Increase in NF-κB binding affinity of the variant C allele of the toll-like receptor 9 -1237T/C polymorphism is associated with Helicobacter pylori-induced gastric disease

Mike Tsz Hin Ng, Rob Van't Hof, Julie C. Crockett, Mairi E. Hope, Susan Berry, John Thomson, Mairi H. McLean, Kenneth E. L. McColl, Emad M. El-Omar, Georgina L. Hold

Research output: Contribution to journalArticle

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Abstract

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 well-documented 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-kappa 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-kappa 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.

Original languageEnglish
Pages (from-to)1345-1352
Number of pages8
JournalInfection and Immunity
Volume78
Issue number3
Early online date28 Dec 2009
DOIs
Publication statusPublished - Mar 2010

Keywords

  • single-nucleotide polymorphisms
  • cytokine gene polymorphisms
  • dendritic cells
  • gastroduodenal diseases
  • epithelial-cells
  • increased risk
  • bacterial-DNA
  • cutting edge
  • CPG DNA
  • cancer

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