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Colonization of the gastric mucosa by Helicobacter pylori can lead to serious clinical outcomes, including gastric cancer. Toll-like receptors (TLRs) play an important role in the host response to H. pylori through the recognition of pathogen-associated molecular patterns. TLR9, in particular, is partly responsible for initiating bacterial induced immunity by binding unmethylated CpG-DNA, which is abundant in bacteria. A welldocumented single nucleotide polymorphism (SNP) within the TLR9 promoter (TLR9 ؊1237T/C), is associated with a variety of inflammatory disorders, including allergic asthma, inflammatory bowel disease, and atopy. Analysis of the TLR9 promoter gene sequence has shown that carriage of the variant "C" allele at position ؊1237 creates a potential NF-B binding site that would theoretically increase the transcriptional activity of the gene. In this study, we report that the TLR9 ؊1237 C allele was significantly associated with the development of H. pylori-induced premalignant gastric changes. Functional analysis of the SNP, supporting the data generated from the genetic association study, showed that carriage of the C allele increased TLR9 transcriptional activity driven mainly by activation of NF-B. Collectively, these findings confirm that the TLR9 ؊1237T/C polymorphism is a risk factor for the development of H. pylori-induced premalignant gastric changes and provide a plausible mechanistic explanation.

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IntroductionUpper gastrointestinal malignancies comprising gastric and oesophageal cancers remain a major global health problem. Recently, genome wide association studies have been used to identify risk factors for several diseases. Four SNPs identified at chromosome regions 8q24 and 9p24 (rs6983267, rs10505477, rs1447295 and rs719725) have been shown to increase risk of various solid tumours including prostate and colorectal cancer, but have not been studied in the context of upper GI cancer.MethodsTwo case-control studies were used to assess SNP frequency: Study 1- a gastric cancer case-control study derived from a Caucasian population in Warsaw, Poland with DNA available from 312 non-cardia gastric adenocarcinoma patients and 419 controls, Study 2- a multicentre oesophageal and gastric cancer study from the US with DNA available from 307 subjects with gastric adenocarcinoma, 159 subjects with oesophageal cancer and 211 population controls. DNA was genotyped by 5′ nuclease PCR assay. Hardy-Weinberg equilibrium of alleles at individual loci was assessed using χ2 test. OR with Cornfield 95% CIs were computed by logistic regression using Stata V.7.0 software.ResultsGenotyping and statistical analysis of the 4 SNPs was completed on 765 cases and 583 controls. Individuals carrying the C/C genotype of rs1447295 had an elevated risk for non-cardia gastric cancer (OR 1.57, 95% CI 1.03 to 2.45). Individuals carrying the A/A genotype of rs1447295 had an increased risk of squamous cell oesophageal cancer (OR 7.4, 95% CI 1.4 to 49). None of the other three SNPs tested in this study showed any statistically significant associations.ConclusionThe association between the rs1447295 SNP and risks of gastric and oesophageal cancer are novel and offer an opportunity to explore the genetic basis of these malignancies. Our study has extended the genetic link between the 8q24 region and risk of yet another group of solid tumours. Extensive efforts should focus on evaluating the functional significance of this region in the context of the molecular pathogenesis of these malignancies.