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

Cite this

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

In: Infection and Immunity, Vol. 78, No. 3, 03.2010, p. 1345-1352.

Research output: Contribution to journalArticle

Ng, Mike Tsz Hin ; Van't Hof, Rob ; Crockett, Julie C. ; Hope, Mairi E. ; Berry, Susan ; Thomson, John ; McLean, Mairi H. ; McColl, Kenneth E. L. ; El-Omar, Emad M. ; Hold, Georgina L. / 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. In: Infection and Immunity. 2010 ; Vol. 78, No. 3. pp. 1345-1352.
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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.",
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AU - Ng, Mike Tsz Hin

AU - Van't Hof, Rob

AU - Crockett, Julie C.

AU - Hope, Mairi E.

AU - Berry, Susan

AU - Thomson, John

AU - McLean, Mairi H.

AU - McColl, Kenneth E. L.

AU - El-Omar, Emad M.

AU - Hold, Georgina L.

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N2 - 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.

AB - 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.

KW - single-nucleotide polymorphisms

KW - cytokine gene polymorphisms

KW - dendritic cells

KW - gastroduodenal diseases

KW - epithelial-cells

KW - increased risk

KW - bacterial-DNA

KW - cutting edge

KW - CPG DNA

KW - cancer

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