Seigo Yoneyama

Systemic risk factors associated with polypoidal choroidal vasculopathy and neovascular age-related macular degeneration.

Purpose: To compare the association of systemic risk factors between neovascular age-related macular degeneration (nAMD) and polypoidal choroidal vasculopathy (PCV). Methods: Seven hundred and three patients (235 with nAMD and 468 with PCV) were included. Associated systemic conditions, including hypertension, cardiovascular disease, stroke, diabetes mellitus, and end-stage renal disease, were investigated through an interview and questionnaire. Results: The prevalence of diabetes mellitus and end-stage renal disease in nAMD was significantly higher than that in PCV (P < 0.001 and P = 0.021, respectively, multivariate logistic regression analysis). Moreover, in diabetic patients with nAMD or PCV, the more severe form of diabetic retinopathy was more prevalent in nAMD cases than in PCV cases (P = 0.006, multivariate logistic regression analysis). Conclusion: Diabetes mellitus and end-stage renal disease are more prevalent in patients with nAMD than in those with PCV. Specific systemic conditions might be associated with the development of nAMD.

Aqueous Humor Cytokine Levels in Patients with Polypoidal Choroidal Vasculopathy and Neovascular Age-Related Macular Degeneration

Purpose: To investigate the possible roles of various cytokines or growth factors in the pathogenesis of exudative age-related macular degeneration (AMD) by comparing aqueous humor levels of 14 cytokines between eyes with polypoidal choroidal vasculopathy (PCV) and those with neovascular AMD. Methods: Forty eyes from 40 patients with treatment-naïve exudative AMD consisting of 18 eyes with neovascular AMD and 22 eyes with PCV were studied. Twenty eyes from 20 patients with no retinal pathology who underwent cataract surgery served as controls. Aqueous humor samples were collected just before intravitreal ranibizumab injection in 40 eyes with exudative AMD and before cataract surgery in 20 control eyes. Concentrations of 14 cytokines were determined by chemiluminescence-based ELISA: interleukin (IL)-1α, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, IL-13, IL-15, IL-17, vascular endothelial growth factor (VEGF), monocyte chemoattractant protein 1, interferon-γ-inducible protein (IP)-10 and C-reactive protein (CRP). Results: After adjusting for gender, age and axial length, concentrations of CRP and IP-10 were significantly higher in eyes with neovascular AMD or PCV compared with control eyes (p < 0.05), and IP-10 levels were strongly associated with lesion size (p = 0.002). None of the 14 cytokines, including VEGF, were significantly different between eyes with neovascular AMD and those with PCV. Conclusion: Aqueous humor concentrations of CRP and IP-10 were elevated in eyes with PCV or neovascular AMD. IP-10 could be associated with the pathogenesis of neovascular AMD and PCV.

Prevalence and Genetic Characteristics of Geographic Atrophy among Elderly Japanese with Age-Related Macular Degeneration

Objective To investigate the prevalence and genetic characteristics of geographic atrophy (GA) among elderly Japanese with advanced age-related macular degeneration (AMD) in a clinic-based study. Methods Two-hundred and ninety consecutive patients with advanced AMD were classified into typical neovascular AMD, polypoidal choroidal vasculopathy (PCV), retinal angiomatous proliferation (RAP) or geographic atrophy (GA). Genetic variants of ARMS2 A69S (rs10490924) and CFH I62V (rs800292) were genotyped using TaqMan Genotyping Assays. The clinical and genetic characteristics were compared between patients with and without GA. Results The number of patients diagnosed as having typical neovascular AMD, PCV, RAP and GA were 98 (33.8%), 151 (52.1%), 22 (7.5%) and 19 (6.6%), respectively. Of 19 patients with GA, 13 patients (68.4%) had unilateral GA with exudative AMD in the contralateral eye. Patients with GA were significantly older, with a higher prevalence of reticular pseudodrusen, bilateral involvement of advanced AMD and T-allele frequency of ARMS2 A69S compared with those with typical AMD and PCV; although there were no differences in the genetic and clinical characteristics among patients with GA and RAP. Conclusions The prevalence of GA was 6.6% among elderly Japanese with AMD. Patients with GA and RAP exhibited genetic and clinical similarities.

Genetic Variants in the SKIV2L Gene in Exudative Age-related Macular Degeneration in the Japanese Population

Abstract Background: To investigate whether genetic variant in superkiller viralicidic activity 2-like (SKIV2L) gene is associated with exudative age-related macular degeneration (AMD) including neovascular AMD, polypoidal choroidal vasculopathy (PCV), and retinal angiomatous proliferation (RAP). Materials and Methods: A total of 517 patients with exudative AMD comprised of 157patients with neovascular AMD, 333 patients with PCV, and 27patients with RAP, and 205 controls were enrolled in this study. Rs429608 inSKIV2L, rs800292 in complement factor H (CFH), rs10490924 in age-related maculopathy susceptibility2 (ARMS2) gene was genotyped using TaqMan technology. Logistic regression analysis was performed to correlate the risk for exudative AMD with demographic and genetic factors. Results: The A allele frequency of rs429608 in the SKIV2L gene was significantly higher in controls (13.9%) than in those with neovascular AMD (5.7%, p = 0.002), PCV (7.2%, p = 0.003) and RAP (3.7%, p = 0.0345). After adjusting for age, gender, ARMS2 A69S, and CFHI62V, the A allele of rs429608 was significantly protective against neovascular AMD (odds ratio [OR] 0.24, 95% confidence interval [CI] 0.122–0.484, p < 0.001), PCV (OR 0.43, 95% CI 0.262–0.704, p = 0.001), RAP (OR 0.09, 95% CI 0.014–0.581, p = 0.011). Conclusions: A SKIV2L variant was associated with protection against exudative AMD regardless of subtypes in the Japanese population.

GENETIC FACTORS ASSOCIATED WITH CHOROIDAL VASCULAR HYPERPERMEABILITY AND SUBFOVEAL CHOROIDAL THICKNESS IN POLYPOIDAL CHOROIDAL VASCULOPATHY.

Purpose: To investigate genetic factors associated with choroidal vascular hyperpermeability (CVH) and subfoveal choroidal thickness in eyes with treatment-naive polypoidal choroidal vasculopathy. Methods: We studied 149 consecutive patients with polypoidal choroidal vasculopathy. The presence of CVH was evaluated using indocyanine green angiography. Subfoveal choroidal thickness and axial length were measured by spectral domain optical coherence tomography and optical biometry, respectively. Genotyping of three single nubleotide polymorphisms (SNPs), including age-related maculopathy susceptibility 2 (ARMS2) A69S (rs10490924), complement factor H (CFH) I62V (rs800292), and CFH (rs1329428), which are reportedly associated with central serous chorioretinopathy, was conducted using TaqMan technology. Results: Thicker subfoveal choroidal thickness was associated with younger age, shorter axial length, G-allele frequency in ARMS2 A69S (rs10490924), and T-allele frequency in CFH (rs1329428) (P = 0.001, P < 0.001, P = 0.004, and P = 0.002, respectively; multiple regression analysis). Among 149 eyes with polypoidal choroidal vasculopathy, 35 eyes (23.5%) exhibited CVH on indocyanine green angiography. Patients with CVH had a significantly higher frequency of the G allele of ARMS2 A69S (rs10490924) and the T allele of CFH (rs1329428), which are reported to be risk alleles for central serous chorioretinopathy (P = 0.006 and P = 0.032, respectively; multivariate regression analysis). Conclusion: Subfoveal choroidal thickness and CVH in eyes with treatment-naive polypoidal choroidal vasculopathy were associated with ARMS2 A69S (rs10490924) and CFH (rs1329428).

A prospective multicenter study on genome wide associations to ranibizumab treatment outcome for age-related macular degeneration

We conducted a genome-wide association study (GWAS) on the outcome of anti-VEGF treatment for exudative age-related macular degeneration (AMD) in a prospective cohort. Four hundred and sixty-one treatment-naïve AMD patients were recruited at 13 clinical centers and all patients were treated with 3 monthly injections of ranibizumab followed by pro re nata regimen treatment for one year. Genomic DNA was collected from all patients for a 2-stage GWAS on achieving dry macula after the initial treatment, the requirement for an additional treatment, and visual acuity changes during the 12-month observation period. In addition, we evaluated 9 single-nucleotide polymorphisms (SNPs) in 8 previously reported AMD-related genes for their associations with treatment outcome. The discovery stage with 256 patients evaluated 8,480,849 SNPs, but no SNPs showed genome-wide level significance in association with treatment outcomes. Although SNPs with P-values of <5 × 10−6 were evaluated in replication samples of 205 patients, no SNP was significantly associated with treatment outcomes. Among AMD-susceptibility genes, rs10490924 in ARMS2/HTRA1 was significantly associated with additional treatment requirement in the discovery stage (P = 0.0023), and pooled analysis with the replication stage further confirmed this association (P = 0.0013). ARMS2/HTRA1 polymorphism might be able to predict the frequency of injection after initial ranibizumab treatment.

Incidence and risk factors of retreatment after three-monthly aflibercept therapy for exudative age-related macular degeneration

Though anti-vascular endothelial growth factor therapy has become the standard treatment for exudative age-related macular degeneration (AMD), retreatment after the initial loading injection is inevitable in most eyes with residual or recurrent exudative changes. In the present study, we studied 140 treatment naïve eyes with typical neovascular AMD (n = 71) or polypoidal choroidal vasculopathy (PCV) (n = 69) and investigated the incidence and risk factors of retreatment after 3-monthly intravitreal aflibercept injection for exudative AMD during the 12-month period. At 12 months, best-corrected visual acuity (BCVA) improved significantly from 0.45 ± 0.39 to 0.26 ± 0.33 (P = 4.1 × 10−11). Multiple regression analysis revealed that better baseline BCVA (P = 3.6 × 10−14) and thicker subfoveal choroidal thickness (P = 0.039) were associated with better BCVA at 12-months. Retreatment was required in 94 out of 140 (67.1%) eyes. Multivariate logistic regression analysis revealed that older age (P = 7.2 × 10−3) and T-allele of ARMS2 A69S (rs10490924) variants (P = 1.9 × 10−3) were associated with retreatment. Cox-regression analysis revealed that older age (P = 1.0 × 10−2) and T-allele of the ARMS2 gene (P = 6.0 × 10−3) were associated with retreatment-free period. The number of retreatment episodes was significantly different among the ARMS2 genotypes (P = 8.1 × 10−4). These findings might be helpful for physicians when considering the optimal treatment regimen for exudative AMD.

Prevalence and characteristics of pseudodrusen subtypes in advanced age-related macular degeneration

PurposeThe purpose of our study was to investigate the clinical and genetic characteristics of pseudodrusen subtypes and their incidence in advanced age-related macular degeneration (AMD).MethodsWe studied 84 eyes from 84 patients with pseudodrusen associated with advanced AMD, including typical AMD, polypoidal choroidal vasculopathy (PCV), retinal angiomatous proliferation (RAP), and geographic atrophy (GA). Multiple imaging modalities, including color fundus photography, spectral-domain optical coherence tomography (SD-OCT), near-infrared reflectance, and fundus autofluorescence, were employed to diagnose pseudodrusen and its subtypes. Subfoveal choroidal thickness was measured using SD-OCT. Subject eyes were classified into two subtypes, dot-dominant or ribbon-dominant, according to the maximum length of ribbon pseudodrusen. Genotyping was performed for ARMS2 A69S (rs10490924) and CFH I62V (rs800292) variants.ResultsThe percentage of ribbon-dominant type pseudodrusen was significantly higher in eyes with RAP (69.6%) and GA (78.6%) compared with those with typical AMD (31.1%) (p = .0025 and .0017, respectively). Multivariate logistic regression analysis disclosed that incidence of female patients and coexisting large soft drusen was significantly higher in ribbon- than dot-dominant types (P = 0.014 and P = 0.008, respectively), while age, subfoveal choroidal thickness, and risk allele frequency for both ARMS2 A69S (rs10490924) and CFH I62V (rs800292) were not different between the two pseudodrusen subtypes.ConclusionsAmong eyes with advanced AMD associated with pseudodrusen, ribbon-dominant type pseudodrusen were more prevalent in eyes with GA or RAP and were associated with large soft drusen and female patients.

Genetic Variant Near PLXDC2 Influences the Risk of Primary Open-angle Glaucoma by Increasing Intraocular Pressure in the Japanese Population

Purpose: The purpose of this study is to assess the association between the genetic variants that were previously reported to be associated with primary open-angle glaucoma (POAG) in the Japanese population and the phenotypic features. Methods: A total of 661 Japanese patients including 417 patients with POAG [normal tension glaucoma (NTG), n=210; high tension glaucoma (HTG), n=207] and 244 control subjects without glaucoma were analyzed for 3 genetic variants: rs547984 (near gene: ZP4), rs7081455 (PLXDC2), and rs7961953 (TMTC2). The allele frequency differences between POAG (NTG or HTG) patients and control subjects were estimated. The association between these genetic variants and the phenotypic features, including the maximum intraocular pressure (IOP) and the vertical cup-to-disc ratio, was evaluated. Results: There was a significant difference in the rs7081455 (PLXDC2) allele frequencies between the POAG (P=0.0050) patients and the control subjects. An almost 1.5 increase in the risk of POAG (P=0.0042, odds ratio 1.52) was found with a G allele of rs7081455 (PLXDC2). The maximum IOP [23.5±10.3 mm Hg (mean±SD)] in patients with the GG genotype of rs7081455 (PLXDC2) was significantly higher (P=0.0037) than that (19.9±7.4 mm Hg) in patients with the TT genotype. Conclusions: The genetic variant near the PLXDC2 gene was found to influence the risk of POAG by increasing IOP in the Japanese population.

Risk Factors for Second Eye Involvement in Eyes with Unilateral Polypoidal Choroidal Vasculopathy

Abstract Purpose: To investigate risk factors associated with developing polypoidal choroidal vasculopathy (PCV) lesions in the unaffected fellow eye of patients with unilateral PCV. Methods: We studied 179 patients with initial unilateral PCV who were followed up for a period of 24 months or longer to monitor for second eye involvement. All patients underwent genotyping for CFH I62V (rs800292) and ARMS2 A69S (rs10490924) using TaqMan technology. Results: During the follow-up period ranging from 5–180 months, 20 (11.2%) of 179 patients developed PCV in the initially unaffected fellow eye. The risk allele (T) of ARMS2 A69S was significantly more prevalent in patients with second eye involvement compared to those without PCV in the fellow eye (p = 0.0046). Cox regression analysis demonstrated that the ARMS2 A69S genotype is a risk factor for developing PCV in the fellow eye (p = 0.027, odds ratio 2.53, confidence interval 1.11–5.73). Survival analysis revealed that the fellow eye of patients with the risk-associated homozygous genotype (TT) of ARMS2 A69S was affected significantly earlier than those with other genotypes (p = 0.0177, log rank test). Conclusions: Development of PCV in the unaffected fellow eye is associated with ARMS2 A69S genotype in patients with unilateral PCV.