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

doi:10.1167/iovs.07-1575

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

Etsuko Shibuya,¹^,2 Akira Meguro,¹^,2 Masao Ota,³ Kenji Kashiwagi,⁴ Fumihiko Mabuchi,⁴ Hiroyuki Iijima,⁴ Kazuhide Kawase,⁵ Tetsuya Yamamoto,⁵ Makoto Nakamura,⁶ Akira Negi,⁶ Takeshi Sagara,⁷ Teruo Nishida,⁷ Masaru Inatani,⁸ Hidenobu Tanihara,⁸ Makoto Aihara,⁹ Makoto Araie,⁹ Takeo Fukuchi,¹⁰ Haruki Abe,¹⁰ Tomomi Higashide,¹¹ Kazuhisa Sugiyama,¹¹ Takashi Kanamoto,¹² Yoshiaki Kiuchi,¹² Aiko Iwase,¹³ Shigeaki Ohno,¹⁴ Hidetoshi Inoko,¹⁵ and Nobuhisa Mizuki¹

^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 receptorthat mediates immune responses to exogenous and endogenous ligandsand interacts with heat shock proteins, which are reportedlyinvolved in normal tension glaucoma (NTG). This study was undertakento investigate whether TLR4 polymorphisms are associated withNTG.

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

RESULTS. Strong linkage disequilibrium was observed among allSNPs (D' $≥$ 0.85), which were located in one haplotype block.With respect to allelic diversity, the minor allele of threeSNPs (rs10759930, rs1927914, and rs7037117) carried a significantlyincreased risk of NTG. With regard to genotypic diversity, individualswith the minor allele of six SNPs (rs10759930, rs1927914, rs1927911,rs12377632, rs2149356, and rs7037117) had a 1.47- to 1.65-foldincreased risk of NTG. rs7037117, located in the 3'-untranslatedregion of TLR4, was most strongly associated with NTG, and whenincorporated into a haplotype with rs10759930, the strongestassociation was detected (P = 0.0038, P_c = 0.0095).

CONCLUSIONS. Multiple SNPs in the TLR4 gene are associated withthe risk of NTG. This finding suggests that the ligands and/orcytokines involved in the TLR4 signaling network may be riskfactors for the development of NTG.