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Discovery of a Single Nucleotide Polymorphism in TLR4 Gene that is Associated with the Onset/Progression of Periodontal Disease and Elucidation of its Biological Effects

July 26, 2012

A research group consisting of Professor Yoshitaka Hara, Associate Professor Atsutoshi Yoshimura, and graduate student Kayo Sato of the Department of Periodontology, Nagasaki University Graduate School of Biomedical Sciences, have discovered that a single nucleotide polymorphism (SNP) in the TLR4 gene is associated with the onset/progression of periodontal disease, and clarified its biological effects.

Bacteria in dental plaque are the main cause of periodontal disease, and lipopolysaccharide (LPS), an outer membrane component of periodontopathic bacteria, activates the innate immune system through Toll-like receptor 4 (TLR4).
The research team of the Department of Periodontology, together with Professor Koichiro Yoshiura of the Department of Human Genetics, Atomic Bomb Disease Institute, Nagasaki University, analyzed the relationship between the polymorphisms in TLR4 gene and chronic periodontitis. They discovered that a SNP in the 3’-untranslated region, rs11536889, was associated with moderate to severe periodontitis in Japanese subjects. The C/C genotype of rs11536889 was more frequently found in both the moderate and the severe periodontitis group than in the control group.

The research team together with Professor Yorimasa Ogata of Nihon University School of Dentistry at Matsudo, has also analyzed the effects of rs11536889 gene polymorphism on the expression and function of TLR4.
The expression of TLR4 protein on the surface of monocytes in subjects with the C/C genotype was significantly higher than that in subjects with G/G or G/C genotypes. A similar tendency was also seen in the LPS reactivity of peripheral blood mononuclear cells, however, no significant difference between the genotypes was found in the level of TLR4 mRNA expression.
This is because two microRNAs, hsa-miR-1236 and hsa-miR-642a, bind to the rs11536889 region of G allele resulting in suppression of gene expression. On the contrary, these microRNAs do not bind to the rs11536889 region of C allele, and thus gene expression is not suppressed.

These results suggest that the genetic variation of rs11536889 could be an excellent risk marker for certain inflammatory diseases like periodontitis, and may provide a novel approach for therapeutic interventions.

The results of this study were published in the July 20, 2012 issue of Journal of Biological Chemistry.

Title:
A Single Nucleotide Polymorphism in 3’-Untranslated Region Contributes to the Regulation of Toll-like Receptor 4 Translation

Authors:
Kayo Sato, Atsutoshi Yoshimura, Takashi Kaneko, Takashi Ukai, Yukio Ozaki, Hirotaka Nakamura, Xinyue Li, Hiroyoshi Matsumura, Yoshitaka Hara and Yorimasa Ogata

Journal:
Journal of Biological Chemistry,2012 Jul 20;287(30):25163-72.