Fumihiko Mabuchi

High prevalence of anxiety and depression in patients with primary open-angle glaucoma.

PurposeTo assess anxiety and depression in patients with primary open-angle glaucoma (POAG). DesignMulticenter prospective case-control study. ParticipantsTwo hundred thirty patients with POAG and 230 sex-matched and age-matched reference subjects with no chronic ocular conditions except cataracts. InterventionAnxiety and depression were evaluated using Hospital Anxiety and Depression Scale (HADS) questionnaire, which consists of 2 subscales with ranges of 0 to 21, representing anxiety (HADS-A) and depression (HADS-D). Main Outcome MeasureThe prevalence of POAG patients with anxiety (a score of more than 10 on the HADS-A) or depression (a score of more than 10 on the HADS-D) was compared with that in the reference subjects. The prevalence of patients with depression was compared between the POAG patients with and without current β-blocker eye drops. ResultsThe prevalence (13.0%) of POAG patients with anxiety was significantly higher (P=0.030) than in the reference subjects (7.0%). The prevalence (10.9%) of POAG patients with depression was significantly higher (P=0.026) than in the reference subjects (5.2%). Between the POAG patients with and without β-blocker eye-drops, no significant difference (P=0.93) in the prevalence of depression was noted. ConclusionsPOAG was related to anxiety and depression. No significant relationship between the use of β-blocker eye-drops and depression was noted.

The association between Japanese primary open-angle glaucoma and normal tension glaucoma patients and the optineurin gene

Glaucoma represents one of the most common eye diseases and is characterized by progressive loss of visual fields. In the more advanced stages bilateral blindness may result, due to optic nerve atrophy and an excavated optic nerve head. Open-angle glaucoma is one of the main disease subsets, which may be further divided into high tension primary open-angle glaucoma (POAG) and normal tension glaucoma (NTG). Recently, the optineurin (OPTN) gene was identified as a causative factor for NTG. Alterations in this gene were found in Caucasian families with NTG. In particular, c.458G>A, c.691-692insAG and c.1944G>A were shown to be risk factors. Since NTG is reported to be the most common form of glaucoma in Japan, and to identify if the OPTN gene plays a role in POAG, the DNAs from 148 unrelated Japanese patients with NTG, 165 patients with POAG and 196 unrelated controls who were not suffering glaucoma were investigated by appropriate genotyping techniques. No glaucoma-specific mutations were found in the OPTN gene in Japanese glaucoma patients. However, some novel single-nucleotide polymorphisms (SNPs) in the exons and introns are reported in this paper for the first time.

Association of LOC387715 A69S with vitreous hemorrhage in polypoidal choroidal vasculopathy.

PURPOSE To investigate whether the LOC387715 polymorphism is associated with polypoidal choroidal vasculopathy (PCV) and with vitreous hemorrhage (VH), one of the most severe clinical phenotypes, in the Japanese population. DESIGN Cross-sectional case-control association study. METHODS One hundred and nine Japanese patients with PCV, composed of nine patients associated with VH (VH group) and 100 patients without VH (non-VH group), and 85 control subjects were analyzed for the LOC387715 polymorphism (rs = 10490924), using denaturing high-performance chromatography. RESULTS There was a significant difference in the T allele frequency between PCV patients and control subjects (P < .0001). In comparison with wild-type homozygosity (GG), homozygosity for the at-risk allele genotype (TT) increased the likelihood for PCV 8.4-fold (3.6 to 19.5, 95% confidence interval [CI]) and heterozygosity for the at-risk allele genotype (TG) increased the likelihood for PCV 4.0-fold (1.9 to 8.4, 95% CI). There was a significant difference in the genotypic frequency at the LOC387715 site between the VH and non-VH groups (P = .0099, Chi-square test) with the TT genotype occurring in 88.9% in the VH group and 37.0% in the non-VH group. The frequency of the T allele in the VH group was significantly greater than that in the non-VH group (0.944 vs 0.610; P = .0039, Fisher exact test). CONCLUSIONS The LOC387715 polymorphism is associated with PCV and clinical severity in the subgroups of PCV in the Japanese population.

Common Variants on Chromosome 9p21 Are Associated with Normal Tension Glaucoma

Although intraocular pressure (IOP) is the most definitive cause of glaucoma, a subtype of open angle glaucoma (OAG) termed normal tension glaucoma (NTG), which occurs in spite of normal IOP, accounts for a large part of glaucoma cases, especially in Japan. To find common genetic variants contributing to NTG in Japanese patients, we conducted a genome-wide association study (GWAS). We performed the first screening for 531,009 autosomal SNPs with a discovery cohort of 286 cases and 557 controls, and then a second screening for the top 30 suggestive loci in an independent cohort of 183 cases and 514 controls. Our findings identified a significantly associated SNP; rs523096 [combined p-value = 7.40× 10−8, odds ratio (OR)  = 2.00 with 95% confidence interval (CI) 1.55–2.58] located 10 kbp upstream of CDKN2B on chromosome 9p21. Moreover, analysis of another independent case-control set successfully replicated the results of the screening studies (combined values of all 3 stages p = 4.96 × 10−11, OR  = 2.13 with 95% CI 1.69–2.68). The SNPs near rs523096 were recently reported to be associated with OAG associated with elevated IOP in primary open-angle glaucoma (POAG), the predominant subtype of glaucoma in Caucasian populations. Our results revealed that the 9p21 locus is also associated with NTG in Japanese. In addition, we identified SNPs more strongly associated with NTG.

Risk factors for anxiety and depression in patients with glaucoma

Aim To assess the risk factors for anxiety and depression in patients with glaucoma. Methods Anxiety and depression in 408 patients with glaucoma were evaluated using the hospital anxiety and depression scale (HADS) questionnaire, which consists of two subscales, representing HADS-anxiety (HADS-A) and HADS-depression (HADS-D). To identify the risk factors for anxiety and depression, the stepwise and multiple linear regression analyses were carried out with the HADS-A and HADS-D subscores as dependent variables and demographic and clinical features as independent variables. Results A stepwise linear regression analysis revealed the significantly related factors to be age for HADS-A (β=−0.046, p=0.0007) and HADS-D (β=0.035, p=0.011) and the mean deviation of the Humphrey Visual Field Analyzer 30-2 (HFA30-2) in the better eye for HADS-D (β=−0.095, p=0.0026). Based on multiple linear regression analyses, significant relationships were confirmed between age and the HADS-A subscore (β=−0.046, p=0.0008). Significant relationships were also confirmed between age (β=0.037, p=0.0077) or the mean deviation of HFA30-2 in the better eye (β=−0.094, p=0.0036) and the HADS-D subscore. Conclusion A younger age was thus found to be a risk factor for anxiety, while an older age and increasing glaucoma severity were risk factors for depression in patients with glaucoma.

Association of LOC387715 A69S genotype with visual prognosis after photodynamic therapy for polypoidal choroidal vasculopathy.

Purpose: To investigate whether there is an association of the LOC387715 A69S genotype with visual prognosis after photodynamic therapy in eyes with polypoidal choroidal vasculopathy (PCV). Methods: Photodynamic therapy was repeated every 3 months until the disappearance of angiographic signs of active lesions in 71 eyes of 71 patients with PCV who were followed-up for at least 12 months. All patients were genotyped for LOC387715 A69S polymorphism (rs10490924, risk-allele T). Results: Although there was no statistically significant difference in the mean baseline visual acuity (P = 0.53) among the 3 genotypes, there was a statistically significant difference in the visual acuity both at the 12-month and final visits (P = 0.002 and P < 0.001, respectively) with the poorer acuity in patients with the higher “T-”allele frequency. “T” allele was more frequently observed in those with the recurred PCV lesions (odds ratio: 5.8, 95% confidential interval: 2.3-15.1, T vs. G). Conclusion: There is a pharmacogenetic association between the LOC387715 A69S variant and the long-term results after photodynamic therapy in eyes with PCV. The LOC387715 A69S genotype is of clinical importance to predict the visual prognosis after photodynamic therapy in eyes with PCV. These results should be confirmed or refuted by replication studies.

Association between Genetic Variants Associated with Vertical Cup-to-Disc Ratio and Phenotypic Features of Primary Open-Angle Glaucoma

PURPOSE To assess the association between the genetic variants associated with the optic nerve vertical cup-to-disc ratio (VCDR) and the phenotypic features in patients with primary open-angle glaucoma (POAG), including normal-tension glaucoma (NTG) and high-tension glaucoma (HTG). DESIGN Case-control study. PARTICIPANTS AND CONTROLS Japanese patients with NTG (n = 213) and HTG (n = 212) and 191 control subjects without glaucoma. METHODS DNA samples were genotyped for 7 single nucleotide polymorphisms (SNPs) associated with VCDR: rs1063192 (near gene: CDKN2B), rs10483727 (SIX1), rs17146964 (SCYL1), rs1547014 (CHEK2), rs1900004 (ATOH7), rs1926320 (DCLK1), and rs12015126 (RERE). MAIN OUTCOME MEASURES The VCDR was compared between genotypes, and allele frequency differences were compared between NTG or HTG subjects and control subjects. Demographic and clinical features were compared between alleles in patients with NTG or HTG. RESULTS There were significant VCDR differences (P = 0.0077 and P = 0.019) between the genotypes for rs1063192 (CDKN2B) and rs1547014 (CHEK2), respectively. There were significant differences in the rs1063192 (CDKN2B) and rs1900004 (ATOH7) allele frequencies between the NTG subjects and control subjects (P = 0.0023 and P = 0.028, respectively) and a significant difference (P = 0.013) in the rs1547014 (CHEK2) allele frequencies between the HTG subjects and control subjects. Ages at diagnosis were significantly different in the NTG subjects with and without the rs10483727 (SIX1) C allele (P = 0.017) or the rs1926320 (DCLK1) T allele (P = 0.040). Likewise, the age at diagnosis was significantly different (P = 0.037) in the HTG subjects with and without the rs12025126 (RERE) T allele. There were no significant associations between the maximum intraocular pressure (IOP) and 7 genotyped SNP alleles in patients with NTG or HTG. CONCLUSIONS The rs1063192 (CDKN2B) and rs1900004 (ATOH7) seem to be non-IOP-related genetic risk factors for NTG, and the rs1547014 (CHEK2) is a genetic risk factor for HTG. Although the rs10483727 (SIX1), rs1926320 (DCLK1), or rs12025126 (RERE) alone may not be sufficient for the development of POAG, the association of these SNPs with a phenotypic feature in patients with NTG or HTG suggests that these loci contribute to the pathogenesis of POAG.

Angiographic lesion size associated with LOC387715 A69S genotype in subfoveal polypoidal choroidal vasculopathy.

Purpose: To investigate whether the LOC387715/ARMS2 variants are associated with an angiographic phenotype, including lesion size and composition, in subfoveal polypoidal choroidal vasculopathy. Methods: Ninety-two subjects with symptomatic subfoveal polypoidal choroidal vasculopathy, whose visual acuity was from 0.1 to 0.5 on the Landolt chart, were genotyped for the LOC387715 polymorphism (rs10490924) using denaturing high-performance chromatography. The angiographic phenotype, including lesion composition and size, was evaluated by evaluators who were masked for the genotype. Lesion size was assessed by the greatest linear dimension based on fluorescein or indocyanine green angiography. Results: Although there was no statistically significant difference in lesion size on indocyanine green angiography (P = 0.36, Kruskal-Wallis test) and in lesion composition (P = 0.59, chi-square test) among the 3 genotypes, there was a statistically significant difference in lesion size on fluorescein angiography (P = 0.0022, Kruskal-Wallis test). Conclusion: The LOC387715 A69S genotype is not associated with lesion composition or size on indocyanine green angiography but with lesion size on fluorescein angiography in patients with subfoveal polypoidal choroidal vasculopathy. Because fluorescein angiography findings represent secondary exudative changes, including subretinal hemorrhages and retinal pigment epithelial detachment, the results in the present study likely indicate that the T allele at the LOC387715 gene is associated with the exudative activity of polypoidal lesions.

Mutations in the optineurin gene in Japanese patients with primary open‐angle glaucoma and normal tension glaucoma

The optineurin gene (OPTN) was identified as a gene that causes primary open‐angle glaucoma (POAG) and normal tension glaucoma (NTG). To investigate the frequency of sequence changes in OPTN in Japanese glaucoma patients, single‐strand conformation polymorphism analysis and subsequent sequence analysis were performed for genotyping OPTN in 165 unrelated Japanese patients with POAG and 148 patients with NTG, with 196 control subjects without glaucoma as reference subjects. Out of four mutations reported to be associated with risk and to cause disease in Caucasian patients, sequence alterations in 458G > A and 691_692insAG were not detected in any investigated Japanese patients with glaucoma, and alterations in 1944G > A and 603T > A, were present in similar frequencies in glaucoma patients and control subjects. The current results suggest that there may be certain racial differences between Japanese and Caucasians with respect to OPTN genotypes.

Role of Complement Factor H I62V and Age-Related Maculopathy Susceptibility 2 A69S Variants in the Clinical Expression of Polypoidal Choroidal Vasculopathy

PURPOSE To investigate the role of complement factor H (CFH) I62V (rs800292) and age-related maculopathy susceptibility 2 (ARMS2) A69S (rs10490924) variants in the clinical characteristics of polypoidal choroidal vasculopathy (PCV). DESIGN Cross-sectional study. PARTICIPANTS A total of 226 Japanese patients with PCV in both eyes (44 cases) or in 1 eye (182 cases). METHODS Genotyping was performed in all cases for CFH I62V using TaqMan technology and for ARMS2 A69S by denaturing high-performance chromatography. The incidence of 5 characteristic funduscopic findings was studied, including serous retinal detachment, subretinal hemorrhage, serous pigment epithelial detachment (PED), hemorrhagic PED, and classic choroidal neovascularization (CNV). MAIN OUTCOME MEASURES The association of clinical phenotypes, including the incidence of each of 5 specific fundus findings, bilaterality of the disease, and age at onset, with variants of CFH I62V or ARMS2 A69S. RESULTS Although there was no association of CFH I62V variants with any of the phenotypes in PCV, at-risk variants of ARMS2 A69S were associated with higher incidences of subretinal hemorrhage, serous PED, and hemorrhagic PED. In particular, the at-risk allele homozygosity of ARMS2 A69S increased the likelihood for hemorrhagic PED by 12.4-fold compared with non-carriers of the allele (confidence interval, 1.60-95.1, P = 0.0001). However, the at-risk allele of ARMS2 A69S was associated with a lower incidence of serous retinal detachment (P = 0.0092). Classic CNV was not associated with either variant. The mean age at the onset of PCV was significantly younger (68.8 years) in those with homozygosity of the at-risk allele of ARMS2 A69S than in those with heterozygosity (71.6 years) or in non-carriers (72.6 years) (P = 0.026). Moreover, the at-risk allele frequencies of the ARMS2 A69S were significantly higher in bilateral cases than in unilateral cases (75.0% vs. 59.3%, P = 0.007). CONCLUSIONS ARMS2 A69S variants were significantly associated with hemorrhagic or subpigment epithelium lesions of PCV, and with earlier onset and bilateral involvement. The genotyping of ARMS2 A69S is more informative than that of CFH I62V in understanding the clinical features in patients with PCV.