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Jafari N, Khajenabi F, Masumi N, Abediankenari S, Ranjbaran H. Evaluation of HLA-DR and HLA-DQ expression in gastric cancer tissues. J Cancer Res Ther 2024; 20:204-210. [PMID: 38554322 DOI: 10.4103/jcrt.jcrt_144_22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Accepted: 09/15/2022] [Indexed: 04/01/2024]
Abstract
BACKGROUND AND OBJECTIVES Despite recent advances in understanding the gastric cancer (GC) biology, the precise molecular mechanism of gastric carcinogenesis and role of deregulated immune responses in GC progression are still not well understood. In this study, mRNA levels of human leukocyte antigen (HLA)-DRA and -DQA1 were assessed in GC patients to find a potential association between expression of these HLA-II molecules and gastric carcinogenesis. METHODS Using quantitative real-time (qRT)-PCR, mRNA levels of HLA-DRA and -DQA1 were assessed in 20 pairs of matched GC and normal tissues. RESULTS Our results showed that overall mRNA level of HLA-DRA was decreased in the tumor samples relative to control tissues (median fold change [FC] = 0.693; P = 0.445). Overall HLA-DQA1 level was increased in the tumor samples relative to control tissues (median FC = 1.659; P = 0.5117). However, the mentioned data were not statistically significant. Meanwhile, using a ≥ 2.5 FC as the cutoff to determine upregulation or downregulation, 35% of patients showed a downregulated expression of HLA-DRA, while 10% of those showed upregulation in HLA-DRA expression. Upregulation and downregulation of HLA-DQA1 expression were detected, respectively, in 35% and 25% of samples. A strong positive correlation was determined between HLA-DRA and HLA-DQA1 levels in tumor tissues (r = 0.7298; P = 0.0003). CONCLUSION The results reported here along with future studies can be useful to understand the interplay between immune system and GC, therefore, may be helpful to design an effective immune-based therapy.
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Affiliation(s)
- Narjes Jafari
- Immunogenetics Research Center, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | - Fatemeh Khajenabi
- Department of Medical Laboratory Sciences, Khatam Al-Anbia Hospital, Behshahr, Iran
| | - Nastaran Masumi
- Immunogenetics Research Center, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | - Saeid Abediankenari
- Immunogenetics Research Center, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
- Department of Immunology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | - Hossein Ranjbaran
- Immunogenetics Research Center, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
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Ghazy AA, Taha AE. Association of human leukocyte antigen DQ-rs3920AG genotype with Helicobacter pylori recurrence in Kafrelsheikh, Egypt. J Appl Microbiol 2022; 133:1688-1696. [PMID: 35717663 DOI: 10.1111/jam.15673] [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: 12/20/2021] [Revised: 06/02/2022] [Accepted: 06/14/2022] [Indexed: 11/30/2022]
Abstract
AIMS The aim was to evaluate the role of HLA-DP/DQ single-nucleotide polymorphisms (SNPs) in Helicobacter pylori infection in Kafrelsheikh governorate, Egypt. METHODS AND RESULTS The study enrolled 120 persons; 48 naïve H. pylori-infected patients, 42 relapsers and 30 H. pylori-free controls. Gastroscopy, H. pylori stool antigen, anti-CagA and anti-VacA antibodies were determined. Genotyping of HLA-DPA1rs3077 (A/G) SNP and HLA-DQ-rs3920(A/G) SNP was done using real-time PCR. The antibody profile against H. pylori showed that 85.7% of patients with recurrent infection have IgG against CagA (p = 0.001*). There was a significant association between the occurrence of H. pylori infection and both HLA-DPA1rs3077AA and HLA-DQ-rs3920AG genotypes. Concerning H. pylori relapse, the HLA-DQ-rs3920AG genotype was detected in 78.6% of patients with recurrent infection (p = 0.002*). Patients carrying this genotype tend to be relapsers 9.8 times more than patients carrying other genotypes. CONCLUSIONS HLA-DPA1rs3077AA and/or HLA-DQ-rs3920AG genotypes could be risk factors for the occurrence of H. pylori infection. HLA-DQ-rs3920AG genotype is markedly linked to recurrent H. pylori infection. SIGNIFICANCE AND IMPACT OF THE STUDY Host factors as HLA gene polymorphism could be a predisposing factor for susceptibility, recurrence or chronicity of H. pylori and should be studied in different ethnic groups.
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Affiliation(s)
- Amany A Ghazy
- Medical Microbiology and Immunology Unit, Department of Pathology, College of Medicine, Jouf University, Sakaka, Saudi Arabia.,Department of Microbiology & Medical Immunology, Faculty of Medicine, Kafrelsheikh University, Kafrelsheikh, Egypt
| | - Ahmed E Taha
- Medical Microbiology and Immunology Unit, Department of Pathology, College of Medicine, Jouf University, Sakaka, Saudi Arabia.,Medical Microbiology and Immunology Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt
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Ahmed AR, Anwar S, Reche PA. Molecular Basis for Global Incidence of Pemphigoid Diseases and Differences in Phenotypes. Front Immunol 2022; 13:807173. [PMID: 35126393 PMCID: PMC8813746 DOI: 10.3389/fimmu.2022.807173] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2021] [Accepted: 01/03/2022] [Indexed: 12/11/2022] Open
Abstract
Pemphigoid (Pg) diseases are a group of potentially fatal autoimmune mucocutaneous diseases. They have different clinical phenotypes, involving only the skin or multiple mucous membranes. They occur globally and frequently affect the elderly. The common marker among all variants is the presence of autoantibodies targeting the dermal-epidermal or mucosal-submucosal junctions, or basement membrane zone (BMZ). Four target antigens in the BMZ were studied. These included BPAG1, BPAG2 and subunits of α6 and β4 human integrins. Our objective was to find a molecular basis for the global incidence of Pg diseases and a mechanism that will explain the vast differences in clinical phenotypes and outcomes. All the variants of Pg that were analyzed had a statistically significant association with HLA-DQβ1*03:01 in ten countries on four continents. This explains the reason for global incidence. Prediction models discovered multiple peptides in each of the four antigens that serve as T cell epitopes. These T cell epitopes were shown to bind to HLA-DQβ1*03:01. In addition, structure modelling demonstrated the peptide-HLA complex bound to the T cell receptor. These autoreactive T cells would stimulate B cells to produce specific anti-BMZ autoantibodies. Anti-BMZ autoantibodies with different specificities will produce different phenotypes, which will account for involvement of different tissues and organs in different molecules. The contribution this study makes is that it provides a molecular basis of why a similar disease occurs in different racial groups. Furthermore, it provides the basis for the production of autoantibodies with different specificities, which resultantly produces different phenotypes.
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Affiliation(s)
- A. Razzaque Ahmed
- Department of Dermatology, Center for Blistering Diseases, Tufts University School of Medicine, Boston, MA, United States
| | - Sarah Anwar
- Tufts University School of Medicine, Boston, MA, United States
| | - Pedro A. Reche
- Department of Immunology & O2, Faculty of Medicine, University Complutense of Madrid, Madrid, Spain
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Saribas S, Demiryas S, Yilmaz E, Uysal O, Kepil N, Demirci M, Caliskan R, Dinc HO, Akkus S, Gareayaghi N, Kirmusaoglu S, Ozbey D, Tokman HB, Koksal SS, Tasci I, Kocazeybek B. Association between human leukocyte antigen gene polymorphisms and multiple EPIYA-C repeats in gastrointestinal disorders. World J Gastroenterol 2020; 26:4817-4832. [PMID: 32921959 PMCID: PMC7459208 DOI: 10.3748/wjg.v26.i32.4817] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Revised: 07/02/2020] [Accepted: 08/20/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Polymorphisms of human leukocyte antigen (HLA) genes are suggested to increase the risk of gastric cancer (GC). AIM To investigate the HLA allele frequencies of patients with GC relative to a control group in terms of CagA+ multiple (≥ 2) EPIYA-C repeats. METHODS The patient group comprised 94 patients [44 GC and 50 duodenal ulcer (DU) patients], and the control group comprised 86 individuals [(50 non-ulcer dyspepsia patients and 36 people with asymptomatic Helicobacter pylori (H. pylori)]. Polymerase chain reaction was performed for the amplification of the H. pylori cagA gene and typing of EPIYA motifs. HLA sequence-specific oligonucleotide (SSO) typing was performed using Lifecodes SSO typing kits (HLA-A, HLA-B HLA-C, HLA-DRB1, and HLA-DQA1-B1 kits). RESULTS The comparison of GC cases in terms of CagA+ multiple (≥ 2) EPIYA-C repeats showed that only the HLA-DQB1*06 allele [odds ratio (OR): 0.37, P = 0.036] was significantly lower, but significance was lost after correction (Pc = 0.1845). The HLA-DQA1*01 allele had a high ratio in GC cases with multiple EPIYA-C repeats, but this was not significant in the univariate analysis. We compared allele frequencies in the DU cases alone and in GC and DU cases together using the same criterion, and none of the HLA alleles were significantly associated with GC or DU. Also, none of the alleles were detected as independent risk factors after the multivariate analysis. On the other hand, in a multivariate logistic regression with no discriminative criterion, HLA-DQA1*01 (OR = 1.848), HLA-DQB1*06 (OR = 1.821) and HLA-A*02 (OR = 1.579) alleles were detected as independent risk factors for GC and DU. CONCLUSION None of the HLA alleles were detected as independent risk factors in terms of CagA+ multiple EPIYA-C repeats. However, HLA-DQA1*01, HLA-DQB1*0601, and HLA-A*2 were independent risk factors with no criterion in the multivariate analysis. We suggest that the association of these alleles with gastric malignancies is not specifically related to cagA and multiple EPIYA C repeats.
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Affiliation(s)
- Suat Saribas
- Department of Medical Microbiology, Istanbul University-Cerrahpasa, Cerrahpasa Medical Faculty, Istanbul 34098, Turkey
| | - Suleyman Demiryas
- Department of General Surgery, Istanbul University-Cerrahpasa, Cerrahpasa Medical Faculty, Istanbul 34098, Turkey
| | - Erkan Yilmaz
- Department of Organ Transplantation, HLA Laboratory, Istanbul University-Cerrahpasa, Cerrahpasa Medical Faculty, Istanbul 34098, Turkey
| | - Omer Uysal
- Deparment of Biostatistics, Medical School of Bezmialem Vakif University, Istanbul 34093, Turkey
| | - Nuray Kepil
- Department of Pathology, Istanbul University-Cerrahpasa, Cerrahpasa Medical Faculty, Istanbul 34098, Turkey
| | - Mehmet Demirci
- Department of Medical Microbiology, Beykent University Medical Faculty, Istanbul 34520, Turkey
| | - Reyhan Caliskan
- Department of Medical Microbiology, Istanbul University-Cerrahpasa, Cerrahpasa Medical Faculty, Istanbul 34098, Turkey
| | - Harika Oyku Dinc
- Department of Medical Microbiology, Istanbul University-Cerrahpasa, Cerrahpasa Medical Faculty, Istanbul 34098, Turkey
| | - Seher Akkus
- Department of Medical Microbiology, Istanbul University-Cerrahpasa, Cerrahpasa Medical Faculty, Istanbul 34098, Turkey
| | - Nesrin Gareayaghi
- Center for Blood, Istanbul Sisli Hamidiye Etfal Training and Research Hospital, University of Health Sciences, Istanbul 34360, Turkey
| | - Sahra Kirmusaoglu
- Department of Molecular Biology and Genetics, T.C. Halic University, Faculty of Arts & Sciences, Istanbul 34381, Turkey
| | - Dogukan Ozbey
- Department of Medical Microbiology, Istanbul University-Cerrahpasa, Cerrahpasa Medical Faculty, Istanbul 34098, Turkey
| | - Hrisi B Tokman
- Department of Medical Microbiology, Istanbul University-Cerrahpasa, Cerrahpasa Medical Faculty, Istanbul 34098, Turkey
| | - Serdar S Koksal
- Department of Public Health, Istanbul University-Cerrahpasa, Cerrahpasa Medical Faculty, Istanbul 34098, Turkey
| | - Ihsan Tasci
- Department of General Surgery, Istanbul University-Cerrahpasa, Cerrahpasa Medical Faculty, Istanbul 34098, Turkey
| | - Bekir Kocazeybek
- Department of Medical Microbiology, Istanbul University-Cerrahpasa, Cerrahpasa Medical Faculty, Istanbul 34098, Turkey
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Shete S, Liu H, Wang J, Yu R, Sturgis EM, Li G, Dahlstrom KR, Liu Z, Amos CI, Wei Q. A Genome-Wide Association Study Identifies Two Novel Susceptible Regions for Squamous Cell Carcinoma of the Head and Neck. Cancer Res 2020; 80:2451-2460. [PMID: 32276964 PMCID: PMC7299763 DOI: 10.1158/0008-5472.can-19-2360] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2019] [Revised: 02/06/2020] [Accepted: 04/07/2020] [Indexed: 12/13/2022]
Abstract
To identify genetic variants for risk of squamous cell carcinoma of the head and neck (SCCHN), we conducted a two-phase genome-wide association study consisting of 7,858,089 SNPs in 2,171 cases and 4,493 controls of non-Hispanic white, of which, 434,839 typed and 7,423,250 imputed SNPs were used as the discovery. SNPs with P < 1 × 10-3 were further validated in the OncoArray study of oral and pharynx cancer (5,205 cases and 3,232 controls of European ancestry) from databases of Genotypes and Phenotypes. Meta-analysis of the discovery and replication studies identified one novel locus 6p22.1 (P = 2.96 × 10-9 for the leading rs259919) and two cancer susceptibility loci 6p21.32 (rs3135001, HLA-DQB1) and 6p21.33 (rs1265081, CCHCR1) associated with SCCHN risk. Further stratification by tumor site revealed four known cancer loci (5p15.33, 6p21.32, 6p21.33, and 2p23.1) associated with oral cavity cancer risk and oropharyngeal cancer risk, respectively. In addition, one novel locus 18q22.2 (P = 2.54 × 10-9 for the leading SNP rs142021700) was identified for hypopharynx and larynx cancer risk. For SNPs in those reported or novel loci, we also performed functional annotations by bioinformatics prediction and expression quantitative trait loci analysis. Collectively, our identification of four reported loci (2p23.1, 5p15.33, 6p21.32, and 6p21.33) and two novel loci (6p22.1 and 18q22.2) for SCCHN risk highlight the importance of human leukocyte antigen loci for oropharyngeal cancer risk, suggesting that immunologic mechanisms are implicated in the etiology of this subset of SCCHN. SIGNIFICANCE: Two novel risk loci for SCCHN in non-Hispanic white individuals highlight the importance of immunologic mechanism in the disease etiology.
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Affiliation(s)
- Sanjay Shete
- Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Hongliang Liu
- Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina
- Department of Medicine, Duke University School of Medicine, Durham, North Carolina
| | - Jian Wang
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Robert Yu
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Erich M Sturgis
- Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Guojun Li
- Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Kristina R Dahlstrom
- Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Zhensheng Liu
- Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina
- Department of Medicine, Duke University School of Medicine, Durham, North Carolina
| | - Christopher I Amos
- The Institute for Clinical and Translational Research, Baylor College of Medicine, Houston, Texas
| | - Qingyi Wei
- Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina.
- Department of Medicine, Duke University School of Medicine, Durham, North Carolina
- Department of Population Health Sciences, Duke University Medical School, Durham, North Carolina
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Pérez-Rodríguez M, Partida-Rodríguez O, Camorlinga-Ponce M, Flores-Luna L, Lazcano E, Gómez A, Herrera-Goepfert R, Medrano-Guzmán R, Torres J. Polymorphisms in HLA-DQ genes, together with age, sex, and Helicobacter pylori infection, as potential biomarkers for the early diagnosis of gastric cancer. Helicobacter 2017; 22. [PMID: 27334226 DOI: 10.1111/hel.12326] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Polymorphisms in inflammation-related genes are factors associated with the development of gastroduodenal diseases in Helicobacter pylori-infected individuals. MATERIALS AND METHODS We aimed to analyze polymorphisms in HLA-DQ, together with other host and H. pylori variables as risk factors for precancerous and cancerous gastric lesions. 1052 individuals were studied, including nonatrophic gastritis (NAG), intestinal metaplasia (IM), gastric cancer (GC) or duodenal ulcer (DU) patients, and healthy volunteers. RESULTS Patients with alleles DQA*01:01 (OR 0.78), *01:02 (OR 0.29), *01:03 (OR 0.31), and DQB*02:01/02 (OR 0.40) showed a reduced risk for GC. A multivariate logistic regression analyses showed that patients with homozygote genotypes DQA1*03:01 (OR 7.27) and DQA1*04:01 (OR 8.99) and DQB1*05:01:01 (OR 12.04) were at significantly increased risk for GC. Multivariate analyses also demonstrated that age (OR>10.0) and gender (OR>2.0) were variables that influenced significantly the risk for GC, while H. pylori infection (OR>2.5) increased the risk for IM. CONCLUSIONS We identified HLA-DQ alleles associated with IM and GC, and confirm that age, sex, and H. pylori infection are variables that also influence the risk for disease. The use of multiple markers, HLA-DQ alleles, age, sex, and H. pylori infection may be useful biomarkers for the early diagnosis of patients with IM and GC.
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Affiliation(s)
| | | | | | - Lourdes Flores-Luna
- Research Center in Health Population, National Institute of Public Health, Cuernavaca, Morelos, Mexico
| | - Eduardo Lazcano
- Research Center in Health Population, National Institute of Public Health, Cuernavaca, Morelos, Mexico
| | - Alejandro Gómez
- Infectious Diseases Research Unit, CMN S-XXI, IMSS, Mexico City, Mexico
| | | | | | - Javier Torres
- Infectious Diseases Research Unit, CMN S-XXI, IMSS, Mexico City, Mexico
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Wang J, Zhang Q, Liu Y, Han J, Ma X, Luo Y, Liang Y, Zhang L, Hu Y. Association between HLA-Ⅱgene polymorphism and Helicobacter pylori infection in Asian and European population: A meta-analysis. Microb Pathog 2015; 82:15-26. [PMID: 25773770 DOI: 10.1016/j.micpath.2015.03.011] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2015] [Revised: 03/08/2015] [Accepted: 03/11/2015] [Indexed: 02/06/2023]
Abstract
BACKGROUND It is generally considered that HLA-Ⅱ genes contribute to the Helicobacter pylori (Hp) infection and disease development process. AIMS To perform a meta-analysis to explore the relationship between HLA-Ⅱgene polymorphism and host susceptibility to Hp infection. METHODS Relevant cohort studies, case-control studies and cross-sectional studies were identified by searching Cochrane Library, PubMed, EMBASE, Web of Science and CBM up to July 2014. The data were extracted and methodological quality of the studies were evaluated. RevMan5.0 software was used to perform statistical analysis. RESULTS In Asian population, HLA-DQB1*0303 acted as the protective gene in Hp infection (statistically significant pooled OR = 0.54) and the susceptible genes in Hp infection involved HLA-DQB1*0401, HLA-DQA1*0103 and HLA-DQA1*0301 (statistically significant pooled OR and 95%CI were 3.34(1.93,5.77), 1.64(1.16,2.33) and 2.03(1.20,3.44) respectively). No statistically significant difference between DQB1*0303, HLA-DQA1*0103 and DQA1*0301 and Hp infection in European population (P>0.05). And no statistically significant difference (P>0.05) in the overall effect of the association between the rest of HLA-Ⅱalleles and Hp infection. CONCLUSIONS In Asian population, the protective gene HLA-DQB1*0303 and the susceptible genes HLA-DQB1*0401, HLA-DQA1*0103 and HLA-DQA1*0301 in Hp infection were established by meta-analysis. And there was no HLA-Ⅱallele was found to associate with Hp infection among European population.
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Affiliation(s)
- Jingqiu Wang
- College of Veterinary Medicine, Gansu Agricultural University, Lanzhou 730070, China; School of Basic Medical Sciences of Lanzhou University, Lanzhou 730000, China
| | - Qun Zhang
- General Hospital of Lanzhou Petrochemical Company, Lanzhou 730060, China
| | - Yali Liu
- Evidence-based Medicine Center of Lanzhou University, Lanzhou 730000, China
| | - Jian Han
- School of Basic Medical Sciences of Lanzhou University, Lanzhou 730000, China
| | - Xingming Ma
- School of Basic Medical Sciences of Lanzhou University, Lanzhou 730000, China
| | - Yanping Luo
- School of Basic Medical Sciences of Lanzhou University, Lanzhou 730000, China
| | - Yaling Liang
- School of Basic Medical Sciences of Lanzhou University, Lanzhou 730000, China
| | - Lifeng Zhang
- School of Basic Medical Sciences of Lanzhou University, Lanzhou 730000, China
| | - Yonghao Hu
- College of Veterinary Medicine, Gansu Agricultural University, Lanzhou 730070, China.
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Bilici M, Okcu N, Cayır K, Pirim I, Tekin SB, Gundogdu C. Distribution of HLA Tissue Groups in Patients with Gastric Cancer. Eurasian J Med 2015; 42:9-11. [PMID: 25610109 DOI: 10.5152/eajm.2010.03] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2010] [Accepted: 04/13/2010] [Indexed: 12/20/2022] Open
Abstract
OBJECTIVE Gastric cancer is an important disease that is seen all over the world and that threats public health. At the same time, gastric cancer is a heterogeneous disorder with multifactorial etiologies. Recent studies have shown a significant association between HLA antigens and gastric adenocarcinoma. The aim of the present study was to determine the distribution of HLA class I (HLA-A, B and C) and class II (HLA-DR, DQ and DP) antigens in Turkish patients with gastric adenocarcinoma. MATERIALS AND METHODS HLA alleles or HLA haplotypes associated with gastric cancer were established in the Turkish population using PSR-SSP analysis in 71 unrelated patients with gastric cancer and in 82 unrelated healthy controls. The statistical significance of differences in allele frequencies between patients and controls was measured by the Chi-square test with Yates's correction. RESULTS The study revealed that the HLA-Cw5 antigen is more prevalent in patients with gastric cancer (p=0.042) and that the HLA-DRB1*15 antigen is more prevelent in the control group (p=0.021). CONCLUSION It is probable that HLA-Cw5 is a risk factor for gastric cancer whereas HLA-DRB1*15 plays a protective role for this disease. The results show that different loci on HLA may control resistance to or tendency for any disease in different societies; each society should determine its own tissue group.
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Affiliation(s)
- Mehmet Bilici
- Department of Internal Medicine, Faculty of Medicine, Ataturk University, Erzurum, Turkey
| | - Nihat Okcu
- Department of Internal Medicine, Faculty of Medicine, Ataturk University, Erzurum, Turkey
| | - Kerim Cayır
- Department of Internal Medicine, Faculty of Medicine, Ataturk University, Erzurum, Turkey
| | - Ibrahim Pirim
- Department of Medical Biology, Faculty of Medicine, Ataturk University, Erzurum, Turkey
| | - Salim B Tekin
- Department of Internal Medicine, Faculty of Medicine, Ataturk University, Erzurum, Turkey
| | - Cemal Gundogdu
- Department of Pathology, Faculty of Medicine, Ataturk University, Erzurum, Turkey
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Abstract
The major histocompatibility complex class I polypeptide-related sequence A gene (MICA) encodes a membrane-bound protein acting as a ligand to stimulate an activating receptor, NKG2D, expressed on the surface of essentially all human natural killer (NK), γδ T and CD8(+) αβ T cells. MICA protein is absent from most cells but can be induced by infections and oncogenic transformation and is frequently expressed in epithelial tumors. Upon binding to MICA, NKG2D activates cytolytic responses of NK and γδ T cells against infected and tumor cells expressing MICA. Therefore, membrane-bound MICA acts as a signal during the early immune response against infection or spontaneously arising tumors. On the other hand, human tumor cells spontaneously release a soluble form of MICA, causing the downregulation of NKG2D and in turn severe impairment of the antitumor immune response of NK and CD8(+) T cells. This is considered to promote tumor immune evasion and also to compromise host resistance to infections. MICA is the most polymorphic non-classical class I gene. A possible association of MICA polymorphism with genetic predisposition to different cancer types has been investigated in candidate gene-based studies. Two genome-wide association studies have identified loci in MICA that influence susceptibility to cervical neoplasia and hepatitis C virus-induced hepatocellular carcinoma, respectively. Given the current level of interest in the field of MICA gene, we discuss the genetics and biology of the MICA gene and the role of its polymorphism in cancer. Gaps in our understanding and future research needs are also discussed.
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Affiliation(s)
- Dan Chen
- Ministry of Education and Shanghai Key Laboratory of Children's Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China; Department of Immunology, Genetics and Pathology, Science for Life Laboratory Uppsala, Uppsala University, Biomedical Center, Box 815, 75108 Uppsala, Sweden
| | - Ulf Gyllensten
- Department of Immunology, Genetics and Pathology, Science for Life Laboratory Uppsala, Uppsala University, Biomedical Center, Box 815, 75108 Uppsala, Sweden
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He C, Chen M, Liu J, Yuan Y. Host genetic factors respond to pathogenic step-specific virulence factors of Helicobacter pylori in gastric carcinogenesis. MUTATION RESEARCH. REVIEWS IN MUTATION RESEARCH 2014; 759:14-26. [PMID: 24076409 DOI: 10.1016/j.mrrev.2013.09.002] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/28/2013] [Revised: 09/13/2013] [Accepted: 09/13/2013] [Indexed: 12/18/2022]
Abstract
The interindividual differences in risk of Helicobacter pylori (H. pylori)-associated gastric cancer involve significant heterogeneities of both host genetics and H. pylori strains. Several recent studies proposed a distinct sequence for H. pylori exerting its virulence in the host stomach: (i) adhering to and colonizing the surface of gastric epithelial cells, (ii) evading and attenuating the host defense, and (iii) invading and damaging the gastric mucosa. This review focuses on several key issues that still need to be clarified, such as which virulence factors of H. pylori are involved in the three pathogenic steps, which host genes respond to the step-specific virulence factors, and whether and/or how the corresponding host genetic variations influence the risk of gastric carcinogenesis. Urease, BabA and SabA in the adhesion-step, PGN and LPS in the immune evasion-step, and CagA, VacA and Tipα in the mucosal damage-step were documented to play an important role in step-specific pathogenicity of H. pylori infection. There is evidence further supporting a role of potentially functional polymorphisms of host genes directly responding to these pathogenic step-specific virulence factors in the susceptibility of gastric carcinogenesis, especially for urease-interacting HLA class II genes, BabA-interacting MUC1, PGN-interacting NOD1, LPS-interacting TLR4, and CagA-interacting PTPN11 and CDH1. With the continuous improvement of understanding the genetic profile of H. pylori-associated gastric carcinogenesis, a person at increased risk for gastric cancer may benefit from several aspects of efforts: (i) prevent H. pylori infection with a vaccine targeting certain step-specific virulence factor; (ii) eradicate H. pylori infection by blocking step-specific psychopathological characteristics of virulence factors; and (iii) adjust host physiological function to resist the carcinogenic role of step-specific virulence factors or interrupt the cellular signal transduction of the interplay between H. pylori and host in each pathogenic step, especially for the subjects with precancerous lesions in the stomach.
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Affiliation(s)
- Caiyun He
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Affiliated Hospital of China Medical University; Key Laboratory of Cancer Etiology and Prevention (China Medical University), Liaoning Provincial Education Department, Shenyang 110001, China
| | - Moye Chen
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Affiliated Hospital of China Medical University; Key Laboratory of Cancer Etiology and Prevention (China Medical University), Liaoning Provincial Education Department, Shenyang 110001, China
| | - Jingwei Liu
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Affiliated Hospital of China Medical University; Key Laboratory of Cancer Etiology and Prevention (China Medical University), Liaoning Provincial Education Department, Shenyang 110001, China
| | - Yuan Yuan
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Affiliated Hospital of China Medical University; Key Laboratory of Cancer Etiology and Prevention (China Medical University), Liaoning Provincial Education Department, Shenyang 110001, China.
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Atoum MF, Tanashat RQ, Mahmoud SAH. Negative Association of the HLA-DQB1*02 Allele with Breast Cancer Development among Jordanians. Asian Pac J Cancer Prev 2013; 14:7007-10. [DOI: 10.7314/apjcp.2013.14.11.7007] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
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Ando T, Ishikawa T, Kato H, Yoshida N, Naito Y, Kokura S, Yagi N, Takagi T, Handa O, Kitawaki J, Nakamura N, Hasegawa G, Fukui M, Imamoto E, Nakamura C, Oyamada H, Isozaki Y, Matsumoto N, Nagao Y, Okita M, Nakajima Y, Kurokawa M, Nukina M, Ohta M, Mizuno S, Ogata M, Obayashi H, Park H, Kitagawa Y, Nakano K, Yoshikawa T. Synergistic effect of HLA class II loci and cytokine gene polymorphisms on the risk of gastric cancer in Japanese patients with Helicobacter pylori infection. Int J Cancer 2009; 125:2595-602. [PMID: 19544559 DOI: 10.1002/ijc.24666] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
It has been reported that polymorphisms of human leukocyte antigen (HLA) genes and several cytokine genes are associated with an increased risk of developing gastric cancer (GC). However, the results of studies from different geographic regions, ethnic groups and study groups are inconsistent. The aim of this study was to evaluate the influence of H. pylori infection and host genetic factors on GC susceptibility in Japanese patients with GC. We analyzed genotypes for HLA class I and II, tumor necrosis factor alpha, interleukin (IL)-1beta, IL-1 receptor, IL-4, IL-4Ralpha and IL-10 in 330 H. pylori-infected noncardia patients with GC and 190 H. pylori-infected nonulcer dyspeptic controls. Haplotype analyses indicated that the frequencies of the HLA DRB1*0405 and DQB1*0401 alleles were increased in the patients with intestinal-type GC when compared with controls (both DRB1*0405 and DQB1*0401: p = 0.015, OR = 1.57, 95% CI = 1.09-2.26), but the changes were not statistically significant after correction for multiple comparisons. None of the cytokine gene polymorphisms were associated with GC susceptibility, whether patients with GC were analyzed as a group according to the histological subtype. Of interest was the comparison of controls and patients with intestinal-type GC. The frequency of an IL-10-592AA homozygote showing concomitant carriage of the HLA DRB1*0405-DQB1*0401 haplotype was significantly higher in patients with intestinal-type GC (chi(2) = 6.369, p = 0.0116, p(c) = 0.0464, OR = 2.43, 95% CI = 1.21-4.48). Our results suggest that the HLA class II and IL-10-592A/C polymorphisms synergistically affect the susceptibility to GC development of H. pylori-infected individuals in the Japanese population.
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Affiliation(s)
- Takashi Ando
- Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
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Lee HW, Hahm KB, Lee JS, Ju YS, Lee KM, Lee KW. Association of the human leukocyte antigen class II alleles with chronic atrophic gastritis and gastric carcinoma in Koreans. J Dig Dis 2009; 10:265-71. [PMID: 19906105 DOI: 10.1111/j.1751-2980.2009.00395.x] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVE Gastric carcinogenesis is a multi-step process and is influenced by several etiological agents, including the host's genetic factors. Since whether a patient remains with chronic superficial gastritis (CSG) or progresses to either chronic atrophic gastritis (CAG) or gastric carcinoma (GC) could be a genetic predisposition unique in each population, we hypothesized that host human leukocyte antigen (HLA) alleles could be discriminative in predicting the risk of CSG progression to precancerous CAG and GC in Koreans. METHODS A total of 165 patients with gastric disorders (CSG, 62; CAG, 69 and GC, 34), were selected to investigate the association of HLA class II alleles with the progression of CSG to CAG or GC. HLA genotypes were obtained by the polymerase chain reaction-sequence based typing method. RESULTS The phenotypic frequencies of DRB1*1101 and DQA1*0505 were significantly higher in the CAG group compared to those in the CSG group. In the subjects with Helicobacter pylori (H. pypori) (+), the frequencies of DRB1*1501 and DQB1*0602 were significantly lower in the CAG compared to those in the CSG. Further analysis showed that sex (P < 0.05, OR = 0.41-0.42) and age (P < 0.05, OR = 1.05) also affected the risk of progression from CSG to CAG in H. pylori (+) patients carrying the DRB1*1501 or DQB1*0602 allele. Additionally, the frequency of DRB1*0404 in the GC group was significantly higher than that in the gastritis group. CONCLUSION Our findings strongly imply an association between HLA class II alleles and the risk of CAG development and GC progression in Koreans.
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Affiliation(s)
- Hae-Wan Lee
- Department of Surgery, Hallym University Sacred Heart Hospital, Anyang, Korea
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Gates JD, Carmichael MG, Benavides LC, Holmes JP, Hueman MT, Woll MM, Ioannides CG, Robson CH, McLeod DG, Ponniah S, Peoples GE. Longterm Followup Assessment of a HER2/neu Peptide (E75) Vaccine for Prevention of Recurrence in High-Risk Prostate Cancer Patients. J Am Coll Surg 2009; 208:193-201. [DOI: 10.1016/j.jamcollsurg.2008.10.018] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2008] [Revised: 09/24/2008] [Accepted: 10/23/2008] [Indexed: 11/25/2022]
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El-Omar EM. Role of Host Genetic Susceptibility in the Pathogenesis of Gastric Cancer. THE BIOLOGY OF GASTRIC CANCERS 2009:235-250. [DOI: 10.1007/978-0-387-69182-4_9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Mbulaiteye SM, Hisada M, El-Omar EM. Helicobacter Pylori associated global gastric cancer burden. FRONT BIOSCI-LANDMRK 2009; 14:1490-504. [PMID: 19273142 DOI: 10.2741/3320] [Citation(s) in RCA: 72] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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Morselli-Labate AM, Pezzilli R. Usefulness of serum IgG4 in the diagnosis and follow up of autoimmune pancreatitis: A systematic literature review and meta-analysis. J Gastroenterol Hepatol 2009; 24:15-36. [PMID: 19067780 DOI: 10.1111/j.1440-1746.2008.05676.x] [Citation(s) in RCA: 92] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
High circulating serum immunoglobulin G4 (IgG4) levels have been proposed as a marker of autoimmune pancreatitis (AIP). The aim of the present study was to review the data existing in the English literature on the usefulness of the IgG4 serum levels in the diagnosis and follow up of patients with AIP. A total of 159 patients with AIP and 1099 controls were described in seven selected papers reporting the usefulness of serum IgG4 in diagnosing AIP. In total, 304 controls had pancreatic cancer, 96 had autoimmune diseases, and the remaining 699 had other conditions. The summary receiver-operating characteristic curve analysis was carried out by means of Meta-DiSc open-access software. Serum IgG4 showed good accuracy in distinguishing between AIP and the overall controls, pancreatic cancer and other autoimmune diseases (area under the curve [+/- SE]: 0.920 +/- 0.073, 0.914 +/- 0.191, and 0.949 +/- 0.024, respectively). The studies analyzed showed significantly heterogeneous specificity values in each of the three analyses performed. The analysis of the four studies comparing AIP and pancreatic cancers also showed significantly heterogeneous values of sensitivities and odds ratios. Regarding the usefulness of IgG4 as a marker of efficacy of steroid treatment, a decrease in the serum concentrations of IgG4 was found in the four available studies. The serum IgG4 subclass is a good marker of AIP, and its determination should be included in the diagnostic workup of this disease. However, the heterogeneity of the studies published until now means that more studies are necessary in order to better evaluate the true accuracy of IgG4 in discriminating AIP versus other autoimmune diseases.
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Amieva MR, El-Omar EM. Host-bacterial interactions in Helicobacter pylori infection. Gastroenterology 2008; 134:306-23. [PMID: 18166359 DOI: 10.1053/j.gastro.2007.11.009] [Citation(s) in RCA: 387] [Impact Index Per Article: 22.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2007] [Accepted: 10/21/2007] [Indexed: 02/07/2023]
Abstract
Helicobacter pylori are spiral-shaped gram-negative bacteria with polar flagella that live near the surface of the human gastric mucosa. They have evolved intricate mechanisms to avoid the bactericidal acid in the gastric lumen and to survive near, to attach to, and to communicate with the human gastric epithelium and host immune system. This interaction sometimes results in severe gastric pathology. H pylori infection is the strongest known risk factor for the development of gastroduodenal ulcers, with infection being present in 60%-80% of gastric and 95% of duodenal ulcers.(1)H pylori is also the first bacterium to be classified as a definite carcinogen by the World Health Organization's International Agency for Research on Cancer because of its epidemiologic relationship to gastric adenocarcinoma and gastric mucosa-associated lymphoid tissue lymphoma.(2) In the last 25 years, since H pylori was first described and cultured, a complete paradigm shift has occurred in our clinical approach to these gastric diseases, and more than 20,000 scientific publications have appeared on the subject. From the medical point of view, H pylori is a formidable pathogen responsible for much morbidity and mortality worldwide. However, H pylori infection occurs in approximately half of the world population, with disease being an exception rather than the rule. Understanding how this organism interacts with its host is essential for formulating an intelligent strategy for dealing with its most important clinical consequences. This review offers an insight into H pylori host-bacterial interactions.
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Affiliation(s)
- Manuel R Amieva
- Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California, USA
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19
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Chen PC, Tsai EM, Er TK, Chang SJ, Chen BH. HLA-DQA1 and -DQB1 allele typing in southern Taiwanese women with breast cancer. Clin Chem Lab Med 2007; 45:611-4. [PMID: 17484621 DOI: 10.1515/cclm.2007.132] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
BACKGROUND The pathogenesis of breast cancer is multifactorial. Genetic predisposition, environmental factors, hormones and even infection agents are thought to interact in the manifestation of breast cancer. In particular, human leukocyte antigen (HLA) alleles play a pivotal role in cellular immunity and may be an important genetically determined host trait. Regardless of the importance and functions of HLA genes in the evolution of cancer, the allele-specific association of HLA molecules in cancer patients has not been well established. Recently, a few studies have concentrated on the association between HLA and breast cancer, but the results of these studies are controversial. METHODS We designed a study to evaluate the association between the genotype of HLA class II genes and breast cancer. HLA-DQA1 and -DQB1 polymorphisms were determined by PCR with sequence-specific primers (PCR-SSP) in 101 Taiwanese women patients with breast cancer and 115 matched control subjects. RESULTS Using PCR-SSP typing, HLA-DQA1 and -DQB1 locus comparison of allele frequencies between breast cancer patients and healthy controls showed no significant difference. CONCLUSIONS We have established a significant lack of HLA-DQA1 and -DQB1 association with breast cancer in southern Taiwanese women. The results of this study may provide information for further clarification of the etiology of breast cancer in this region.
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Affiliation(s)
- Po-Chih Chen
- Department of Laboratory Medicine, Kaohsiung Medical University Chung-Ho, Memorial Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
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Lo SS, Lin SC, Wu CW, Chen JH, Yeh WI, Chung MY, Lui WY. Heme oxygenase-1 gene promoter polymorphism is associated with risk of gastric adenocarcinoma and lymphovascular tumor invasion. Ann Surg Oncol 2007; 14:2250-6. [PMID: 17520317 DOI: 10.1245/s10434-006-9290-7] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2006] [Revised: 09/27/2006] [Accepted: 09/28/2006] [Indexed: 11/18/2022]
Abstract
PURPOSE Heme oxygenase-1 (HO-1) gene, which encodes an oxidative response protein, plays a role in cytoprotection. A (GT)n dinucleotide repeat in HO-1 promoter is polymorphic and modulates the transcriptional activity of the gene. A HO-1 gene promoter polymorphism was reported to be associated with the risks of lung adenocarcinoma and oral squamous cancer. In this study, the correlation between the HO-1 gene promoter polymorphism and the clinicopathological characteristics, along with the risk of gastric cancer, was analyzed. EXPERIMENTAL DESIGN We examined the genotypic frequencies of (GT)n repeats in 183 gastric cancer patients and 250 control subjects by PCR-based genotyping and DNA sequencing. The length polymorphisms of (GT)n repeats were classified into short (S) component (n <or= 25), medium (M) component (26 <or= n <or= 30) and long (L) component (n >or= 31). The distribution of S, M and L components in patient and control groups were evaluated to determine the correlation with susceptibility and clinicopathological characteristics of gastric adenocarcinoma. RESULTS Higher frequencies of L-allele, L-allele carrier (S/L, M/L, L/L) and S/L genotype were found in gastric cancer patients. The frequencies of M-allele, M-allele carrier (M/M, M/L, M/S) and M/M genotype were significantly lower in patients with gastric cancer than controls. Furthermore, the frequency of lymphovascular tumor invasion was significantly lower in M-allele carriers compared to non-M-allele carriers (S/S, S/L, L/L) (p = 0.009). CONCLUSIONS These findings suggest that the long (GT)n repeat of HO-1 gene promoter was associated with a higher frequency of gastric adenocarcinoma, and the medium (GT)n repeat might possess protective effect against gastric adenocarcinoma with a lower frequency of lymphovascular invasion in tumors.
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Affiliation(s)
- Su-Shun Lo
- Division of General Surgery, Taipei Veterans General Hospital and National Yang Ming University, No 201, Sec 2, Shih-Pai Rd, Taipei, Taiwan.
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Herrera-Goepfert R, Yamamoto-Furusho JK, Onate-Ocana LF, Camorlinga-Ponce M, Munoz L, Ruiz-Morales JA, Vargas-Alarcon G, Granados J. Role of the HLA-DQ locus in the development of chronic gastritis and gastric carcinoma in Mexican patients. World J Gastroenterol 2006; 12:7762-7. [PMID: 17203517 PMCID: PMC4087539 DOI: 10.3748/wjg.v12.i48.7762] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To determine the HLA-DQ locus in Mexican patients with Chronic gastritis and gastric adenocarcinoma.
METHODS: Oligotyping for HLA-DQ locus was performed in 45 Mexican patients with chronic gastritis and 13 Mexican patients with diffuse-type gastric adenocarcinoma, and was then compared with 99 clinically healthy unrelated individuals. H pylori infection and CagA status were assessed in patients by enzyme-linked immunosorbent assay (ELISA) method.
RESULTS: We found a significant increased frequency of HLA-DQB1*0401 allele in H pylori-positive patients with chronic gastritis when compared with healthy subjects [19 vs 0%, P = 1 × 10-7, odds ratio (OR) = 4.96; 95% confidence interval (95% CI), 3.87-6.35]. We also found a significant increased frequency of HLA-DQB1*0501 in patients with diffuse-type gastric carcinoma in comparison with healthy individuals (P = 1 × 10-6, OR = 13.07; 95% CI, 2.82-85.14).
CONCLUSION: HLA-DQ locus may play a different role in the development of H pylori-related chronic gastritis and diffuse-type gastric adenocarcinoma in the Mexican Mestizo population.
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Touati E, Michel V, Thiberge JM, Avé P, Huerre M, Bourgade F, Klungland A, Labigne A. Deficiency in OGG1 protects against inflammation and mutagenic effects associated with H. pylori infection in mouse. Helicobacter 2006; 11:494-505. [PMID: 16961812 DOI: 10.1111/j.1523-5378.2006.00442.x] [Citation(s) in RCA: 59] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Helicobacter pylori infection is associated with gastric cancer. Study with the Big Blue mouse model has reported a mutagenic effect associated with the H. pylori infection, as a result in part of oxidative DNA damage. The present work investigates the consequences of a deficiency in the OGG1 DNA glycosylase, responsible for the excision of 8-oxo guanine, on the inflammatory and genotoxic host response to the infection. MATERIALS AND METHODS Big Blue Ogg1-/- C57BL/6 mice were orally inoculated with H. pylori strain SS1 or vehicle only, and sacrificed after 1, 3, or 6 months. The serologic response, histologic lesions, mutant frequency, and spectra of mutations were assessed in the stomach and compared to what observed in the wild-type (Wt) context. RESULTS Inflammatory lesions induced in the gastric mucosa of H. pylori-infected mice, corresponding to a moderate gastritis, were less severe in Ogg1-/- than in Wt Big Blue mice. Analysis of antimicrobial humoral immunity exhibited a lower IgG2a serum level (Th1 response) after 6 months of infection in Ogg1-/- than in the Wt mice. In these conditions, the H. pylori-SS1 infection in the Ogg1-/- mice did not induce a mutagenic effect at the gastric epithelial cells level, either after 3 or 6 months. CONCLUSIONS The inactivation of the OGG1 DNA glycosylase in mouse leads to less severe inflammatory lesions and abolished the mutagenic effect at the gastric epithelial cells level, induced by the H. pylori infection. These data suggest for the OGG1deficiency a protective role against inflammation and genotoxicity associated to the H. pylori infection.
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Affiliation(s)
- Eliette Touati
- Unité de Pathogénie Bactérienne des Muqueuses, Institut Pasteur, Paris, France.
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Watanabe Y, Aoyama N, Sakai T, Shirasaka D, Maekawa S, Kuroda K, Wambura C, Tamura T, Nose Y, Kasuga M. HLA-DQB1 locus and gastric cancer in Helicobacter pylori infection. J Gastroenterol Hepatol 2006; 21:420-4. [PMID: 16509868 DOI: 10.1111/j.1440-1746.2005.04112.x] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
BACKGROUND AND AIMS It has been suggested that the incidence of digestive diseases associated with Helicobacter pylori is influenced by the strain diversity of H. pylori, factors involving the host or environment, and the duration of infection. The authors have previously reported that human leukocyte antigen (HLA)-DQB1*0401 plays an important role in the development of atrophic gastritis in H. pylori infected patients. The aim of the present study was to investigate the relationship between HLA-DQB1 genotype and cancer development. METHODS HLA-DQB1 genotyping was performed by the PCR-RFLP method on 122 H. pylori-infected non-ulcer dyspepsia (NUD) patients, 53 gastric cancer patients and 28 uninfected controls. To reliably estimate the grade of atrophic gastritis, histological evaluation was performed. RESULTS The allele frequency of DQB1*0401 was significantly higher in intestinal type cancer patients compared with age- and sex-matched H. pylori-infected NUD patients. There was no significant difference in the mean atrophic scores of the biopsy samples from the lesser curvature of the mid-corpus between these groups. CONCLUSIONS HLA-DQB1*0401 is a useful marker for determining susceptibility to intestinal type gastric cancer.
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Affiliation(s)
- Yoshinori Watanabe
- Division of Diabetes, Digestive and Kidney Diseases, Department of Clinical Molecular Medicine, Kobe University School of Medicine, Kobe, Japan
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Abstract
Gastric cancer is the second most common cause of cancer death worldwide. It is estimated that 5-10% of gastric cancer cases have a familial association; however, knowledge concerning the genetic predisposition to familial gastric cancer is currently limited. In this chapter we discuss what is known about the aetiology and pathogenesis of both the diffuse and intestinal forms of familial gastric cancer. We focus particularly on hereditary diffuse gastric cancer because the discovery of germ-line E-cadherin mutations in a number of affected families has opened the prospect of identifying gene carriers, with implications for clinical management. The interplay of other conventional risk factors, such as Helicobacter pylori infection, with genetic factors is also discussed. It is hoped that understanding the genetic basis for familial gastric cancer will facilitate the development of clinically useful screening and preventative procedures.
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Affiliation(s)
- Miriam Barber
- MRC Cancer Cell Unit, Hutchison/MRC Research Centre, Cambridge, UK
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van Amsterdam K, van Vliet AHM, Kusters JG, van der Ende A. Of microbe and man: determinants ofHelicobacter pylori-related diseases. FEMS Microbiol Rev 2006; 30:131-56. [PMID: 16438683 DOI: 10.1111/j.1574-6976.2005.00006.x] [Citation(s) in RCA: 59] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
The human gastric pathogen Helicobacterpylori infects the human gastric mucus layer of approximately half of the world's population. Colonization with this bacterium results in superficial gastritis without clinical symptoms, but can progress into gastric or duodenal ulcers, gastric malignancies and mucosa-associated lymphoid tissue-lymphomas. Disease outcome is affected by a complex interplay between host, environmental and bacterial factors. Irrespective of disease outcome, the majority of H. pylori infected individuals remain colonized for life. Changing conditions in the human gastric mucosa may alter gene expression and/or result in the outgrowth of more fit H. pylori variants. As such, H. pylori is a highly flexible organism that is optimally adapted to its host. the heterogeneity in H. pylori populations make predictions on H. pylori-related pathogenesis difficult. In this review, we discuss host, environmental and bacterial factors that are important in disease progression. Moreover, H. pylori adaptive mechanisms, which allow its life-long survival and growth in the gastric mucosa are considered.
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Affiliation(s)
- Karin van Amsterdam
- Department of Medical Microbiology, Academic Medical Center, Amsterdam, The Netherlands
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Abstract
Gastric cancer remains a major health problem particularly in the developing world. Helicobacter pylori (H. pylori) infection is the most recognised aetiological risk factor for this malignancy. The infection causes a chronic gastritis that is the precursor to all the pathophysiological abnormalities characteristic of gastric carcinogenesis. Genetic polymorphisms have emerged in recent years as important determinants of disease susceptibility and severity. In the case of H. pylori-induced gastric cancer, host genetic polymorphisms play an important role both in the precancerous stages and in the transition to cancer. In particular, polymorphic genes of the adaptive and innate immune response are involved in all stages of the neoplastic process. This field is rapidly expanding and many other genetic determinants are currently being defined. The ultimate value of host genetics should be in understanding the pathogenesis of the disease, which would offer a true opportunity to defeat this global killer.
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Affiliation(s)
- Emad M El-Omar
- Department of Medicine and Therapeutics, Aberdeen University, Institute of Medical Sciences, Foresterhill, Aberdeen, Scotland, UK.
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Abstract
Over the past 20 years, there has been marked progress in our understanding of the role of genetic and environmental factors in the etiology of gastroduodenal disease. Helicobacter pylori infection now is recognized to be the most important environmental factor for both noncardia gastric cancer and peptic ulcer disease. The likelihood of the infection resulting in significant disease depends on genetic polymorphisms influencing the virulence of the organism. However, the specific pattern of disease induced by the infection is determined to a great extent by genetic polymorphisms in the host that govern the local gastric immune response elicited. Genetic factors also are important in the treatment of gastroduodenal diseases. Polymorphisms of host CYP2C19 influence the pharmacokinetics and clinical efficacy of proton pump inhibitor therapy.
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Affiliation(s)
- Derek Gillen
- Division of Gastroenterology, Department of Medicine and Therapeutics, The University of Glasgow, The Western Infirmary, Glasgow, Scotland, United Kingdom.
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Peoples GE, Gurney JM, Hueman MT, Woll MM, Ryan GB, Storrer CE, Fisher C, Shriver CD, Ioannides CG, Ponniah S. Clinical Trial Results of a HER2/neu (E75) Vaccine to Prevent Recurrence in High-Risk Breast Cancer Patients. J Clin Oncol 2005; 23:7536-45. [PMID: 16157940 DOI: 10.1200/jco.2005.03.047] [Citation(s) in RCA: 172] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023] Open
Abstract
Purpose E75 is an immunogenic peptide from the HER2/neu protein that is highly expressed in breast cancer. We are conducting a clinical trial of an E75 + granulocyte-macrophage colony-stimulating factor vaccine to assess safety, immunologic response, and the prevention of clinical recurrences in patients with disease-free, node-positive breast cancer (NPBC). Patients and Methods Fifty-three patients with NPBC were enrolled and HLA typed. HLA-A2+ patients (n = 24) were vaccinated, and HLA-A2− patients (n = 29) are observed prospectively as clinical controls. Local/systemic toxicities, immunologic responses, and time to recurrence are being measured. Results Only minor toxicities have occurred (one grade 3 [4%]). All patients have demonstrated clonal expansion of E75-specific CD8+T cells that lysed HER2/neu-expressing tumor cells. An optimal dosage and schedule have been established. Patients have developed delayed-type hypersensitivity reactions to E75 postvaccination compared with controls (33 v 7 mm; P < .01). HLA-A2+ patients have been found to have larger, more poorly differentiated, and more hormonally insensitive tumors compared to HLA-A2− patients. Despite this, the only two deaths have occurred in the control group. The disease-free survival in the vaccinated group is 85.7% compared to 59.8% in the controls at 22 months' median follow-up with a recurrence rate of 8% compared to 21%, respectively (P < .19). Median time to recurrence in the vaccinated patients was prolonged (11 v 8 months), and recurrence correlated with a weak delayed-type hypersensitivity response. Conclusion This HER2/neu (E75) vaccine is safe and effective in eliciting a peptide-specific immune response in vivo. Induced HER2/neu immunity seems to reduce the recurrence rate in patients with NPBC.
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Affiliation(s)
- George E Peoples
- Clinical Breast Care Project, Walter Reed Army Medical Center, Washington, DC 20307-5001, USA.
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Hueman MT, Dehqanzada ZA, Novak TE, Gurney JM, Woll MM, Ryan GB, Storrer CE, Fisher C, McLeod DG, Ioannides CG, Ponniah S, Peoples GE. Phase I Clinical Trial of a HER-2/neu Peptide (E75) Vaccine for the Prevention of Prostate-Specific Antigen Recurrence in High-Risk Prostate Cancer Patients. Clin Cancer Res 2005; 11:7470-9. [PMID: 16243821 DOI: 10.1158/1078-0432.ccr-05-0235] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
PURPOSE The E75 peptide is an immunogenic peptide from the HER-2/neu protein that is substantially expressed in prostate cancer. We are conducting a clinical trial of an E75/granulocyte macrophage colony-stimulating factor vaccine to prevent post-prostatectomy prostate-specific antigen (PSA) recurrences in high-risk prostate cancer (HRPC) patients. EXPERIMENTAL DESIGN Prostate cancer patients at high risk for recurrence were prospectively evaluated and identified by the validated Center for Prostate Disease Research (CPDR)/CaPSURE high-risk equation. From these high-risk equation patients, 27 HER-2/neu-expressing prostate cancer patients were enrolled. HLA-A2+ patients (n = 17) were vaccinated, whereas HLA-A2- patients (n = 10) were followed as clinical controls. Local/systemic toxicities, immunologic responses, and time to recurrence were measured. RESULTS This vaccine is safe with only minor toxicities observed. Additionally, the vaccine is immunogenic with all patients showing both in vivo and in vitro phenotypic and functional immune responses, although variable. HLA-A2+ patients were found to have larger tumors, higher postoperative Gleason scores, and more high-risk CPDR scores than HLA-A2- patients. Despite these differences, disease-free survival was not different between the vaccinated HLA-A2+ patients and the HLA-A2- controls at a median follow up of 23 months. Three of the four vaccinated patients that recurred had rising PSAs at the initiation of the trial. Ex vivo phenotypic assays were predictive of recurrences and correlated in general with functional assays. CONCLUSIONS The E75 vaccine strategy is safe and effective in eliciting an immune response against the HER-2/neu protein in HRPC patients and may be useful as a preventive strategy against disease recurrence. Vaccination in response to a rising PSA may be too late.
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Affiliation(s)
- Matthew T Hueman
- Clinical Breast Care Project, Department of Surgery and Center for Prostate Disease Research, Department of Urology, Walter Reed Army Medical Center, Washington, District of Colombia, USA
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Ang TL, Fock KM, Dhamodaran S, Teo EK, Tan J. Racial differences in Helicobacter pylori, serum pepsinogen and gastric cancer incidence in an urban Asian population. J Gastroenterol Hepatol 2005; 20:1603-9. [PMID: 16174081 DOI: 10.1111/j.1440-1746.2005.03898.x] [Citation(s) in RCA: 48] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
BACKGROUND In Singapore, the highest incidence of gastric cancer occurs in the Chinese (C), with lower rates among Malay (M) and Indian (I) subjects. The purpose of the present paper was to examine whether racial differences in the prevalence of Helicobacter pylori and serum pepsinogen (PG) could account for this difference. METHODS A randomized community health survey involving 7000 asymptomatic healthy individuals was conducted. Among the Chinese, Malay and Indian respondents, subjects were matched for age, gender and race and a total of 595 sera were obtained. The H. pylori seropositivity and serum PG levels were determined by ELISA. The dependency of the cumulative gastric incidence rate on H. pylori seroprevalence was evaluated by linear regression. The racial difference in the seroprevalence of H. pylori and low serum PG was determined. RESULTS The H. pylori seroprevalence was similar between Chinese and Indian subjects, but significantly lower among Malay subjects (C, 46.3%; M, 27.9%; I, 48.1%). The gastric cancer incidence rates correlated with H. pylori seropositivity for the Chinese and Malay subjects, but not for the Indian subjects. The prevalence of low PG was highest in Indian subjects (PG I low: C, 2.1%; M, 5.4%; I, 14.2%; P < 0.0001; PG I:II ratio low: C, 5.3%; M, 5.9%; I, 12.6%; P = 0.012), even when adjusted for gender and the presence of H. pylori. CONCLUSIONS The difference in gastric cancer incidence correlated with H. pylori seroprevalence for Chinese and Malay subjects. The lower incidence of gastric cancer among Indian subjects cannot be explained by differences in H. pylori or serum PG. Other modifying factors such as host and environmental factors may be important.
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Affiliation(s)
- Tiing Leong Ang
- Division of Gastroenterology, Changi General Hospital, Singapore.
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Quintero E, Pizarro MA, Rodrigo L, Piqué JM, Lanas A, Ponce J, Miño G, Gisbert J, Jurado A, Herrero MJ, Jiménez A, Torrado J, Ponte A, Díaz-de-Rojas F, Salido E. Association of Helicobacter pylori-related distal gastric cancer with the HLA class II gene DQB10602 and cagA strains in a southern European population. Helicobacter 2005; 10:12-21. [PMID: 15691311 DOI: 10.1111/j.1523-5378.2005.00287.x] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND Distinct human leukocyte antigen (HLA)-DQ genes have been associated with an increased or reduced risk for gastric cancer, but its association with Helicobacter pylori status is controversial. In the present study we evaluated the influence of host HLA DQA1 and DQB1 loci, H. pylori genotype, and socio-economic factors on predicting H. pylori-associated distal gastric cancer in a southern European population. MATERIAL AND METHODS In a prospective case-control (1 : 2) study, 42 patients with H. pylori-associated distal gastric cancer were matched by age (+/-5 years) and gender to 84 patients with H. pylori-associated benign gastroduodenal disease (controls). The level of education received, smoking status, alcohol consumption, origin and familial history of gastric cancer were registered at inclusion. HLA DQA1 and DQB1 typing and H. pylori genotyping were determined from endoscopic gastric mucosal biopsies. RESULTS Compared with control patients, a positive association with cagA(+) strains (p < .002) and a negative association with vacA-s2 strains (p < .02) was found in patients with distal gastric cancer. At the DQB1 locus, the (*)0602 allele was more frequent in distal gastric cancer than in controls (26.2% vs. 4.8%; p < .005). After correction for multiple comparisons (exact multiple regression analysis) the cagA(+) status and the DQB1(*)0602 allele were associated with an increased distal gastric cancer risk (OR 3.7; 95% CI = 1.33-12.26 and OR 4.82; 95% CI = 1.24-19.83, respectively) whereas the vacA-s2 status was associated with a decreased risk (OR 0.33; 95% CI = 0.10-0.94). CONCLUSION Our findings suggest that in the H. pylori-infected southern European population, the cagA genotype and the HLA-DQB1(*)0602 gene confer an increased risk for distal gastric cancer.
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Affiliation(s)
- Enrique Quintero
- Gastroenterology Department, University Hospital of the Canary Islands, Spain.
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Li Z, Chen D, Zhang C, Li Y, Cao B, Ning T, Zhao Y, You W, Ke Y. HLA polymorphisms are associated with Helicobacter pylori infected gastric cancer in a high risk population, China. Immunogenetics 2005; 56:781-7. [PMID: 15650879 DOI: 10.1007/s00251-004-0723-9] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2004] [Revised: 08/31/2004] [Indexed: 12/29/2022]
Abstract
Helicobacter pylori is one of the most common bacterial infections associated with an increased risk of gastric cancer, but its association with host factors, particularly polymorphisms of the immune response genes, such as human leukocyte antigen (HLA) genes, is still unclear. To investigate the role of HLA polymorphisms in the risk of gastric cancer among subjects with H. pylori infection, a case-control study involving 52 gastric cancer patients and 139 non-cancer controls was conducted in Linqu County, China, an area with a high incidence of gastric cancer. Polymorphisms of HLA class I and class II alleles were determined by PCR with sequence-specific primers (PCR-SSP). The information about H. pylori infection was obtained from previous records. Among 48 class I and 19 class II HLA alleles detected in this study, two alleles, CW*03 and DRB1*01, were found to be distributed significantly differently between patients and controls [odds ratio(OR)=1.95, 95% confidence interval (CI)=1.13-3.35, P=0.017 and OR=4.39, 95% CI=1.39-13.84, P=0.012, respectively). The OR of gastric cancer risk in individuals carrying CW*03/CW*03 or CW*03/CW*N was 2.06, 95% CI=1.05-4.02, P=0.035, while the OR was 3.49, 95% CI=1.0-12.4, P=0.04 for DRB1*01/DRB1*01 or DRB1*01/DRB1*N carriers. The analysis of the interaction between H. pylori infection and HLA risk genotypes of CW*03 or DRB1*01 revealed that the effect of CW*03 and DRB1*01 genotypes on gastric cancer risk was manifested stronger in H. pylori-positive individuals (OR=5.30, 95% CI=1.73-16.29, P=0.004 and OR=13.38, 95% CI=2.52-70.98, P=0.002, respectively) than in H. pylori-negative ones (OR=1.25, 95% CI=0.25-6.12, P=0.785 and OR=2.26, 95% CI=0.18-28.88, P=0.531, respectively). The combined effect of the two risk HLA genotypes on gastric cancer risk was also analysed. The result showed that the individuals carrying both the CW*03 and DRB1*01 alleles could only be found in cancer patients (5/52), and not in controls (0/139), further suggesting that CW*03 and DRB1*01 are risk alleles advancing the progression of tumorigenesis. These observations demonstrate that host HLA genotypes may play an important role in the risk of gastric cancer, especially among persons with H. pylori infection.
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Affiliation(s)
- Zhaohui Li
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, People's Republic of China
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Lo SS, Lee YJ, Wu CW, Liu CJ, Huang JW, Lui WY. The increase of MICA gene A9 allele associated with gastric cancer and less schirrous change. Br J Cancer 2004; 90:1809-13. [PMID: 15150599 PMCID: PMC2409751 DOI: 10.1038/sj.bjc.6601750] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Since surgical resection is the principal treatment of gastric cancer, early detection is the only effective strategy against this disease at present. Recently, a new polymorphic gene family, the major histocompatibility complex class I chain-related (MIC) genes located about 40 kb centromeric to HLA-B gene has been proposed. This family consists of five genes (A, B, C, D and E). Among them, MICA has five various alleles (A4, A5, A5.1, A6 and A9), which can be used as a polymorphic marker for genetic mapping and for disease susceptibility. The MICA polymorphism was studied in our gastric cancer patients to see if there is any possible correlation with genetic predisposition and clinicopathological factors. Genomic DNA was extracted from fresh or frozen peripheral blood leukocytes in 107 patients with gastric adenocarcinoma who underwent gastrectomy in our hospital and 351 noncancer controls. MICA polymorphism was analysed by using PCR-based technique. The results showed both phenotypic and allele frequencies of allele A9 in patients with gastric cancer were significantly higher than controls (33 vs 17.6%, P=0.005; 17 vs 9.9%, P=0.02). Gastric adenocarcinoma with allele A9 was associated with less schirrous change than those without (P=0.014). MICA gene A9 allele might confer the risk of gastric cancer and associate with less schirrous change. The mechanisms among them deserve further investigation.
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Affiliation(s)
- S-S Lo
- I-Lan Hospital, DOH, Taipei, Taiwan.
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Kouerinis IA, Zografos G, Tarassi KE, Athanasiades TH, Liontos M, Gorgoulis VG, Korkolis D, Konstandoulakis MM, Fotiadis CI, Androulakis G, Papasteriades CA. Human leukocyte antigens as genetic markers in Greek patients with sporadic pancreatic cancer. Pancreas 2004; 29:41-4. [PMID: 15211110 DOI: 10.1097/00006676-200407000-00054] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
PURPOSE In this study we investigated the relationship between specific HLA antigens and sporadic pancreatic cancer in Greek population. METHODS The allele frequencies of serologically and molecular defined class I and II HLA antigens were studied in 60 unrelated patients with pancreatic cancer histologically confirmed. The results obtained for HLA frequencies were compared with those of 105 healthy control subjects (control group). RESULTS Increased frequencies of HLA-A30 (16.7 vs. 3.8%; P < 0.01; OR = 5.05), A31 (9.5 vs. 1.9%; P < 0.05; OR = 5.72), B18 (31.7 vs. 14.3%; P < 0.05; OR = 2.78) and Cw7 (53.3 vs. 21.9%; P < 0.01; OR = 4.07) were observed in patients with pancreatic cancer in comparison to the control subjects. CONCLUSIONS This study demonstrates the association between specific HLA antigens and pancreatic cancer development in whites and suggests a genetic susceptibility factor for the disease.
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Affiliation(s)
- I A Kouerinis
- First Propaudeutic Surgical Department, School of Medicine, University of Athens, Greece.
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Russo A, Maconi G, Lombardo C, Settesoldi D, Ferrari D, Ravagnani F, Andreola S, Pizzetti P, Spinelli P, Bertario L. Human leukocyte antigen class II genes and Helicobacter pylori infection: does genotype overwhelm environmental exposure? Nutrition 2003; 19:708-15. [PMID: 12921878 DOI: 10.1016/s0899-9007(02)01034-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
OBJECTIVE We investigated associations between human leukocyte antigen class II genes, environmental exposures, and Helicobacter pylori infection. METHODS Sixty-eight subjects with histologically confirmed H. pylori and intestinal metaplasia (cases) and 70 healthy subjects without H. pylori (controls) matched for age, sex, and year of birth were included in this study. All patients answered a detailed questionnaire designed to collect sociodemographic characteristics, smoking, alcohol drinking, and dietary habits. Human leukocyte antigen class II genes were typed with genomic DNA. The cytotoxins CagA and VacA were investigated with serology. Odds ratios and corresponding 95% confidence intervals were estimated from multivariate conditional logistic regression. Multiple correspondence analysis was used to represent the interrelationships of a multiple contingency table. RESULTS Human leukocyte antigen DRB1, DQA1, and DQB1 genotypes were not significantly associated with H. pylori infection and intestinal metaplasia. No significant association with blood group or Lewis antigen system was found. However, multiple correspondence analysis clearly associated H. pylori with environmental exposure: the control group largely consumed olive oil, fresh fruits, and vegetables and histories of never or formerly smoking and the case group (those positive for H. pylori and metaplasia) largely consumed eggs, meat and butter and had histories of smoking cigarettes. CONCLUSIONS These findings suggested that H. pylori infection is not influenced by a genetic compound and confirmed the relevance of environmental exposure.
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Affiliation(s)
- Antonio Russo
- Epidemiology Unit, Local Health Authority of Milan, Milan, Italy
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Abstract
Helicobacter pylori is one of the most common pathogenic bacterial infections, colonizing an estimated half of all humans. In a subset of individuals, the infection leads to serious gastroduodenal disease such as peptic ulcers and gastric adenocarcinoma. The factors contributing to skewing this, in most cases benign, relationship into disease development are largely unknown. However, factors emanating from the bacterium, host and the environment have been shown to affect the risk for disease, although no factor can be singled out to be most important. The known factors are associated with affecting the risk of disease, and are not absolute. Virulence of H. pylori is affected by the existence and regulation of certain genes present in the bacterial population in a stomach. The effects of H. pylori on gastric cancer development have been challenged and the risk associated with infection with virulent (i.e. Cag PAI positive) H. pylori has likely been underestimated.
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Affiliation(s)
- B Björkholm
- Swedish Institute for Infectious Disease Control, 171 82 Solna, Sweden.
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Björkholm BM, Guruge JL, Oh JD, Syder AJ, Salama N, Guillemin K, Falkow S, Nilsson C, Falk PG, Engstrand L, Gordon JI. Colonization of germ-free transgenic mice with genotyped Helicobacter pylori strains from a case-control study of gastric cancer reveals a correlation between host responses and HsdS components of type I restriction-modification systems. J Biol Chem 2002; 277:34191-7. [PMID: 12105196 DOI: 10.1074/jbc.m203613200] [Citation(s) in RCA: 39] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Helicobacter pylori infects the stomachs of half of all humans. It has a relatively benign relationship with most hosts but produces severe pathology, including gastric cancer, in others. Identifying the relative contributions of host, microbial, and environmental factors to the outcome of infection has been challenging. Here we describe one approach for identifying microbial genes that affect the magnitude of host responses to infection. Single colony purified H. pylori isolates were obtained from 25 cases and 71 controls in a Swedish case-control study of gastric cancer. Strains were first phenotyped based on their ability to produce adhesins that recognize two classes of human gastric epithelial receptors. Thirteen binding strains and two non-binding controls were then subjected to whole genome genotyping using H. pylori DNA microarrays. A cohort of "variable" genes was identified based on a microarray-determined call of "absent" in at least one member of the strain panel. Each strain was subsequently introduced into two types of germ-free transgenic mice, each programmed to express a different host factor postulated to pose increased risk for development of severe pathology. Expression of biomarkers of host defense was quantitated 4 weeks after inoculation, and the magnitude of the response correlated with bacterial genotype. The proportion of genes encoding HsdS homologs (specificity subunit of hetero-oligomeric type I restriction-modification systems) was significantly higher in the pool of 18 variable genes whose presence directly correlated with a robust host response than their proportion in the remaining 352 members of the variable gene pool. This suggests that the functions of these HsdS homologs may include control of expression of microbial determinants that affect the extent of gastric responses to this potentially virulent pathogen.
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Affiliation(s)
- Britta M Björkholm
- Department of Molecular Biology and Pharmacology, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, USA
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Abstract
The aim of the present paper is to review and evaluate, in a comprehensive manner, the most recent published evidence on the contribution of genetic susceptibility to gastric cancer risk in humans. We have identified all studies available in MEDLINE published up to October 2001. Only studies carried out in humans and comparing gastric cancer cases with at least 1 standard control group were included in the analysis. We were able to find 31 articles based on 25 case-control studies carried out in Caucasian, Asian and African populations. Most of the studies assess the effect of genes involved in detoxifying pathways (n = 12) and inflammatory responses (n = 7). The most widely studied is the GSTM1 null polymorphism. Only a very few studies have evaluated the risk of gastric cancer associated with genes acting on mucosa protection, oxidative damage and DNA repair. The most consistent results are the increased gastric cancer risk associated with IL1B and NAT1 variants, which may account for up to 48% of attributable risk of gastric cancer. Only polymorphisms at HLA-DQ, TNF and CYP2E genes may confer some protective effect against gastric cancer. The most important limitations that preclude definitive conclusions are (i) the lack of appropriate control of potential sources of bias (only 5 population-based studies have been published so far); (ii) the low number of cases analyzed (14 studies included fewer than 99 cases); and (iii) the low number of studies (n = 3) offering concomitant analysis of genetic susceptibility and exposure to relevant cofactors (Helicobacter pylori infection, diet and smoking). We conclude that the scientific data on the role of genetic factors in gastric cancer risk are promising. The lack of association reported so far should be considered with caution due to significant limitations in study design. Cohort studies taking into account simultaneously the different genetic and environmental factors potentially involved in gastric tumorigenesis are needed to ascertain not only the relative contribution of these factors to tumor development but also the contribution of their putative interactions.
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Affiliation(s)
- Carlos A González
- Epidemiology and Cancer Registry Unit, Catalan Institute of Oncology, Barcelona, Spain.
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Lee JE, Abdalla J, Porter GA, Bradford L, Grimm EA, Reveille JD, Mansfield PF, Gershenwald JE, Ross MI. Presence of the human leukocyte antigen class II gene DRB1*1101 predicts interferon gamma levels and disease recurrence in melanoma patients. Ann Surg Oncol 2002; 9:587-93. [PMID: 12095976 DOI: 10.1007/bf02573896] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
BACKGROUND Increased interferon gamma (IFN-gamma) levels are an independent predictor of melanoma recurrence. Human leukocyte antigen (HLA) class II genes can regulate cytokine production; we investigated whether these genes would predict IFN-gamma levels and recurrence in melanoma patients. METHODS Of 591 patients who presented with localized melanoma, 579 underwent identification of HLA class II alleles; 233 melanoma patients and 90 controls underwent determination of plasma IFN-gamma levels. HLA class II genes were examined for association with IFN-gamma levels and disease recurrence. RESULTS After a median follow-up of 60 months, melanoma patients with IFN-gamma levels above the mean control value were more likely to have developed disease recurrence compared with patients with levels below the mean. The HLA class II gene HLA-DRB1*1101 was the strongest predictor of recurrence, and HLA-DRB1*1101-positive melanoma patients had increased levels of IFN-gamma compared with patients lacking the gene. CONCLUSIONS Among patients with localized melanoma, both HLA-DRB1*1101 and increased IFN-gamma levels were associated with an increased risk for recurrence; HLA-DRB1*1101-positive patients had relatively increased levels of IFN-gamma. HLA class II genes may mediate cytokine production in melanoma patients, and this mechanism may help determine the risk of disease recurrence.
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Affiliation(s)
- Jeffrey E Lee
- Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston 77030, USA.
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Wu MS, Hsieh RP, Huang SP, Chang YT, Lin MT, Chang MC, Shun CT, Sheu JC, Lin JT. Association of HLA-DQB1*0301 and HLA-DQB1*0602 with different subtypes of gastric cancer in Taiwan. Jpn J Cancer Res 2002; 93:404-10. [PMID: 11985790 PMCID: PMC5927011 DOI: 10.1111/j.1349-7006.2002.tb01271.x] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Gastric cancer (GC) is a heterogeneous disorder with multifactorial etiologies. Genetic predisposition, environmental factors, and Helicobacter pylori infection are thought to interact in the manifestation of GC. Particular human leukocyte antigen (HLA) alleles play a pivotal role in cellular immunity and may be an important genetically determined host trait. To elucidate the association between the genotype of HLA class II genes and the clinical phenotype of GC, polymorphisms of HLA-DRB1 and HLA-DQB1 were determined by polymerase chain reaction with sequence-specific primers in 106 Taiwanese patients with GC and in 208 healthy controls. Comparison of allele frequencies between GC patients and healthy controls showed no significant difference at the HLA-DRB1 locus. Patients with GC had a higher frequency of DQB1(*)0602 (9.4% vs. 3.6%, P < 0.05, odds ratio 2.79, 95% confidence interval 1.41 - 5.47) and a lower frequency of DQB1(*)0301 (14.6% vs. 23.8%, P < 0.05, odds ratio 0.55, 95% confidence interval 0.35 - 0.85) compared to healthy controls. Correlation of HLA-DQB1 status with clinicopathologic features revealed predominance of male gender (16/3 vs. 50/37, P < 0.05) and proximal location (12/7 vs. 28/59, P < 0.05) in patients with positive HLA-DBQ1(*)0602 compared to those with negative HLA-DBQ1(*)0602. In contrast, a higher ratio of diffuse/intestinal subtype (20/10 vs. 30/46, P < 0.05) and a lower seropositivity of Helicobacter pylori (14/30 vs. 58/76, P < 0.005) were noted in patients with positive HLA-DQB1(*)0301 compared to those with negative HLA-DQB1(*)0301. In conclusion, HLA-DQB1(*)0602 confers susceptibility to gastric cancer, especially for male Taiwanese and proximal tumor location, while HLA-DQB1(*)0301 may have a protective effect on GC, probably through resistance to Helicobacter pylori infection. HLA-DQB1 alleles are associated with susceptibility or resistance to GC and also influence its clinical features.
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Affiliation(s)
- Ming-Shiang Wu
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
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Wu MS, Huang SP, Chang YT, Lin MT, Shun CT, Chang MC, Wang HP, Chen CJ, Lin JT. Association of the -160 C --> a promoter polymorphism of E-cadherin gene with gastric carcinoma risk. Cancer 2002; 94:1443-8. [PMID: 11920500 DOI: 10.1002/cncr.10371] [Citation(s) in RCA: 56] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
BACKGROUND A -160 C --> A polymorphism in the promoter region of E-cadherin has been shown to decrease gene transcription. This allelic variation might be a potential genetic marker for identifying individuals at risk for cancer. There remains no report regarding the polymorphism of E-cadherin in gastric carcinoma (GC). METHODS A hospital-based case-control study, including 201 GC cases and 196 unaffected controls, was performed. DNA from peripheral blood samples was examined by polymerase chain reaction-restriction fragment length polymorphism. Logistic regression analyses were used to compute odds ratio (OR) and 95% confidence interval (CI) after adjusted for Helicobacter pylori infection, smoking, and other relevant factors. RESULTS In 196 healthy Taiwanese, the distribution of genotype C/C was 42.3%, C/A was 48.0%, and A/A was 9.7%. The frequency of variant A/A genotype in GC case (4 of 201, 2%) was significantly lower than that of controls (19 of 196, 9.7%) (P < 0.005), conferring a 5-fold decrease in the risk of GC (OR, 0.20; 95% CI, 0.06-0.56) compared with the C/C genotype. Stratification of the GC cases according to their location (cardia and noncardia), histology (intestinal and diffuse), tumor stage (early and advanced), and lymph node metastasis (positive and negative) failed to reveal any heterogeneity with respect to E-cadherin genotype. CONCLUSIONS The authors' data suggest that individuals with E-cadherin -160 A/A genotype have a decreased risk of GC. Further work is mandatory to clarify the functional relevance of the A allele in vivo and to confirm the inverse association of the A/A genotype with GC in large epidemiologic studies.
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Affiliation(s)
- Ming-Shiang Wu
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
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De Block CEM, De Leeuw IH, Bogers JJPM, Pelckmans PA, Ieven MM, Van Marck EAE, Van Hoof V, Máday E, Van Acker KL, Van Gaal LF. Helicobacter pylori, parietal cell antibodies and autoimmune gastropathy in type 1 diabetes mellitus. Aliment Pharmacol Ther 2002; 16:281-9. [PMID: 11860411 DOI: 10.1046/j.1365-2036.2002.01186.x] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
BACKGROUND Fifteen to 20% of type 1 diabetic patients exhibit parietal cell antibodies (PCA), which are associated with autoimmune gastritis, hypochlorhydria, iron deficiency and pernicious anaemia. AIM To examine whether Helicobacter pylori infection could explain the high prevalence of PCA and autoimmune gastropathy in diabetes. If so, H. pylori eradication could prevent autoimmune gastritis. METHODS In 229 type 1 diabetics (M/F: 135/94; age: 41 +/- 12 years) PCA were measured. H. pylori infection was assessed by serology, urea breath test in all and by histology (updated Sydney system) in 88 subjects. Pentagastrin tests were performed in 42 patients. RESULTS Sixty-nine patients were PCA-positive. H. pylori infection was present in 72 patients and was negatively associated with HLA-DQA1*0103-B1*0603 (OR=0.12, P=0.015) and positively with DQA1*0501-B1*0201 (OR=1.9, P=0.032). PCA-positivity was linked to HLA-DQA1*0501-B1*0301 (OR=3.9, P=0.017). A link between H. pylori and PCA was observed when PCA-positivity was defined as a titre > or = 1/20 (OR=2.0, P=0.03), but not if > or =1/40 was the cut-off point. PCA-positivity, but not H. pylori infection, was associated with iron deficiency anaemia (OR=2.7, P=0.008), pernicious anaemia (OR= 33.5, P < 0.0001), hypochlorhydria (OR=12.1, P=0.0008) and autoimmune gastritis (OR=12.5, P < 0.0001). CONCLUSIONS The HLA-bound susceptibility of H. pylori and PCA differed. PCA-positivity but not ongoing H. pylori infection is associated with autoimmune gastritis. Low titres of PCA might reflect H. pylori infection rather than autoimmune gastropathy.
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Affiliation(s)
- C E M De Block
- Department of Endocrinology-Diabetology, University of Antwerp, University Hospital Antwerp, Wilrijkstraat 10, B-2650 Edegem, Belgium.
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Perri F, Piepoli A, Quitadamo M, Quarticelli M, Merla A, Bisceglia M. HLA-DQA1 and -DQB1 genes and Helicobacter pylori infection in Italian patients with gastric adenocarcinoma. TISSUE ANTIGENS 2002; 59:55-7. [PMID: 11972882 DOI: 10.1034/j.1399-0039.2002.590112.x] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Both HLA-DQA1 and -DQB1 genes and Helicobacter pylori infection have been linked to gastric cancer. The aim of this work was to determine if HLA-DQA1 and -DQB1 alleles are presented at altered frequency in Italian patients with gastric adenocarcinoma and H. pylori infection. Oligotyping for HLA-DQA1 and -DQB1 and H. pylori serology was performed for 50 patients with gastric adenocarcinoma and compared with 80 patients with colonic adenocarcinoma and 179 healthy subjects. H. pylori infection was present in 76% of gastric cancer patients, 77.5% of colonic cancer patients, and 72% of controls. The prevalence of infection was not significantly different in the three groups of subjects sorted according to their HLA-DQA1 or -DQB1 status. Apart from HLA-DQA1* 0201, which was less common in patients with colonic carcinoma than controls, no other HLA-DQA1 and no HLA-DQB1 allele were present at altered frequency in patients with gastric or colonic cancer. Neither anatomical location and histological type of cancer nor the presence of lymph node or distant metastases were significantly associated with specific HLA-DQA1 or -DQB1 alleles or H. pylori infection. Both HLA-DQA1 and -DQB1 genes have a minor, if any, role in H. pylori infection and gastric carcinogenesis.
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Affiliation(s)
- F Perri
- Department of Internal Medicine, Gastroenterology Unit, Casa Sollievo della Sofferenza Hospital, I.R.C.C.S., San Giovanni Rotondo, Italy.
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Rolfs BK, Wu CC, Lerche NW, Smith DG. Major histocompatibility complex class II polymorphisms in Macaca mulatta: factors influencing comprehensive genotyping of Macaca mulatta (Mamu)-DQA1 alleles by PCR-RFLP in archival samples. AMERICAN JOURNAL OF PHYSICAL ANTHROPOLOGY 2001; 116:296-301. [PMID: 11745081 DOI: 10.1002/ajpa.1126] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
In the last 5 years, HLA class II genotyping methods have been adapted for genotyping of class II loci in rhesus macaques. Since previously published typing protocols were used on samples that were collected and stored under ideal conditions, it was of interest to determine if these methods were adequate for genotyping a large collection of archival samples from which DNA had been isolated and stored under various conditions. Established macaque DQA1 typing protocols were modified to optimize the typing procedure and enhance the ability to successfully genotype DNA from samples that were of poor quality and/or quantity. Long-term storage of whole-blood buffy coats or stored DNA extracted from whole-blood buffy coats did not affect typing success; however, amplification and typing of DNA extracted from archival samples of plasma were difficult and resulted in a low success rate. This suggests that amplification and DQA1-genotyping of archival samples is possible with a modified protocol, but is influenced by the age and source of the sample, and to a lesser extent, the method used to extract DNA from sample substrates.
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Affiliation(s)
- B K Rolfs
- Department of Medicine and Epidemiology, School of Veterinary Medicine, University of California at Davis, Davis, California 95616, USA.
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45
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De Luis DA, Aller R. [Diabetes mellitus and Helicobacter pylori infection]. Med Clin (Barc) 2001; 117:627-31. [PMID: 11714472 DOI: 10.1016/s0025-7753(01)72201-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Affiliation(s)
- D A De Luis
- Instituto de Endocrinología y Nutrición, Hospital Universitario Río Hortega, Valladolid, Spain.
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46
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Santolaria S, Barrios Y, Benito R, Piazuelo E, Quintero E, Lanas A. [Helicobacter pylori and immunogenetic factors of the host: relevance of the HLADQA1 *0102 and *0301 alleles in peptic ulcer]. GASTROENTEROLOGIA Y HEPATOLOGIA 2001; 24:117-21. [PMID: 11261221 DOI: 10.1016/s0210-5705(01)70136-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
AIM To investigate the potential contribution of the *0102 and *0301 alleles of the HLADQA1 gene in Helicobacter pylori infection and peptic ulcer disease in a Spanish Caucasian population. PATIENTS AND METHODS We studied 163 patients with peptic ulcer (117 duodenal ulcers and 46 gastric ulcers; 111 with recent upper gastrointestinal hemorrhage) and 90 controls. The *0102 and *0301 alleles of the HLADQA1 gene were typed by polymerase chain reaction using genomic DNA. H. pylori infection were determined by breath test and/or serology. The cytotoxins CagA and VacA were investigated using serology (Western-blot) in 98 patients and 48 controls with H. pylori infection. RESULTS H. pylori infection was found in 94.6% of patients with duodenal ulcer, in 84.4% of those with gastric ulcer and in 67.4% of controls (p < 0.001). The distribution of the *0102 allele of the HLADQA1 gene was similar in patients (31.9%) and in controls (36.7%). The *0301 was more frequent in patients with gastric ulcer (32.6%) than in those with duodenal ulcer (16.2%) (p < 0.05) but no differences were found on comparison with the control group (24.4%). No differences were found when the groups were analyzed according to H. pylori infection, CagA- and VacA-positive strains, consumption of non-steroidal antiinflammatory drugs or previous history of ulcer or hemorrhage. CONCLUSION The *0102 and *0301 alleles of the HLADQA1 gene did not alter susceptibility to H. pylori infection or the evolution of peptic ulcer disease in a Caucasian population in Spain.
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Affiliation(s)
- S Santolaria
- Servicio de Aparato Digestivo, Hospital Universitario de Canarias, 38291 La Laguna, Tenerife.
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Abstract
Greater than one-half of the world's population harbors Helicobacter pylori. The majority of infected individuals, however, remain asymptomatic, with only 10% to 20% developing diseases, including peptic ulcer disease, gastric cancer, and gastric mucosa-associated lymphoid tissue lymphoma. This article reviews host factors that may predispose an individual to both the acquisition of H. pylori infection and subsequent clinical outcome. Individuals with specific blood group antigens and human leukocyte antigen genotypes may be more susceptible to H. pylori infection. Additional factors, such as the age of acquisition, the host immune response, the site of infection, acid secretion, and interactions with nonhost factors (including bacterial virulence factors and environmental influences) may play a role in determining clinical outcome. Further investigation is required to clarify the mechanisms by which these interactions occur and, more critically, to determine their relative importance. This knowledge will enable the identification of individuals at risk of developing clinical disease with H. pylori infection.
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Affiliation(s)
- T N Nguyen
- Division of Gastroenterology, McGill University, Montreal, Quebec, Canada
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48
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Luo M, Blanchard J, Pan Y, Brunham K, Brunham RC. High-resolution sequence typing of HLA-DQA1 and -DQB1 exon 2 DNA with taxonomy-based sequence analysis (TBSA) allele assignment. TISSUE ANTIGENS 1999; 54:69-82. [PMID: 10458325 DOI: 10.1034/j.1399-0039.1999.540108.x] [Citation(s) in RCA: 40] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
High-resolution DNA sequencing of exon 2 of DQA1 and DQB1 genes that uses a taxonomy-based sequence analysis (TBSA) method to assign alleles was developed. The system uses fewer primers for polymerase chain reaction (PCR) amplification and sequencing than other methods and yields accurate DQA1 and DQB1 typing when either homozygous or heterozygous DNA samples are tested. The approach was initially corroborated by the correct typing of 10 blinded samples that had been previously typed by PCR using sequence-specific oligonucleotide probes (PCR-SSOP) or serology, and subsequently confirmed by sequencing of cloned PCR products. DNA from peripheral blood cell samples of 130 individuals enrolled in a case-control analysis of HLA determinants of abdominal aortic aneurysm were subsequently evaluated. Overall, 8 different DQA1 and 19 DQB1 alleles were identified. All 21 DQA1 heterozygous combinations and 45 of 49 DQB1 heterozygous combinations were successfully resolved with TBSA. The two pairs of heterozygous DQB1 combinations that were not unambiguously typed required sequence specific PCR amplification for correct allele identification. We conclude that the method provides precise analysis for HLA-DQ typing.
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Affiliation(s)
- M Luo
- Department of Medical Microbiology, University of Manitoba, Winnipeg, Canada
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Silva B, Vargas-Alarcón G, Zúñiga-Ramos J, Rodríguez-Reyna TS, Hernández-Martinez B, Osnaya N, Kofman S, Torres-Lobatón A, Granados J. Genetic features of Mexican women predisposing to cancer of the uterine cervix. Hum Pathol 1999; 30:626-8. [PMID: 10374768 DOI: 10.1016/s0046-8177(99)90085-0] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Cervical carcinoma is the most common neoplasia in Mexican women. Previous studies report association of this neoplasia with the major histocompatibility complex (MHC) antigens in Caucasians. In the present study, we compared antigen frequencies of class I and class II MHC phenotypes in patients and ethnically matched healthy controls. Patients had significantly increased frequencies of HLA-A2 (PC = .000003) and HLA-DR5 (PC = .01) as compared with healthy controls. Conversely, we found a significant decrease of HLA-DR6 (PC = .01), HLA-DR2 (PC = .0005) and HLA-DR1 (PC = .0009) as compared with healthy controls. These results confirm some previous studies on HLA-associations with cervical carcinoma and reinforce the theory of independent mechanisms of MHC class I and class II genes in the etiopathogenesis of this disease.
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Affiliation(s)
- B Silva
- Department of Genetics and Oncology, Hospital General de México, Mexico City
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50
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Blanchard TG, Czinn SJ, Nedrud JG. Host response and vaccine development to Helicobacter pylori infection. Curr Top Microbiol Immunol 1999; 241:181-213. [PMID: 10087662 DOI: 10.1007/978-3-642-60013-5_10] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Studies in both humans and animals demonstrate that H. pylori is capable of illiciting an innate response that in part is regulated by the genetic makeup of the host. These innate responses includes stimulating immune effector mechanisms at the cellular and biochemical level resulting in the influx of neutrophils into the lamina propria and have even been shown to modify gastric acid secretion. The availability of good animal models of chronic Helicobacter infection has also allowed investigators to begin to examine how the adaptive host immune response prevents and/or exacerbates Helicobacter-induced gastroduodenal disease. The experimental H. felis/mouse model has been utilized by a number of laboratories to investigate mechanisms of host defense against chronic Helicobacter infection. This model and the more recently developed H. pylori rodent model has not only allowed investigators to confirm the feasibility of immunotherapy to prevent and/or cure Helicobacter infection but also to begin to examine how the host immune response prevents and/or exacerbates Helicobacter-induced gastroduodenal disease. Based on these studies a hypothesis is emerging that suggests that protection and/or cure from Helicobacter infection is mediated primarily by an upregulated cellular immune response which may act via an antibody independent mechanism. Paradoxically, following natural infection with H. pylori, a component of the cellular immune response also promotes chronic gastric inflammation without clearance of the organism. The recent development of reliable and reproducible H. pylori/rodent models of disease and the availability of numerous inbred strains, transgenic and knockout animals, will allow investigators to continue to explore the role the host cellular and humoral immune response plays in promoting or preventing this infection.
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MESH Headings
- Adjuvants, Immunologic/administration & dosage
- Administration, Oral
- Animals
- Antibodies, Bacterial/immunology
- Antibody Specificity
- Bacterial Vaccines/administration & dosage
- Bacterial Vaccines/immunology
- Clinical Trials as Topic
- Cytokines/metabolism
- Disease Models, Animal
- Gastric Acid/metabolism
- Gastric Mucosa/immunology
- Gastrointestinal Diseases/immunology
- Gastrointestinal Diseases/microbiology
- Gastrointestinal Diseases/therapy
- Genetic Predisposition to Disease
- Helicobacter Infections/immunology
- Helicobacter Infections/therapy
- Helicobacter pylori/immunology
- Humans
- Immunity, Active
- Immunity, Cellular
- Immunity, Innate
- Immunity, Mucosal/immunology
- Mice
- Vaccines, Synthetic/administration & dosage
- Vaccines, Synthetic/immunology
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Affiliation(s)
- T G Blanchard
- Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA
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