Increase in NF-kappaB binding affinity of the variant C allele of the toll-like receptor 9 -1237T/C polymorphism is associated with Helicobacter pylori-induced gastric disease.
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-kappaB 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-kappaB. 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.
Ng
Mike Tsz Hin
MT
Division of Applied Medicine, Aberdeen University, Aberdeen AB25 2ZD, Scotland, United Kingdom.
Van't Hof
Rob
R
Crockett
Julie C
JC
Hope
Mairi E
ME
Berry
Susan
S
Thomson
John
J
McLean
Mairi H
MH
McColl
Kenneth E L
KE
El-Omar
Emad M
EM
Hold
Georgina L
GL
D015870:Gene Expression; D005787:Gene Frequency; D016481:Helicobacter Infections / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D016480:Helicobacter pylori / Q000276:immunology*; D006801:Humans; D016328:NF-kappa B / Q000276:immunology* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D012606:Scotland; D051217:Toll-Like Receptor 9 / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D015854:Up-Regulation
D016328:NF-kappa B; D051217:Toll-Like Receptor 9