RECURRENCE OF CHOROIDAL NEOVASCULARIZATION LESION ACTIVITY AFTER AFLIBERCEPT TREATMENT FOR AGE-RELATED MACULAR DEGENERATION.

PURPOSE: To examine the recurrence rate of choroidal neovascularization (CNV) lesion activity in age-related macular degeneration (AMD) and associated factors after 1-year aflibercept treatment. METHODS: Age-related macular degeneration eyes with 1-year aflibercept fixed-regimen treatment and a follow-up period of at least 18 months from the initial aflibercept injection for treatment-naive exudative AMD were retrospectively evaluated. The recurrence rate was examined. Age, gender, visual acuity, AMD subtype, greatest linear dimension, and retinal and choroidal thicknesses at the 12th month examination were compared between eyes with and without recurrence. Presence of remnant polyps and pigment epithelial detachment (PED) morphology were also compared in polypoidal choroidal vasculopathy (PCV) eyes. RESULTS: Of the 98 eyes studied, 69 displayed a dry macula at the 12th month examination; 43.7% exhibited recurrence during the subsequent 12-month period in Kaplan-Meier analysis. Although no factors associated with recurrence were detected in AMD, remnant polyps and pigment epithelial detachment morphology at the 12th month examination were significantly associated with recurrence in polypoidal choroidal vasculopathy (P = 0.018 and 0.048, respectively). CONCLUSION: Continuous, proactive treatment would be considered overtreatment for more than half of the AMD eyes that achieved a dry macula. Angiography and optical coherence tomography analyses may be useful for predicting recurrence in polypoidal choroidal vasculopathy eyes.

INCIDENCE AND CAUSES OF VISION LOSS DURING AFLIBERCEPT TREATMENT FOR NEOVASCULAR AGE-RELATED MACULAR DEGENERATION: One-Year Follow-up.

PURPOSE: To investigate the incidence rate, risk factors, and final outcomes of patients with age-related macular degeneration (AMD) who have experienced vision loss despite periodic aflibercept treatment. METHODS: Subjects with treatment-naive AMD were prospectively recruited and treated with three monthly injections followed by two monthly injections of aflibercept. The incidence rate and risk factors of more than two lines of vision loss at any visit were investigated. RESULTS: We included 196 eyes of 196 patients. Vision loss was observed in 16 patients (8.2%). Eleven of 16 patients developed vision loss during the initial 3 months (68.8%). Vision loss remained in 11 eyes (68.8%) at the final visit. The maximum pigment epithelium detachment (PED) height (odds ratio = 1.46 for a 100-µm increase in the PED height) and disruption of the external limiting membrane (odds ratio = 4.45) were identified as risk factors for developing vision loss on logistic regression analysis. CONCLUSION: The incidence rate of vision loss during aflibercept treatment was relatively low. Identifying high-risk patients, those with a high PED height and disruption of the external limiting membrane, would be helpful in ensuring appropriate informed consent before treatment. Further studies are needed to establish optimal treatment for these patients.

MMP20 and ARMS2/HTRA1 Are Associated with Neovascular Lesion Size in Age-Related Macular Degeneration.

PURPOSE: Age-related macular degeneration (AMD) is the leading cause of severe visual impairment. Despite treatment, a central scotoma often remains. The size of the scotoma depends on the lesion size of the choroidal neovascular membrane and significantly affects the patient's quality of life, and the lesion size of neovascularization also affects response to treatments. The aim of this study was to identify genes associated with the neovascular lesion size in neovascular AMD. DESIGN: A genome-wide association study (GWAS). PARTICIPANTS: We included 1146 Japanese patients with neovascular AMD. METHODS: We performed a 2-stage GWAS for the lesion size of AMD as a quantitative trait among 1146 (first stage: 727, second stage: 419) Japanese patients with neovascular AMD. Lesion size was determined by the greatest linear dimension measured with fluorescein angiography examination before treatment. We examined the association between the genotypic distribution of each single nucleotide polymorphism (SNP) and the trait using an additive model adjusted for age and sex. To evaluate the associations between AMD development and SNPs associated with lesion size, we also performed a case-control study by using the genotype data from these 1146 Japanese patients as case subjects and the fixed dataset from the Nagahama Study as control subjects. MAIN OUTCOME MEASURES: Genes associated with the lesion size in neovascular AMD. RESULTS: In the discovery stage, rs10895322 in MMP20 showed a genome-wide significant P value of 6.95×10(-8), and rs2284665 in ARMS2/HTRA1 showed a P value of 1.55×10(-7). The associations of these 2 SNPs were successfully replicated in the replication stage, and a meta-analysis of both stages showed genome-wide significant P values (2.80×10(-9) and 4.41×10(-9), respectively). In a case-control study using 3248 Japanese subjects as controls, we could not find contribution of MMP20 rs10895322 for AMD development. Although MMP20 has been thought to be expressed only in dental tissues, we confirmed MMP20 expression in the human retina and retinal pigment epithelium/choroid with polymerase chain reaction. CONCLUSIONS: The growth of choroidal neovascularization in AMD would be affected by 2 genes: MMP20, a newly confirmed gene expressed in the retina, and ARMS2/HTRA1, a well-known susceptibility gene for AMD.

Vascular endothelial growth factor gene and the response to anti-vascular endothelial growth factor treatment for choroidal neovascularization in high myopia.

PURPOSE: To investigate the association between the vascular endothelial growth factor (VEGF) gene polymorphism and the response to anti-VEGF treatment for choroidal neovascularization (CNV) in highly myopic eyes. DESIGN: Retrospective cohort study. PARTICIPANTS: A total of 357 unrelated highly myopic Japanese patients with axial lengths ≥26.0 mm in both eyes were eligible, and 83 patients who received anti-VEGF therapy for CNV and could be followed for more than 1 year were included. METHODS: We genotyped a functional single nucleotide polymorphism in the VEGF gene, rs2010963. The associations between the distribution of the rs2010963 genotype and the number of eyes with maintained or improved visual acuity (VA) were analyzed. Furthermore, multivariable logistic regression analysis was performed to adjust for 7 possible prognostic factors, including age, sex, CNV size, CNV location, administration of loading dose, pretreatment VA, and number of additional treatments. MAIN OUTCOME MEASURES: The primary end point was maintenance of VA, and secondary end points were progression of chorioretinal atrophy (CRA) and recurrence of CNV. RESULTS: Mean age and mean axial length were not significantly different among 3 genotypes of rs2010963. The percentage of eyes with maintained or improved VA was significantly higher with the G allele of rs2010963 (P =0.016), and stepwise analysis revealed that both rs2010963 and CNV size were associated with VA maintenance (P =0.040 and 0.033, respectively). The secondary analysis revealed that administration of a loading dose was significantly associated with both CRA progression (P =0.031) and recurrence of CNV (P =0.020), whereas rs2010963 was not. CONCLUSIONS: These results suggest that the VEGF polymorphism influences the VA prognosis in highly myopic eyes with CNV within 1 year after anti-VEGF treatment. This association was still observed after removing its confounding effect through CNV size. The rs2010963 polymorphism was not associated with CNV recurrence or CRA progression, which indicates that these changes are not tied to intrinsic factors and may be controllable by improving treatment methods.

Insulin-like growth factor 1 is not associated with high myopia in a large Japanese cohort.

PURPOSE: To investigate whether genetic variations in the insulin-like growth factor 1 (IGF-1) gene are associated with high myopia in Japanese. METHODS: A total of 1,339 unrelated Japanese patients with high myopia (axial length ≥26 mm in both eyes) and two independent control groups were evaluated (334 cataract patients without high myopia and 1,194 healthy Japanese individuals). The mean axial length (mm±SD) in the case group was 29.18±1.85 mm, and the mean spherical equivalent (D±SD) of the phakic eyes was -12.69±4.54 D. We genotyped five tagging single nucleotide polymorphisms (SNPs) in IGF-1: rs6214, rs978458, rs5742632, rs12423791, and rs2162679. Chi-square tests for trend, multivariable logistic regression, and haplotype regression analysis were conducted. RESULTS: We found no significant association between the IGF-1 SNPs and high or extreme myopia (axial length ≥28 mm in both eyes, 837 subjects) in the additive model, even when compared with the cataract and general population controls, with or without adjustments for age and sex. The evaluation using dominant and recessive models also did not reveal any significant associations. The haplotype analysis with a variable-sized sliding-window strategy also showed a lack of association of IGF-1 SNPs with high or extreme myopia. CONCLUSIONS: The results of the present study using a Japanese subset do not support the proposal that the IGF-1 gene determines susceptibility to high or extreme myopia in Caucasians and Chinese. Further studies are needed to confirm our reports in other populations and to identify the underlying genetic determinants of these ocular pathological conditions.

Two-year outcome of photodynamic therapy combined with intravitreal injection of bevacizumab and triamcinolone acetonide for polypoidal choroidal vasculopathy.

PURPOSE: To compare the 2-year results after photodynamic therapy (PDT) alone and PDT combined with intravitreal injections of bevacizumab and triamcinolone acetonide (triple therapy) for polypoidal choroidal vasculopathy (PCV). METHODS: We retrospectively reviewed the medical records of 40 consecutive patients (40 eyes) with subfoveal PCV. Of these 40 eyes, 16 were treated with PDT alone and 24 were treated with triple therapy. RESULTS: The change in visual acuity in the triple therapy group was significantly better than that in the PDT group (P < 0.001). At 24 months, improvement in visual acuity was seen in only two eyes (12.5 %) of the PDT group, while it was seen in ten eyes (41.7 %) of the triple therapy group. Retreatment was given to 12 eyes (75.0 %) in the PDT group and to nine eyes (37.5 %) in the triple therapy group, although the retreatment-free period was significantly longer in the triple therapy group than in the PDT group (P < 0.001). Post-treatment vitreous hemorrhage was seen in only two eyes (12.5 %), all of which were in the PDT group. CONCLUSION: Compared with PDT alone, triple therapy appears to reduce the postoperative hemorrhagic complications and recurrences of PCV and to improve the 2-year visual outcomes of PCV.

Association of paired box 6 with high myopia in Japanese.

PURPOSE: The objective of this study was to investigate whether genetic variations in the paired box 6 (PAX6) gene are associated with high myopia in Japanese subjects. METHODS: A total of 1,307 unrelated Japanese patients with high myopia (axial length ≥26 mm in both eyes) and two independent control groups were evaluated (333 cataract patients without high myopia and 923 age-matched healthy Japanese individuals). We genotyped three tag single-nucleotide polymorphisms (SNPs) in PAX6: rs2071754, rs644242, and rs3026354. These SNPs provided 100% coverage of all phase II HapMap SNPs within the PAX6 region (minor allele frequency ≥0.10; r(2) threshold: 0.90). Chi-square tests for trend and multivariable logistic regression were conducted. RESULTS: Genotype distributions in the three SNPs were in accordance with the Hardy-Weinberg equilibrium. After adjusting for age and sex, evaluation of cataract control showed a marginal association with high myopia in rs644242 (odds ratio [95% confidence interval]=0.69 [0.49-0.96], p=0.026), and a significant association was observed in healthy Japanese controls (0.79 [0.66-0.96], p=0.015). We pooled two control cohorts to evaluate the association. This analysis revealed a strong association between rs644242 and high myopia (0.78 [0.65-0.92], p=0.0045). The rs644242 A allele was a protective allele for development of high myopia. Subanalysis also revealed that rs644242 was significantly associated with extreme high myopia (0.78 [0.64-0.95], p=0.0165). The other two SNPs did not show a significant association with this condition. CONCLUSIONS: The current study showed a significant association of PAX6 with high and extreme myopia in Japanese participants. The A allele of rs644242 is a protective allele.

Relationship between retinal morphological findings and visual function in age-related macular degeneration.

BACKGROUND: We aimed to study the retinal morphological findings associated with exudative age-related macular degeneration (AMD) and their association with visual prognosis. METHODS: We retrospectively reviewed the medical records of 96 consecutive patients (96 eyes) with exudative AMD. Retinal structural changes were examined using optical coherence tomography (OCT). RESULTS: Initial OCT examination showed cystoid macular edema in 18 eyes (18.8%), fibrin exudate in 56 eyes (58.3%), and hyperreflective foci within the neurosensory retina in 78 eyes (81.3%). Upon initial examination, an external limiting membrane (ELM) line was detected under the fovea in 64 eyes (66.7%). Using Pearson's correlation analyses, final visual acuity (VA) was correlated with initial VA (r = 0.61, p < 0.001), age (r = 0.34, p < 0.001), initial total foveal thickness (r = 0.41, p < 0.001), presence of hyperreflective foci (r = 0.40, p < 0.001), and detection of a foveal ELM line (r = 0.55, p < 0.001). After multiple regression analysis, final VA correlated with initial VA (r = 0.48, p < 0.001), initial presence of hyperreflective foci (r = 0.23, p = 0.054), and detection of a foveal ELM line (r = 0.36, p = 0.008). CONCLUSIONS: In eyes with exudative AMD, final VA was most correlated with initial VA. In addition, the initial integrity of the foveal outer retina was partially correlated with the visual prognosis. The initial ELM condition was associated with good final VA, while the initial presence of hyperreflective foci in the foveal neurosensory retina was associated with poor final VA.

Retinal sensitivity after resolution of the macular edema associated with retinal vein occlusion.

PURPOSE: To study the correlation of retinal sensitivity with both morphologic changes in the macula and status of retinal capillary perfusion, after resolution of the macular edema associated with retinal vein occlusion (RVO). METHODS: Retinal sensitivity in the macular area was examined with the Micro Perimeter 1 in 24 eyes after resolution of the macular edema associated with RVO. Using spectral-domain optical coherence tomography, 6 mm × 6 mm areas of macula were examined with 256 sequential horizontal scans. Condition of the photoreceptor layer was evaluated depending upon detection of the junctions between inner and outer segments of the photoreceptors (IS/OS). Fluorescein angiography was performed in 19 eyes. RESULTS: Mean retinal sensitivity on the affected side of the retina was significantly decreased (p < 0.001). On the affected side, the mean retinal sensitivity within the area of deteriorated IS/OS was significantly less (3.8 ± 4.8 dB) than that within areas with complete IS/OS (10.1 ± 6.4 dB, p < 0.001). Mean retinal sensitivity within nonperfused areas was extremely low (0.3 ± 1.3 dB), compared with that in perfused retina (10.9 ± 5.9 dB, p < 0.001). In eyes with a broken foveal capillary ring (FCR), the marked decline in retinal sensitivity was seen within the area where the FCR was broken; this was not seen in eyes with an intact FCR. CONCLUSION: Retinal function was decreased markedly in areas with a damaged photoreceptor layer due to RVO, and was lethally decreased within nonperfused areas. Due to the various limitations of the current study, including implementation of fluorescein angiography in limited number of eyes, wide range of follow-up, and heterogeneity of pretreatments, further prospective studies are necessary to confirm the current findings.

Efficacy of Photodynamic Therapy for Polypoidal Choroidal Vasculopathy Associated with and without Pachychoroid Phenotypes.

PURPOSE: To compare the efficacy of photodynamic therapy (PDT) in eyes with polypoidal choroidal vasculopathy (PCV) associated with and without pachychoroid phenotypes (pachychoroid PCV and nonpachychoroid PCV, respectively). DESIGN: Retrospective chart review. PARTICIPANTS: Patients previously diagnosed with PCV and initially treated with PDT. METHODS: Patients were classified as having pachychoroid- or nonpachychoroid-driven conditions. The long-term visual outcome and its associated factors were investigated. MAIN OUTCOME MEASURES: Visual acuity (VA) outcomes at 1, 2, 3, 4, and 5 years after initial PDT in pachychoroid and nonpachychoroid PCV. RESULTS: Of the 158 eyes, 88 (55.7%) met the criteria for pachychoroid PCV; 70 (44.3%) did not (nonpachychoroid PCV). In cases of pachychoroid PCV, VA improved significantly at 1 year (P = 0.042) and maintained baseline level at 5 years (P = 0.38). By contrast, VA continued to deteriorate in the nonpachychoroid PCV group during the follow-up period and had already declined significantly by the second year (P = 0.022, compared with baseline). Despite no difference in baseline VA between pachychoroid and nonpachychoroid PCV groups (P = 0.11), the VA at 5 years was significantly better in the pachychoroid PCV group compared with the nonpachychoroid PCV group (0.54±0.47 vs. 0.93±0.63, respectively; P = 0.23 × 10-3). The incidence of massive submacular hemorrhage (SMH) or vitreous hemorrhage (VH) was not different between groups at 5 years (P = 0.67), and their occurrence was associated with decreased VA in both the nonpachychoroid and pachychoroid PCV groups (coefficient ß, 0.361 and 0.481; P = 0.59 × 10-3 and P < 1.0 × 10-5, respectively). CONCLUSIONS: Five years after PDT treatment, VA was maintained at the baseline level in the pachychoroid PCV group but not in the nonpachychoroid PCV group. Massive SMH or VH during the follow-up period affected the final visual outcomes in both conditions.

Baseline data from a multicenter, 5-year, prospective cohort study of Japanese age-related macular degeneration: an AMD2000 report.

PURPOSE: To report research participants' baseline characteristics in the AMD2000 study, a prospective, multicenter, 5-year, observational cohort study of Japanese age-related macular degeneration (AMD). The characteristics were determined using multimodal imaging. METHODS: Patients with AMD were recruited at 18 clinical sites in Japan between April 2006 and March 2009. Each patient underwent a complete ophthalmic examination, including measurement of best-corrected visual acuity (Landolt chart), indirect ophthalmoscopy, slit-lamp biomicroscopy with a contact lens, optical coherence tomography imaging, fundus photography, and fluorescein and indocyanine green angiography. RESULTS: Four hundred sixty participants (326 men [70.9%]) were included in the study. At enrollment, 131 eyes (28.5%) had hard drusen and 125 eyes (27.2%) had soft drusen in the macular area. A total of 455 eyes (98.9%) were diagnosed as having wet AMD, and 5 eyes (1.1%), as having dry AMD. Of the 455 eyes with wet AMD, 209 eyes (45.4%) had typical AMD, 228 eyes (49.6%) had polypoidal choroidal vasculopathy (PCV), and 18 eyes (3.9%) had retinal angiomatous proliferation. The size of choroidal neovascularization (CNV) was significantly smaller with indocyanine green angiography than with fluorescein angiography (P < 0.001). Poor baseline visual acuity was associated with cystoid macular edema, older age, scar, extrafoveal macular edema, subfoveal CNV, large branching vascular network, and hard exudates. CONCLUSION: Japanese patients with AMD are predominantly male, lack drusen, and have a high rate of PCV.

A 5-year multicenter prospective cohort study on the long-term visual prognosis and predictive factors for visual outcome in Japanese patients with age-related macular degeneration: the AMD2000 study.

PURPOSE: In this study (AMD2000), we aimed to determine the visual prognosis of Japanese patients with age-related macular degeneration (AMD). METHODS: This was a multicenter prospective observational cohort study. In total, 460 patients with AMD were recruited from April 2006 to March 2009 from 18 clinical trial sites in Japan. They were followed up for 5 years, as they continued to receive medical treatment. RESULTS: Of the 409 study eyes followed up for at least 1 year, 243 eyes (59.4%) were treated with photodynamic therapy (PDT) using verteporfin, and 58 eyes (14.2%) were treated with intravitreal injections of antivascular endothelial growth factor agents as the initial treatment. The mean best-corrected visual acuities (BCVA) for typical AMD (tAMD; 0.688 ± 0.498) and polypoidal choroidal vasculopathy (PCV; 0.451 ± 0.395) were significantly less at 2 years (tAMD, 0.779 ± 0.632, P < 0.05; PCV, 0.534 ± 0.618, P < 0.05) and at 5 years (AMD, 0.873 ± 0.718, P < 0.05; PCV, 0.635 ± 0.668, P < 0.05) than at baseline. In eyes with tAMD, absence of blocked fluorescence was associated with 5-year maintenance of the baseline BCVA. Regarding PCV, the presence of polypoidal lesions and cystoid macular edema as well as the lesion size was associated with 5-year maintenance of the baseline BCVA. In some patients, the diagnosis changed: of the 192 eyes initially diagnosed with typical AMD, 19 were newly diagnosed with PCV during follow-up. CONCLUSION: Maintaining the baseline BCVA over the long term is difficult in Japanese eyes with wet AMD.

A genome-wide association study identified a novel genetic loci STON1-GTF2A1L/LHCGR/FSHR for bilaterality of neovascular age-related macular degeneration.

Bilateral neovascular age-related macular degeneration (AMD) causes much more handicaps for patients than unilateral neovascular AMD. Although several AMD-susceptibility genes have been evaluated for their associations to bilaterality, genome-wide association study (GWAS) on bilaterality has been rarely reported. In the present study, we performed GWAS using neovascular AMD cases in East Asian. The discovery stage compared 581,252 single nucleotide polymorphisms (SNPs) between 803 unilateral and 321 bilateral Japanese cases but no SNP showed genome-wide significance, while SNPs at six regions showed P-value < 1.0 × 10-5, STON1-GTF2A1L/LHCGR/FSHR, PLXNA1, CTNNA3, ARMS2/HTRA1, LHFP, and FLJ38725. The first replication study for these six regions comparing 36 bilateral and 132 unilateral Japanese cases confirmed significant associations of rs4482537 (STON1-GTF2A1L/LHCGR/FSHR), rs2284665 (ARMS2/HTRA1), and rs8002574 (LHFP) to bilaterality. In the second replication study comparing 24 bilateral and 78 unilateral cases from Singapore, rs4482537 (STON1-GTF2A1L/LHCGR/FSHR) only showed significant association. Meta-analysis of discovery and replication studies confirmed genome-wide level significant association (P = 2.61 × 10-9) of rs4482537 (STON1-GTF2A1L/LHCGR/FSHR) and strong associations (P = 5.76 × 10-7 and 9.73 × 10-7, respectively) of rs2284665 (ARMS2/HTRA1) and rs8002574 (LHFP). Our GWAS for neovascular AMD bilaterality found new genetic loci STON1-GTF2A1L/LHCGR/FSHR and confirmed the previously reported association of ARMS2/HTRA1.

Detection of Myopic Choroidal Neovascularization Using Optical Coherence Tomography Angiography.

PURPOSE: To assess whether optical coherence tomography angiography (OCTA) can be used as an alternative to conventional fundus fluorescein angiography (FFA) for the detection of myopic choroidal neovascularization (CNV). DESIGN: Validity and reliability analysis. METHODS: Twenty-eight eyes of 26 consecutive Japanese patients with exudative lesions associated with pathologic myopia were included in this institutional study. Myopic CNV was detected in 23 eyes of 22 patients; 5 eyes exhibited simple hemorrhage. The main outcome measure was CNV detection by OCTA and FFA. The CNV area was individually measured by FFA and OCTA. Intraclass correlation coefficients (ICCs) for the CNV area, independently measured by 2 investigators using OCTA and FFA, were determined. RESULTS: OCTA images with sufficient quality for CNV assessment were obtained for 17 eyes with CNV and 4 without. FFA alone detected CNV in all 17 eyes, while OCTA alone detected CNV in 16 (94.1%). The 1 eye for which CNV was not detected by OCTA exhibited a 0.01 mm(2) area on FFA. Both FFA and OCTA did not detect CNV in eyes with simple hemorrhage. The mean CNV areas on FFA and OCTA were 0.59 ± 0.56 mm(2) and 0.51 ± 0.55 mm(2), respectively; the 2 values were significantly correlated (P < .001, r = .86). The ICC (2, 1) values for FFA and OCTA were 0.944 and 0.997, respectively. CONCLUSIONS: Our results indicate that OCTA can detect most myopic CNVs if high-quality images are acquired and can preclude the requirement for FFA in these settings.

Pachychoroid neovasculopathy and age-related macular degeneration.

Pachychoroid neovasculopathy is a recently proposed clinical entity of choroidal neovascularization (CNV). As it often masquerades as neovascular age-related macular degeneration (AMD), it is currently controversial whether pachychoroid neovasculopathy should be distinguished from neovascular AMD. This is because its characteristics have yet to be well described. To estimate the relative prevalence of pachychoroid neovasculopathy in comparison with neovascular AMD and to investigate the phenotypic/genetic differences of the two diseases, we evaluated 200 consecutive Japanese patients who agreed to participate in the genetic study and diagnosed with pachychoroid neovasculopathy or neovascular AMD. Pachychoroid neovasculopathy was observed in 39 individuals (19.5%), which corresponds to one fourth of neovascular AMD. Patients with pachychoroid neovasculopathy were significantly younger (p = 5.1 × 10(-5)) and showed a greater subfoveal choroidal thickness (p = 3.4 × 10(-14)). Their genetic susceptibility to AMD was significantly lower than that of neovascular AMD; ARMS2 rs10490924 (p = 0.029), CFH rs800292 (p = 0.013) and genetic risk score calculated from 11 AMD susceptibility genes (p = 3.8 × 10(-3)). Current results implicate that the etiologies of the two conditions must be different. Thus, it will be necessary to distinguish these two conditions in future studies.

Calcium, ARMS2 genotype, and Chlamydia pneumoniae infection in early age-related macular degeneration: a multivariate analysis from the Nagahama study.

Although various risk factors have been identified for the development of age-related macular degeneration (AMD), risk factors of early AMD have been relatively under studied. We aimed to investigate AMD risk factors by evaluating multiple factors in association with large drusen, an important component of AMD, simultaneously. In a community-based cross-sectional survey in Japan, 971 large drusen cases and 3,209 controls were compared for 65 variables, including systemic, environmental, and genetic factors. The association and the effect size of each factor were evaluated with logistic regression analysis using a backward-elimination approach. Multivariate analyses identified a significant association in serum calcium level (odds ratio [OR] = 0.932, P = 1.05 × 10(-3)), ARMS2 A69S (rs10490924) genotype (OR = 1.046, P < 0.001), Chlamydia pneumoniae IgG (OR = 1.020, P = 0.0440), and age (OR = 1.013, P < 0.001) for large drusen. Hypocalcemia was observed in 7.2% of large drusen cases and in 5.5% of controls (P = 0.0490). C. pneumoniae infections was more frequent in large drusen cases (56.4%) than in controls (51.7%, P = 0.00956). These results suggest that calcium, ARMS2 genotype, C. pneumonia infection, and age are significant factors in the development of the early stages of AMD.

One-year result of aflibercept treatment on age-related macular degeneration and predictive factors for visual outcome.

PURPOSE: To investigate the efficacy of periodic injection of aflibercept in each subtype of age-related macular degeneration (AMD) and to explore the predictive factors for visual outcome in clinical settings. DESIGN: Prospective nonrandomized interventional case series. METHODS: Patients with AMD were recruited and were administered aflibercept injections once a month for 3 months followed by once every 2 months for 8 months. The logarithm of the minimal angle of resolution (logMAR) at 12 months and improvement of vision from baseline were compared among polypoidal choroidal vasculopathy (PCV), retinal angiomatous proliferation (RAP), and typical AMD. Regression rate of polypoidal lesions was assessed. We also performed regression analysis with logMAR at 12 months as the dependent variable. RESULTS: The study sample consisted of 98 patients: 46 had typical AMD, 42 had PCV, and 10 had RAP. Mean logMAR improved from 0.36 to 0.21 in 12 months. While there was no difference in visual improvement between typical AMD and PCV, final logMAR was better in PCV (0.32 ± 0.09 vs 0.08 ± 0.04, P = .016). Thirty-nine PCV patients underwent follow-up angiography, and regression of polyps was observed in 27 cases (69.2%). Multiple regression analysis showed that the presence of external limiting membrane (ELM), smaller greatest linear dimension, and the presence of polypoidal lesion were associated with better visual outcome (R(2) = 0.53, P = 2.73 × 10(-14)). CONCLUSIONS: Periodic injection of aflibercept is effective for PCV as well as for typical AMD. The statuses of ELM, greatest linear dimension, and polypoidal lesion are predictive for visual outcome.

The Contribution of Genetic Architecture to the 10-Year Incidence of Age-Related Macular Degeneration in the Fellow Eye.

PURPOSE: To correlate a genetic risk score based on age-related macular degeneration (AMD) susceptibility genes with the risk of AMD in the second eye. METHODS: This is a retrospective, open cohort study consisting of 891 unilateral AMD patients, who were followed for at least 12 months and recruited from three institutes. DNAs were genotyped using Illumina OmniExpress, HumanOmni2.5-8, and/or HumanExome. Survival analyses and Cox proportional hazard models were used to examine the association between 11 AMD susceptibility genes and the duration until second-eye involvement in 499 samples from Kyoto University, which were replicated in two other cohorts. Genetic risk score (GRS) was also evaluated. RESULTS: The ARMS2 rs10490924 recessive model (hazard ratio [HR]meta = 2.04; Pmeta = 3.4 × 10⁻³) and CFH rs800292 additive model (HRmeta = 1.77; Pmeta = 0.013) revealed significant associations with second-eye involvement. The dominant model of TNFRSF10A rs13278062, VEGFA rs943080, and CFI rs4698775 showed consistent effects across three datasets (I² = 0%; HRmeta = 1.46, 1.30, 1.51, respectively). The GRS using these five single nucleotide polymorphisms (SNPs) was also significantly associated (HRmeta [per score] = 2.42; P = 2.2 × 10⁻5; I² = 0%). After 10 years from the first visit, the patients within the top 10% by GRS showed a 51% hazard rate, in contrast to 2.3% among patients within the lowest 10% by GRS. CONCLUSIONS: We demonstrated that the GRS using ARMS2, CFH, TNFRSF10A, VEGFA, and CFI was significantly associated with second-eye involvement. Genetic risk has high predictive ability for second-eye involvement of AMD.

Central blood pressure relates more strongly to retinal arteriolar narrowing than brachial blood pressure: the Nagahama Study.

OBJECTIVES: Although central blood pressure (BP) is considered to be more closely associated with large arterial remodeling and cardiovascular outcomes than brachial BP, few studies have investigated these associations with changes in small arteries. As morphological changes in retinal vessels might be associated with cardiovascular outcomes, we conducted a cross-sectional study to investigate the association of central BP with retinal vessel caliber. METHODS: The study included 8054 Japanese participants. Central BP was estimated by the radial arterial waveform by calibrating brachial BP. Central retinal arteriolar equivalent (CRAE) was computationally measured using fundus photography. RESULTS: CRAE was most strongly associated with central SBP (r = -0.324, P < 0.001), followed by DBP (r = -0.292, P < 0.001) and central pulse pressure (PP; r = -0.226, P < 0.001). The correlation coefficient between SBP and CRAE was significantly greater in central SBP than in brachial SBP (r = -0.300, P < 0.001). After adjustment for possible covariates, brachial SBP (ß = -0.221, P < 0.001) and central SBP (ß = -0.239, P < 0.001) were independently associated with CRAE. Further, higher brachial SBP (ß = -0.226, P < 0.001) and smaller PP amplification (ß = 0.092, P < 0.001) were identified as independent determinants of narrowing of CRAE in the same equation, which indicated the superiority of central BP. Central BP-determined hypertensive individuals had a significantly narrower CRAE independent of brachial BP (central/brachial: hypertension/hypertension 121.4 ±â€Š11.5, hypertension/normotension 120.9 ±â€Š11.2, normotension/hypertension 125.1 ±â€Š11.9, normotension/normotension 128.1 ±â€Š11.5 µm). CONCLUSION: Central BP was more closely associated with the narrowing of CRAE than brachial BP. Slight increases in central BP might be involved in the morphological changes in small retinal arteries, even in individuals with optimal brachial BP.

Identification of myopia-associated WNT7B polymorphisms provides insights into the mechanism underlying the development of myopia.

Myopia can cause severe visual impairment. Here, we report a two-stage genome-wide association study for three myopia-related traits in 9,804 Japanese individuals, which was extended with trans-ethnic replication in 2,674 Chinese and 2,690 Caucasian individuals. We identify WNT7B as a novel susceptibility gene for axial length (rs10453441, Pmeta=3.9 × 10(-13)) and corneal curvature (Pmeta=2.9 × 10(-40)) and confirm the previously reported association between GJD2 and myopia. WNT7B significantly associates with extreme myopia in a case-control study with 1,478 Asian patients and 4,689 controls (odds ratio (OR)meta=1.13, Pmeta=0.011). We also find in a mouse model of myopia downregulation of WNT7B expression in the cornea and upregulation in the retina, suggesting its possible role in the development of myopia.