Association of Toll-like receptor 4 gene polymorphisms with normal tension glaucoma.
OBJECTIVE
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' >or= 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.
Shibuya
Etsuko
E
Department of Ophthalmology, Yokohama City University School of Medicine, Yokohama, Kanagawa, Japan.
Meguro
Akira
A
Ota
Masao
M
Kashiwagi
Kenji
K
Mabuchi
Fumihiko
F
Iijima
Hiroyuki
H
Kawase
Kazuhide
K
Yamamoto
Tetsuya
T
Nakamura
Makoto
M
Negi
Akira
A
Sagara
Takeshi
T
Nishida
Teruo
T
Inatani
Masaru
M
Tanihara
Hidenobu
H
Aihara
Makoto
M
Araie
Makoto
M
Fukuchi
Takeo
T
Abe
Haruki
H
Higashide
Tomomi
T
Sugiyama
Kazuhisa
K
Kanamoto
Takashi
T
Kiuchi
Yoshiaki
Y
Iwase
Aiko
A
Ohno
Shigeaki
S
Inoko
Hidetoshi
H
Mizuki
Nobuhisa
N
D000328:Adult; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D005902:Glaucoma, Open-Angle / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012307:Risk Factors; D051197:Toll-Like Receptor 4 / Q000235:genetics*
C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4