title: A functional polymorphism of toll-like receptor 4 gene increases risk of gastric carcinoma and its precursors.
abstract: OBJECTIVE
  TLR4 is a cell-surface signaling receptor involved in the recognition and host response to Helicobacter pylori. The TLR4+896A>G polymorphism linked with impaired reactivity to bacterial lipopolysaccharide may play a role in gastric carcinogenesis.
  
  
  METHODS
  We assessed associations with premalignant gastric changes in 149 relatives of gastric cancer patients, including 45 with hypochlorhydria and gastric atrophy. We also genotyped 2 independent Caucasian population-based case-control studies of upper gastrointestinal tract cancer, initially in 312 noncardia gastric carcinoma cases and 419 controls and then in 184 noncardia gastric carcinomas, 123 cardia carcinomas, 159 esophageal cancers, and 211 frequency-matched controls. Odds ratios were computed from logistic models and adjusted for potential confounding factors.
  
  
  RESULTS
  TLR4+896G carriers had an 11-fold (95% confidence interval [CI], 2.5-48) increased odds ratio (OR) for hypochlorhydria; the polymorphism was unassociated with gastric acid output in the absence of H pylori infection. Carriers also had significantly more severe gastric atrophy and inflammation. Seventeen percent of gastric carcinoma patients in the initial study and 15% of the noncardia gastric carcinoma patients in the replication study had 1 or 2 TLR4 variant alleles vs 8% of both control populations (combined OR = 2.3; 95% CI = 1.6-3.4). In contrast, prevalence of TLR4+896G was not significantly increased in esophageal squamous cell (2%, OR = 0.2) or adenocarcinoma (9%, OR = 1.4) or gastric cardia carcinoma (11%, OR = 1.4).
  
  
  CONCLUSIONS
  Our data suggest that the TLR4+896A>G polymorphism is a risk factor for noncardia gastric carcinoma and its precursors. The findings underscore the role of the host innate immune response in outcome of H pylori infection.
authors.affiliation: Department of Medicine and Therapeutics, Aberdeen University, Aberdeen, Scotland.
authors.forename: Georgina L
authors.initials: GL
authors.lastname: Hold
authors.forename: Charles S
authors.initials: CS
authors.lastname: Rabkin
authors.forename: Wong-Ho
authors.initials: WH
authors.lastname: Chow
authors.forename: Malcolm G
authors.initials: MG
authors.lastname: Smith
authors.forename: Marilie D
authors.initials: MD
authors.lastname: Gammon
authors.forename: Harvey A
authors.initials: HA
authors.lastname: Risch
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Vaughan
authors.forename: Kenneth E L
authors.initials: KE
authors.lastname: McColl
authors.forename: Jolanta
authors.initials: J
authors.lastname: Lissowska
authors.forename: Witold
authors.initials: W
authors.lastname: Zatonski
authors.forename: Janet B
authors.initials: JB
authors.lastname: Schoenberg
authors.forename: William J
authors.initials: WJ
authors.lastname: Blot
authors.forename: N Ashley G
authors.initials: NA
authors.lastname: Mowat
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Fraumeni
authors.forename: Emad M
authors.initials: EM
authors.lastname: El-Omar
mesh_terms: D000126:Achlorhydria / Q000235:genetics / Q000382:microbiology; D002277:Carcinoma / Q000235:genetics* / Q000382:microbiology / Q000473:pathology; D016022:Case-Control Studies; D015331:Cohort Studies; D005060:Europe; D005260:Female; D005757:Gastritis, Atrophic / Q000235:genetics / Q000382:microbiology; D015972:Gene Expression Regulation, Neoplastic; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D016481:Helicobacter Infections / Q000150:complications / Q000235:genetics / Q000382:microbiology*; D016480:Helicobacter pylori; D006801:Humans; D016015:Logistic Models; D008297:Male; D016017:Odds Ratio; D010641:Phenotype; D011110:Polymorphism, Genetic; D011159:Population Surveillance; D011230:Precancerous Conditions / Q000235:genetics* / Q000382:microbiology / Q000473:pathology; D012042:Registries; D018570:Risk Assessment; D012307:Risk Factors; D013274:Stomach Neoplasms / Q000235:genetics* / Q000382:microbiology / Q000473:pathology; D051197:Toll-Like Receptor 4 / Q000235:genetics*; D014481:United States
chemical_list: C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4