Variants in optineurin gene and their association with tumor necrosis factor-alpha polymorphisms in Japanese patients with glaucoma.
OBJECTIVE
To investigate sequence variations in the optineurin (OPTN) gene and their association with TNF-alpha polymorphisms in Japanese patients with glaucoma.


METHODS
The OPTN gene was analyzed in blood samples from 629 Japanese subjects. There were 194 patients with primary open-angle glaucoma (POAG), 217 with normal-tension glaucoma (NTG), and 218 with no eye disease (control subjects). The gene was screened for mutations by denaturing high-performance liquid chromatography. Genotyping of three polymorphisms of -308G-->A, -857C-->T, and -863C-->A in the TNF-alpha promoter region was performed. The associations between the genotypes and age, intraocular pressure (IOP), and visual field defects at the time of diagnosis were examined.


RESULTS
A possible glaucoma-causing mutation, His26Asp, was identified in 1 of the 411 Japanese patients with glaucoma. A c.412G-->A (Thr34Thr) polymorphism in the OPTN gene was significantly associated with POAG (genotype frequency, P = 0.011; allele frequency, P = 0.003). The frequency of TNF-alpha/-857T and optineurin/412A carriers was significantly higher (P = 0.006) in patients with POAG than in control subjects. Among the patients with POAG who were carriers of TNF-alpha/-857T, the optineurin/412A carriers had significantly worse (P = 0.020) visual field scores than the non-optineurin/412A ones. The frequency of TNF-alpha/-863A and optineurin/603A (or Lys98) carriers was significantly higher in patients with POAG (P = 0.008) or NTG (P = 0.027) than in control subjects. Among the patients with POAG who were carriers of TNF-alpha/-863A, the ones with optineurin/603A (or Lys98) had significantly worse (P = 0.026) visual field scores than did those with non-optineurin/603A (or Lys98).


CONCLUSIONS
These findings demonstrated that the OPTN gene is associated with POAG rather than NTG in the Japanese. Statistical analysis showed a possible interaction between polymorphisms in the OPTN and the TNF-alpha genes that would increase the risk for glaucoma.
Funayama
Tomoyo
T
Department of Ophthalmology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
Ishikawa
Karin
K
Ohtake
Yuichiro
Y
Tanino
Tomihiko
T
Kurosaka
Daijiro
D
Kimura
Itaru
I
Suzuki
Kotaro
K
Ideta
Hidenao
H
Nakamoto
Kenji
K
Yasuda
Noriko
N
Fujimaki
Takuro
T
Murakami
Akira
A
Asaoka
Ryo
R
Hotta
Yoshihiro
Y
Tanihara
Hidenobu
H
Kanamoto
Takashi
T
Mishima
Hiromu
H
Fukuchi
Takeo
T
Abe
Haruki
H
Iwata
Takeshi
T
Shimada
Naoki
N
Kudoh
Jun
J
Shimizu
Nobuyoshi
N
Mashima
Yukihiko
Y
D000328:Adult; D000375:Aging; D000483:Alleles; D044466:Asian People / Q000235:genetics*; D001224:Aspartic Acid; D018797:Cell Cycle Proteins; D002851:Chromatography, High Pressure Liquid; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D005902:Glaucoma, Open-Angle / Q000235:genetics* / Q000503:physiopathology; D006579:Heterozygote; D006639:Histidine; D006801:Humans; D007429:Intraocular Pressure; D008297:Male; D026901:Membrane Transport Proteins; D008875:Middle Aged; D009154:Mutation; D011110:Polymorphism, Genetic; D013912:Threonine; D035582:Transcription Factor TFIIIA / Q000235:genetics*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*; D014794:Visual Fields
D018797:Cell Cycle Proteins; D026901:Membrane Transport Proteins; C409460:OPTN protein, human; D035582:Transcription Factor TFIIIA; D014409:Tumor Necrosis Factor-alpha; D013912:Threonine; D001224:Aspartic Acid; D006639:Histidine