Gastroenterology

Gastroenterology

Volume 132, Issue 3, March 2007, Pages 905-912
Gastroenterology

Clinical–alimentary tract
A Functional Polymorphism of Toll-Like Receptor 4 Gene Increases Risk of Gastric Carcinoma and Its Precursors

https://doi.org/10.1053/j.gastro.2006.12.026Get rights and content

Background & Aims: 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.

Section snippets

Study Populations

To determine whether the TLR4+896A>G polymorphism is associated with differing outcomes of H pylori infection, we studied a cohort of 149 healthy Caucasian first-degree relatives of gastric cancer patients (GCR) from the West of Scotland. These subjects had been extensively investigated in relation to their H pylori status (assessed by 14C-urea breath test, serology, rapid slide urease test, culture, and histology). Their gastric phenotype was defined histologically by assessment of antral and

Results

In all 3 control populations, the alleles at the TLR4+896 locus were in Hardy-Weinberg equilibrium, With nonsignificant χ2 values. The frequency of the variant allele in the 3 control populations ranged from 3.9% to 4.3%, and was similar to those reported from other studies of Caucasians. The homozygous TLR4+896 G/G genotype was rare, and the A/G and G/G carrier genotypes were combined in the genetic association analyses.

Discussion

In the present study, we have shown that a functional TLR4 polymorphism is associated with the development of the premalignant gastric abnormalities of hypochlorhydria and atrophy, and also with increased risk of noncardia gastric carcinoma. The association with noncardia gastric carcinoma was confirmed in 2 independent population-based case–control studies. No association was seen with cancer of the cardia or esophagus. Although this polymorphism has been associated with risk of other

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    Supported by a grant from Cancer Research UK (C8969/A3868), and by the Intramural Research Program of the National Cancer Institute, National Institutes of Health.

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