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Normal-tension glaucoma (NTG) is a heterogeneous disease characterized by retinal ganglion cell (RGC) death leading to cupping of the optic nerve head and visual field loss at normal intraocular pressure (IOP). The pathogenesis of NTG remains unclear. Here, we describe a single nucleotide mutation in exon 2 of the methyltransferase-like 23 (METTL23) gene identified in 3 generations of a Japanese family with NTG. This mutation caused METTL23 mRNA aberrant splicing, which abolished normal protein production and altered subcellular localization. Mettl23-knock-in ([Mettl23.sup.+/G] and [Mettl23.sup.G/G]) and -knockout ([Mettl23.sup.+/-] and [Mettl23.sup.-/-]) mice developed a glaucoma phenotype without elevated IOP. METTL23 is a histone arginine methyltransferase expressed in murine and macaque RGCs. However, the novel mutation reduced METTL23 expression in RGCs of [Mettl23.sup.G/G] mice, which recapitulated both clinical and biological phenotypes. Moreover, our findings demonstrated that METTL23 catalyzed the dimethylation of H3R17 in the retina and was required for the transcription of pS2, an estrogen receptor [alpha] target gene that was critical for RGC homeostasis through the negative regulation of NF-[kappa]B-mediated TNF-[alpha] and IL-1[beta] feedback. These findings suggest an etiologic role of METTL23 in NTG with tissue-specific pathology., Introduction Glaucoma is the most frequent cause of progressive and irreversible blindness and is characterized by optic nerve head cupping and visual field loss (1). Open-angle glaucoma is the most [...]

Purpose: To compare standard fluorescein angiography (FA) and ultra-wide-field (UWF) FA in evaluating sarcoid uveitis activity using the scoring system adopted by the Angiography Scoring for Uveitis Working Group (ASUWG). Methods: Standard and UWF FA images of 36 eyes with sarcoid uveitis were acquired on the same day. Three graders independently graded 72 FA images using the ASUWG scoring system. We evaluated inter-observer variability using the intra-class correlation coefficient (ICC) and compared scores of each angiographic sign. Results: The ICC was 0.77 for standard FA and 0.87 for UWF FA, with respective total scores of 12.0 and 14.6. UWF FA had higher scores than standard FA for optic disc hyperfluorescence, posterior retinal vascular staining and/or leakage, and peripheral capillary leakage. Conclusions: The scores for UWF FA had a higher ICC than those for standard FA in evaluating sarcoid uveitis. Peripheral capillary leakage scores were particularly high for UWF FA. [ABSTRACT FROM AUTHOR]

Purpose: We investigated clinical characteristics of ocular Behçet's disease (BD) patients treated in the 1990s and the 2000s.Methods: We retrospectively examined records of 68 newly arrived patients with ocular BD followed for more than 4 months during the 2000s and compared to those of 107 patients during the 1990s. Patient profiles, ocular and systemic symptoms, frequency of ocular attacks, BD ocular attack score 24-6 months (BOS24-6M), best-corrected visual acuity (BCVA), and immunomodulatory treatment were noted.Results: Clinical characteristics in the 2000s showed increases in iridocyclitis type, intestinal-, vasculo-, and neuro-BD cases, oral corticosteroid, methotrexate, and infliximab therapy usage, cataract and glaucoma surgery, and pseudophakia, and decreases in BOS24-6M and cyclophosphamide usage. BCVA of 20/30 or better at the final visit was slightly increased in the 2000s.Conclusions: Milder ocular BD tendency was seen in cases in the 2000s, whereas the incidence of special type of BD might be increasing. [ABSTRACT FROM AUTHOR]

Purpose: To test the genetic association between Japanese patients with primary open-angle glaucoma (POAG) and the previously reported POAG susceptibility loci and to perform genotype–phenotype analysis. Methods: Genetic associations for 27 SNPs from 16 loci previously linked to POAG were assessed using genome-wide SNP data of the primary cohort (565 Japanese POAG patients and 1,104 controls). Reproducibility of the assessment was tested in 607 POAG cases and 455 controls (second cohort) with a targeted genotyping approach. For POAG-associated variants, a genotype–phenotype correlation study (additive, dominant, recessive model) was performed using the objective clinical data derived from 598 eyes of 598 POAG patients. Results: Among 27 SNPs from 16 loci previously linked to POAG, genotypes for total of 20 SNPs in 13 loci were available for targeted association study. Among 8 SNPs in 3 loci that showed at least nominal association (P < 5.00E-02) in the primary cohort, a representative SNP for each loci (rs2157719 for CDKN2B-AS1, rs33912345 for SIX6, and rs9913911 for GAS7) were selected. For these SNPs the association was found significant in both the second cohort analysis and meta-analysis. The genotype–phenotype analysis revealed significant correlations between CDKN2B-AS1 (rs2157719) and decreased intraocular pressure (β = -6.89 mmHg, P = 1.70E-04; dominant model) after multiple corrections. In addition, nominal correlation was observed between CDKN2B-AS1 (rs2157719) and optic nerve head blood flow (β = -0.54 and -0.67 arbitrary units (AU), P = 2.00E-02 and 1.39E-02), between SIX6 (rs33912345) and decreased total peripapillary retinal nerve fiber layer thickness (β = -2.16 and -2.82 μm, P = 4.68E-02 and 2.40E-02, additive and recessive model, respectively) and increased optic nerve head blood flow (β = 0.44 AU, P = 2.20E-02; additive model) and between GAS7 (rs9913911) and increased cup volume (β = 0.03 mm3, P = 4.60E-02) and mean cup depth (β = 0.03 mm3, P = 4.11E-02; additive model) and decreased pattern standard deviation (β = -0.87 dB, P = 2.44E-02; dominant model). Conclusion: The association between SNPs near GAS7 and POAG was found in Japanese patients for the first time. Clinical characterization of the risk variants is an important step toward understanding the pathology of the disease and optimizing treatment of patients with POAG. [ABSTRACT FROM AUTHOR]

To investigate the association between the additive effects of genetic variants associated with intraocular pressure (IOP) and IOP, vertical cup-to-disc ratio (VCDR), and high tension glaucoma (HTG) or normal tension glaucoma (NTG) as phenotypic features of primary open-angle glaucoma (POAG), and to evaluate the clinical usefulness of the additive effects of IOP-related genetic variants for predicting IOP elevation, Japanese patients with HTG (n = 255) and NTG (n = 261) and 246 control subjects were genotyped for nine IOP-related genetic variants near CAV2, GAS7, GLCCI1/ICA1, ABCA1, ARHGEF12, FAM125B, FNDC3B, ABO, and PTPRJ/AGBL2. The total number of risk alleles of these genetic variants was calculated for each participant as a genetic risk score (GRS), and the association between the GRS and the maximum IOP, mean VCDR, and phenotype (HTG or NTG) of POAG was evaluated. As the GRS increased, the maximum IOP (P = 0.012) and VCDR (P = 0.010) significantly increased. The GRS (9.1±1.9) in patients with HTG was significantly higher (P = 0.011) than that (8.7±1.8) in control subjects. The patients with GRS≥12 as a cut-off value had a 2.54 times higher (P = 0.0085) risk on HTG (maximum IOP≥22mmHg) compared with all patients. The IOP-related GRS approach substantiated that the IOP and VCDR were increased by the additive effects of IOP-related genetic variants in POAG. The high IOP-related GRS in patients with HTG but not NTG shows that there are differences in the genetic background between HTG and NTG and supports the notion that the phenotype (HTG or NTG) in patients with POAG depends on the additive effects of IOP-related genetic variants. The above-mentioned cut-off value of IOP-related GRS may be clinically useful for predicting the risk of IOP elevation. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the frequencies of the diseases in the new patients with uveitis during 2007–2009 and compare them with previously-reported data from the University of Tokyo Hospital. Methods: We retrospectively analyzed the clinical records of patients who visited the outpatient clinic from January 2007 to December 2009, and compared them with those of 1963–2006. Results: During 2007–2009, 468 new patients visited our hospital. Definite diagnoses were made in 63.0%. Frequent diagnoses include sarcoidosis (9.4%), Vogt-Koyanagi-Harada (VKH) disease (7.9%), herpetic iritis (6.0%), Behçet’s disease (5.6%), Posner-Schlossman syndrome (4.3%), HLA-B27-associated uveitis (3.0%), and intraocular malignant lymphoma (2.8%). Compared with our former findings, the ratios of sarcoidosis, herpetic iritis, CMV retinitis, Fuch’s heterochromic iridocyclitis, acute retinal necrosis and intraocular lymphoma increased, while that of Behçet’s disease decreased. Conclusions: Top three uveitis during 2007–2009 were sarcoidosis, VKH disease, herpetic iritis. Reduced frequency of Behçet’s disease was one of the most prominent characteristics. [ABSTRACT FROM PUBLISHER]

Purpose: It has been suggested that Sairei-to (TJ114), a traditional Japanese herbal medicine, has immunomodulatory activities. To evaluate the effects of TJ114 on uveitis, we examined the effectiveness of oral administration in a murine model of experimental autoimmune uveitis (EAU). Methods: Murine EAU was induced by subcutaneous injection of human inter-photoreceptor retinoid-binding protein (IRBP) peptide mixed with complete Freund’s adjuvant. In the TJ114-treated group, 2 g/kg was administrated orally from 0 to 20 days after immunization. Clinical scoring, histopathological scoring of EAU, cell proliferation, cytokine assessment, and adoptive transfer experiment of splenic T cells into naïve mice were performed. Results: EAU development occurred in 32 of 38 mice (86 %) in the untreated group and 12 of 33 (36 %) in the TJ114-treated group. The clinical scores for EAU in the vehicle-treated and TJ114-treated groups were 1.56 ± 1.65 and 0.59 ± 0.63 respectively, at 14 days after immunization ( p < 0.01, Mann–Whitney U-test), and 2.26 ± 1.56 and 0.75 ± 1.31 respectively at 21 days ( p < 0.001, Mann–Whitney U-test), while the histopathological scores at 21 days were 1.47 ± 1.42 and 0.54 ± 0.84 respectively ( p < 0.01, Mann–Whitney U-test). Interferon (IFN)-γ and tumor necrosis factor (TNF)-α production by cervical lymph node cells obtained from the TJ114-treated group were significantly reduced as compared with those from the vehicle-treated group ( p < 0.01, Student’s unpaired t-test). Moreover, the levels of C-C motif chemokine 2 (CCL2) and IFN-γ were significantly reduced in splenocytes of TJ114-treated mice as compared with the vehicle-treated group ( p < 0.01, Student’s unpaired t-test). Mice that received adoptive transfer of splenic T cells from TJ114-treated EAU mice caused significantly lower severity of EAU compared to those that received from vehicle-treated EAU mice. Conclusion: Oral administration of TJ114 has an inhibitory effect on a murine model of EAU, possibly via reduction in cytokine production by helper type-1 T cells. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the frequency of conditions of newly arrived patients with uveitis from 2010 to 2012 and compare this frequency with that since 2004.Methods: We retrospectively analyzed clinical records of patients who visited the outpatient clinic from January 2010 to December 2012, and compared them with those from 2004-2009.Results: From 2010 to 2012, 695 new patients with uveitis visited Tokyo University Hospital, with a definite diagnosis made in 431 (62.0%). The most common diagnosis was scleritis (8.3%), followed by sarcoidosis (8.1%); herpetic iridocyclitis (5.5%); Behçet disease (4.6%); Vogt-Koyanagi-Harada disease (4.0%); acute anterior uveitis (3.7%); Posner-Schlossman syndrome (3.6%); intraocular malignant lymphoma (3.0%); and bacterial endophthalmitis (1.9%). The most frequent unclassified type of uveitis was sarcoidosis-suspected (14.8%).Conclusions: When compared with years 2004-2009, the present series showed an increasing trend of intraocular malignant lymphoma, bacterial endophthalmitis, and chronic iridocyclitis, and a notable increase in chronic iridocyclitis in young girls, with decreasing trends of scleritis and Vogt-Koyanagi-Harada disease. [ABSTRACT FROM AUTHOR]

Primary open-angle glaucoma (POAG) is the leading cause of irreversible blindness worldwide for which 15 disease-associated loci had been discovered. Among them, only 5 loci have been associated with POAG in Asians. We carried out a genome-wide association study and a replication study that included a total of 7378 POAG cases and 36 385 controls from a Japanese population. After combining the genome-wide association study and the two replication sets, we identified 11 POAG-associated loci, including 4 known (CDKN2B-AS1, ABCA1, SIX6 and AFAP1) and 7 novel loci (FNDC3B, ANKRD55-MAP3K1, LMX1B, LHPP, HMGA2, MEIS2 and LOXL1) at a genome-wide significance level (P < 5.0×10-8), bringing the total number of POAG-susceptibility loci to 22. The 7 novel variants were subsequently evaluated in a multiethnic population comprising non-Japanese East Asians (1008 cases, 591 controls), Europeans (5008 cases, 35 472 controls) and Africans (2341 cases, 2037 controls). The candidate genes located within the new loci were related to ocular development (LMX1B, HMGA2 and MAP3K1) and glaucoma-related phenotypes (FNDC3B, LMX1B and LOXL1). Pathway analysis suggested epidermal growth factor receptor signaling might be involved in POAG pathogenesis. Genetic correlation analysis revealed the relationships between POAG and systemic diseases, including type 2 diabetes and cardiovascular diseases. These results improve our understanding of the genetic factors that affect the risk of developing POAG and provide new insight into the genetic architecture of POAG in Asians.

Aims: To investigate the ability of the Behçet's disease ocular attack score 24 (BOS24) scoring system to predict visual acuity (VA) in patients with ocular Behçet's disease., Design: This is a retrospective study., Methods: We included 91 eyes of 50 patients with ocular Behçet's disease (33 males, 17 females) who were referred to our hospital between 1986 and 2008 with >5 years follow-up. Total BOS24 scores over a 5-year period, BOS24-5Y, were calculated as the sum of BOS24 scores for each attack over the 5-year study period for each eye. Change in VA was defined as change in best-corrected visual acuity (BCVA) from the first remission to the last remission at the end of the target period. Factors related to change in VA (age, gender, BCVA at the first remission, total number of immunosuppressive medications and total number of ocular attacks during the 5-year period and BOS24-5Y) were evaluated using a linear mixed model., Results: BCVA (logarithm of the minimal angle resolution) deteriorated from 0.16±0.30 (mean±SD) to 0.21±0.37 over the 5-year study period, but there was no statistical difference. The total number of ocular attacks during the 5-year period and BOS24-5Y scores were 10.0±7.9 and 36.8±40.8, respectively. Linear mixed-model analysis revealed that BOS24-5Y was the most important index for VA deterioration, followed by BCVA at the first remission., Conclusions: BOS24-5Y was found to be a significant positive prognostic index for VA deterioration in patients with ocular Behçet's disease., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Objectives: Behçet's disease (BD) is known to be associated with HLA-B*51, especially HLA-B*5101, in many different ethnic groups. Recently, several HLA-A or -B alleles have been proposed as possible candidate genes for BD in addition to HLA-B*5101. To investigate those associations, we studied HLA-A and -B alleles in Japanese ocular BD patients and the association of possible susceptibility HLA genes with visual prognosis., Methods: Eighty-eight Japanese BD patients with uveitis and 104 healthy controls were enrolled for analyses of HLA-A and B alleles. Statistical analysis was performed with Fisher's exact test and odds ratio (OR). Association of the possible susceptible HLA gene and visual prognosis was also examined., Results: The phenotype frequency (PF) of HLA-A*2601 was significantly higher in the patients (37.5%) than the controls (14.4%) (pc=0.00529, OR=3.56), especially in patients without HLA-B*5101 (57.4% vs. 14.1%, pc=4.58x10-6, OR=8.21). In contrast, the PF of HLA-A*2601 was not increased in patients with HLA-B*5101 (14.6% vs. 15.8%). Also, the PF in patients possessing HLA-A*2601 or HLAB* 5101 was increased up to 77.3%. Interestingly, the PF of HLA-A*2601 was significantly associated with poor visual prognosis corresponding to visual acuity of 0.1 or less in the worse eye (p=0.0262)., Conclusions: Our results indicate that HLA-A*2601 is possibly associated with ocular BD, independent of HLAB* 5101, indicating that HLA-A*2601 is an additional susceptibility allele candidate of ocular BD in Japan. HLAA* 2601 would also be a possible marker for poor visual prognosis.