Genetic polymorphisms in mediators of inflammation and gastric precancerous lesions

Chronic inflammation induced by Helicobacter pylori is a key process in gastric carcinogenesis. We hypothesized that genetic polymorphisms in important mediators of H. pylori-induced inflammation may influence the risk of developing various grades of precancerous lesions. We studied the associations between single nucleotide polymorphisms (SNPs) in cyclooxygenase 1 and 2 (PTGS1 and PTGS2), inducible nitric oxide synthase (NOS2A), interferon &ggr; (IFNG) and its receptor (IFNGR1), and risk of gastric precancerous lesions in a Venezuelan population characterized by high rates of H. pylori infection. We found no association of precancerous lesions with SNPs in PTGS1 and in IFNG. A nonsynonymous SNP of NOS2A (Ser608Leu) and an SNP located in the promoter of IFNGR1 (C-56T) were associated with higher risk of atrophic gastritis [odds ratio (OR)=1.37, 95% confidence interval (CI)=1.01–1.86, and OR=1.49, 95% CI=1.01–2.19, respectively]. Two SNPs of PTGS2 were associated with risk of dysplasia (OR=1.60, 95% CI=1.01–2.54, and OR=0.66, 95% CI=0.43–0.99). We conclude that genetic variability in the genes we studied does not play a major role in the early stages of gastric carcinogenesis.

[1]  Lippincott-Schwartz,et al.  Supporting Online Material Materials and Methods Som Text Figs. S1 to S8 Table S1 Movies S1 to S3 a " Silent " Polymorphism in the Mdr1 Gene Changes Substrate Specificity Corrected 30 November 2007; See Last Page , 2022 .

[2]  M. Plummer,et al.  Host–bacterial interaction in the development of gastric precancerous lesions in a high risk population for gastric cancer in Venezuela , 2006, International journal of cancer.

[3]  B. Paulweber,et al.  The cyclooxygenase-2 (PTGS2) 8473T>C polymorphism is associated with breast cancer risk. , 2006, Clinical cancer research : an official journal of the American Association for Cancer Research.

[4]  D. Cox,et al.  Haplotype of prostaglandin synthase 2/cyclooxygenase 2 is involved in the susceptibility to inflammatory bowel disease. , 2005, World journal of gastroenterology.

[5]  M. Plummer,et al.  Use of whole genome amplification to rescue DNA from plasma samples. , 2005, BioTechniques.

[6]  S. Czinn,et al.  Vaccination as a Method of Preventing Helicobacter pylori–Associated Gastric Cancer , 2005, Cancer Epidemiology Biomarkers & Prevention.

[7]  G. Abecasis,et al.  A note on exact tests of Hardy-Weinberg equilibrium. , 2005, American journal of human genetics.

[8]  Xinru Wang,et al.  A novel genetic polymorphism of inducible nitric oxide synthase is associated with an increased risk of gastric cancer. , 2004, World journal of gastroenterology.

[9]  C. Prinz,et al.  Cytokine gene polymorphisms influence mucosal cytokine expression, gastric inflammation, and host specific colonisation during Helicobacter pylori infection , 2004, Gut.

[10]  A. Schäffer,et al.  Interferon-γ receptor 1 promoter polymorphisms: population distribution and functional implications , 2004 .

[11]  A. Schäffer,et al.  Interferon-gamma receptor 1 promoter polymorphisms: population distribution and functional implications. , 2004, Clinical immunology.

[12]  B. Müller-Myhsok,et al.  Genomewide linkage analysis identifies polymorphism in the human interferon-gamma receptor affecting Helicobacter pylori infection. , 2003, American journal of human genetics.

[13]  P. Kremsner,et al.  Functional analysis of a promoter variant of the gene encoding the interferon-gamma receptor chain I , 2003, Immunogenetics.

[14]  Jeannette Bigler,et al.  Cyclooxygenase 1 (COX1) polymorphisms in African‐American and caucasian populations , 2002, Human mutation.

[15]  S. Humphries,et al.  Common Promoter Variant in Cyclooxygenase-2 Represses Gene Expression: Evidence of Role in Acute-Phase Inflammatory Response , 2002, Arteriosclerosis, thrombosis, and vascular biology.

[16]  J. Fierer,et al.  Role of Gamma Interferon in Helicobacter pylori Induction of Inflammatory Mediators during Murine Infection , 2002, Infection and Immunity.

[17]  Jacques Ferlay,et al.  Estimating the world cancer burden: Globocan 2000 , 2001, International journal of cancer.

[18]  C. Samuel,et al.  The role of gamma interferon in antimicrobial immunity. , 2001, Current opinion in microbiology.

[19]  A. Gobert,et al.  VacA and urease released by H. Pylori stimulate COX-2 expression in macrophages , 2001 .

[20]  C. Hawkey,et al.  Cyclooxygenase (COX) 1 and 2 in normal, inflamed, and ulcerated human gastric mucosa , 2000, Gut.

[21]  M. Blaser,et al.  Distinct Variants of Helicobacter pylori cagA Are Associated with vacA Subtypes , 1999, Journal of Clinical Microbiology.

[22]  G. Talamini,et al.  Expression of COX-1, COX-2, and inducible nitric oxide synthase protein in human gastric antrum with Helicobacter pylori infection. , 1999, Prostaglandins & other lipid mediators.

[23]  Yoshio Yamaoka,et al.  Role of Gamma Interferon in Helicobacter pylori-Induced Gastric Inflammatory Responses in a Mouse Model , 1999, Infection and Immunity.

[24]  W. Quint,et al.  Typing of Helicobacter pylori vacA Gene and Detection of cagA Gene by PCR and Reverse Hybridization , 1998, Journal of Clinical Microbiology.

[25]  M. Barrett,et al.  Barrett's esophagus: ordering the events that lead to cancer. , 1996, European journal of cancer prevention : the official journal of the European Cancer Prevention Organisation.

[26]  R. DuBois,et al.  Prostaglandin endoperoxide synthase: why two isoforms? , 1996, The American journal of physiology.

[27]  A. Axon,et al.  Antioxidants, Helicobacter pylori and stomach cancer in Venezuela. , 1996, European journal of cancer prevention : the official journal of the European Cancer Prevention Organisation.

[28]  N. Muñoz,et al.  Chemoprevention trial on precancerous lesions of the stomach in Venezuela: summary of study design and baseline data. , 1996, IARC scientific publications.

[29]  T. Macdonald,et al.  Interferon gamma and interleukin 4 secreting cells in the gastric antrum in Helicobacter pylori positive and negative gastritis. , 1995, Gut.

[30]  H. Esumi,et al.  U.S.-Japan Cooperative Cancer Research Program: Seminar on Nitric Oxide Synthase and Cardnogenesis , 1994 .

[31]  H. Esumi,et al.  U.S.-Japan Cooperative Cancer Research Program: seminar on nitric oxide synthase and carcinogenesis. , 1994, Cancer Research.

[32]  J. Wallace.  Gastroduodenal mucosal defense , 1991 .

[33]  C. Brown,et al.  Gastroduodenal mucosal defence , 1990 .

[34]  E. Fontham,et al.  Gastric precancerous process in a high risk population: cohort follow-up. , 1990, Cancer research.

[35]  I. M. Neiman,et al.  [Inflammation and cancer]. , 1974, Patologicheskaia fiziologiia i eksperimental'naia terapiia.