DOI: 10.1016/j.humimm.2011.07.307] [Citation(s) in RCA: 68] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2011] [Revised: 07/06/2011] [Accepted: 07/25/2011] [Indexed: 12/15/2022]
Abstract
Toll-like receptors (TLRs) constitute a family of receptors directly recognizing a wide spectrum of exogenous and endogenous ligands playing the key role in realization of innate and adaptive immune response, and participating in the processes of cell proliferation, survival, apoptosis, angiogenesis, tissue remodeling and repair. Polymorphisms in TLR genes may shift balance between pro- and anti-inflammatory cytokines, modulating the risk of infection, chronic inflammation and cancer. The short list of TLR polymorphisms perspective for oncogenomic investigations can include rs10008492, rs4833103, rs5743815, rs11466657, rs7696175 (TLR1-TLR6-TLR10 gene cluster); rs3804100, rs4696480, -196 - -174 del (Delta22), GT-microsatellite polymorphism (TLR2); 829A/C (TLR3); rs5743836, rs352140 (TLR9). The extended list can additionally include rs4833095 rs5743551, rs5743618 (TLR1); rs5743704, rs62323857, rs1219178642 (TLR2); rs5743305, rs3775291, rs121434431, rs5743316 (TLR3); rs5744168 (TLR5); rs179008 (TLR7); rs3764880, rs2407992 (TLR8); rs352139, rs187084, rs41308230, rs5743844 (TLR9); rs4129009 (TLR10). General reasons for discrepancies between studies are insufficiency of sample size, age/gender/BMI/ethnic/racial differences, differences in prevalence of infectious agent in case and control groups, differences in immune response caused by specific ligand, differences in stratification, methods of diagnostics of cancer or chronic inflammatory conditions, genotyping methods, and chance. Future well-designed studies on large samples should shed light on the significance of TLR polymorphisms for cancer prevention.
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Affiliation(s)
- Anton G Kutikhin
- Department of Epidemiology and Central Research Laboratory, Kemerovo State Medical Academy, Kemerovo, Russian Federation.
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Innate immune sensors and gastrointestinal bacterial infections. Clin Dev Immunol 2011; 2011:579650. [PMID: 21647408 PMCID: PMC3102448 DOI: 10.1155/2011/579650] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2011] [Accepted: 03/04/2011] [Indexed: 12/13/2022]
Abstract
The gastrointestinal microbiota is a major source of immune stimulation. The interaction between host pattern-recognition receptors and conserved microbial ligands profoundly influences infection dynamics. Identifying and understanding the nature of these interactions is a key step towards obtaining a clearer picture of microbial pathogenesis. These interactions underpin a complex interplay between microbe and host that has far reaching consequences for both. Here, we review the role of pattern recognition receptors in three prototype diseases affecting the stomach, the small intestine, and large intestine, respectively (Helicobacter pylori infection, Salmonella infection, and inflammatory bowel disease). Specifically, we review the nature and impact of pathogen:receptor interactions, their impact upon pathogenesis, and address the relevance of pattern recognition receptors in the development of therapies for gastrointestinal diseases.
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Increase in NF-kappaB binding affinity of the variant C allele of the toll-like receptor 9 -1237T/C polymorphism is associated with Helicobacter pylori-induced gastric disease. Infect Immun 2009; 78:1345-52. [PMID: 20038537 DOI: 10.1128/iai.01226-09] [Citation(s) in RCA: 86] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Colonization of the gastric mucosa by Helicobacter pylori can lead to serious clinical outcomes, including gastric cancer. Toll-like receptors (TLRs) play an important role in the host response to H. pylori through the recognition of pathogen-associated molecular patterns. TLR9, in particular, is partly responsible for initiating bacterial induced immunity by binding unmethylated CpG-DNA, which is abundant in bacteria. A well-documented single nucleotide polymorphism (SNP) within the TLR9 promoter (TLR9 -1237T/C), is associated with a variety of inflammatory disorders, including allergic asthma, inflammatory bowel disease, and atopy. Analysis of the TLR9 promoter gene sequence has shown that carriage of the variant "C" allele at position -1237 creates a potential NF-kappaB binding site that would theoretically increase the transcriptional activity of the gene. In this study, we report that the TLR9 -1237 C allele was significantly associated with the development of H. pylori-induced premalignant gastric changes. Functional analysis of the SNP, supporting the data generated from the genetic association study, showed that carriage of the C allele increased TLR9 transcriptional activity driven mainly by activation of NF-kappaB. Collectively, these findings confirm that the TLR9 -1237T/C polymorphism is a risk factor for the development of H. pylori-induced premalignant gastric changes and provide a plausible mechanistic explanation.
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