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Variants in Optineurin Gene and Their Association with Tumor Necrosis Factor- Polymorphisms in Japanese Patients with Glaucoma

¹From the Departments of Ophthalmology, ¹⁰Preventive Medicine and Public Health, and ¹¹Molecular Biology, Keio University School of Medicine, Tokyo, Japan; the ²Ideta Eye Hospital, Kumamoto, Japan; the ³Department of Ophthalmology, Tokyo Metropolitan Police Hospital, Tokyo, Japan; the ⁴Department of Ophthalmology, Juntendo University School of Medicine, Tokyo, Japan; the ⁵Department of Ophthalmology, Hamamatsu University School of Medicine, Hamamatsu, Japan; the ⁶Department of Ophthalmology, Kumamoto University School of Medicine, Kumamoto, Japan; the ⁷Department of Ophthalmology, Hiroshima University School of Medicine, Hiroshima, Japan; the ⁸Department of Ophthalmology, Niigata University School of Medicine, Niigata, Japan; and the ⁹National Tokyo Medical Center, National Institute of Sensory Organs, Tokyo, Japan.

PURPOSE. To investigate sequence variations in the optineurin (OPTN) gene and their association with TNF- 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 –308GA, –857CT, and –863CA in the TNF- 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.412GA (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-/–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-/–857T, the optineurin/412A carriers had significantly worse (P = 0.020) visual field scores than the non–optineurin/412A ones. The frequency of TNF-/–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-/–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- genes that would increase the risk for glaucoma.

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