A functional polymorphism of toll-like receptor 4 gene increases risk of gastric carcinoma and its precursors.
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.
Hold
Georgina L
GL
Department of Medicine and Therapeutics, Aberdeen University, Aberdeen, Scotland.
Rabkin
Charles S
CS
Chow
Wong-Ho
WH
Smith
Malcolm G
MG
Gammon
Marilie D
MD
Risch
Harvey A
HA
Vaughan
Thomas L
TL
McColl
Kenneth E L
KE
Lissowska
Jolanta
J
Zatonski
Witold
W
Schoenberg
Janet B
JB
Blot
William J
WJ
Mowat
N Ashley G
NA
Fraumeni
Joseph F
JF
El-Omar
Emad M
EM
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
C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4