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Association of Toll-like Receptor 4 Gene Polymorphisms with Normal Tension Glaucoma

¹From the Department of Ophthalmology, Yokohama City University School of Medicine, Yokohama, Kanagawa, Japan; the ³Department of Legal Medicine, Shinshu University School of Medicine, Matsumoto, Nagano, Japan; the ⁴Department of Ophthalmology, University of Yamanashi, Faculty of Medicine, Yamanashi, Japan; the ⁵Department of Ophthalmology, Gifu University Graduate School of Medicine, Gifu, Japan; the ⁶Department of Surgery, Division of Ophthalmology, Kobe University Graduate School of Medicine, Kobe, Japan; the ⁷Department of Biomolecular Recognition and Ophthalmology, Yamaguchi University School of Medicine, Yamaguchi, Japan; the ⁸Department of Ophthalmology and Visual Science, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan; the ⁹Department of Ophthalmology, University of Tokyo School of Medicine, Tokyo, Japan; the ¹⁰Division of Ophthalmology and Visual Science, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan; the ¹¹Department of Ophthalmology and Visual Science, Kanazawa University Graduate School of Medical Science, Kanazawa, Ishikawa, Japan; the ¹²Department of Ophthalmology and Visual Science, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan; the ¹³Department of Ophthalmology, Tajimi Municipal Hospital, Tajimi, Gifu, Japan; the ¹⁴Department of Ophthalmology, Hokkaido University School of Medicine, Sapporo, Japan; and the ¹⁵Department of Genetic Information, Division of Molecular Life Science, Tokai University School of Medicine, Isehara, Kanagawa, Japan.

PURPOSE. Toll-like receptor 4 (TLR4) is a transmembrane receptor that mediates immune responses to exogenous and endogenous ligands and interacts with heat shock proteins, which are reportedly involved in normal tension glaucoma (NTG). This study was undertaken to investigate whether TLR4 polymorphisms are associated with NTG.

METHODS. Two hundred fifty Japanese patients with NTG and 318 Japanese healthy control subjects were recruited. Eight single-nucleotide polymorphisms (SNPs) in the TLR4 gene were genotyped, and allelic and phenotypic diversity was assessed between cases and control subjects.

RESULTS. Strong linkage disequilibrium was observed among all SNPs (D' 0.85), which were located in one haplotype block. With respect to allelic diversity, the minor allele of three SNPs (rs10759930, rs1927914, and rs7037117) carried a significantly increased risk of NTG. With regard to genotypic diversity, individuals with the minor allele of six SNPs (rs10759930, rs1927914, rs1927911, rs12377632, rs2149356, and rs7037117) had a 1.47- to 1.65-fold increased risk of NTG. rs7037117, located in the 3'-untranslated region of TLR4, was most strongly associated with NTG, and when incorporated into a haplotype with rs10759930, the strongest association was detected (P = 0.0038, P_c = 0.0095).

CONCLUSIONS. Multiple SNPs in the TLR4 gene are associated with the risk of NTG. This finding suggests that the ligands and/or cytokines involved in the TLR4 signaling network may be risk factors for the development of NTG.

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