Correlation between metamorphopsia and disorganization of the retinal inner layers in eyes with diabetic macular edema.

PURPOSE: To investigate factors associated with the severity of metamorphopsia secondary to diabetic macular edema (ME) by evaluating optical coherence tomography (OCT) parameters including disorganization of the retinal inner layers (DRIL). METHODS: We retrospectively reviewed medical records of 37 eyes of 37 consecutive patients with diabetic ME or resolved diabetic ME, who underwent spectral-domain OCT examination and metamorphopsia assessment with M-CHARTS on the same day between November 2017 and March 2018. Age, sex, visual acuity, lens status, treatment history, and factors analyzed on OCT examination including DRIL length were evaluated in association with M-CHARTS scores. RESULTS: Metamorphopsia was detected in 20 eyes (54%). The patients with metamorphopsia were relatively older than those without it (P = 0.060), and DRIL length was relatively longer in eyes with metamorphopsia (P = 0.065), while visual acuity was significantly better in eyes without metamorphopsia (P = 0.048). In correlation analyses to the severity of metamorphopsia, the DRIL length was the only OCT parameter associated with the M-CHARTS score (P = 0.035), while age, visual acuity, and ME were not significantly associated with the severity of metamorphopsia (P = 0.051, 0.060, and 0.344, respectively). CONCLUSION: The DRIL length was significantly associated with the severity of metamorphopsia secondary to diabetic ME. The inner retinal layer plays a key role in the development of metamorphopsia in eyes with diabetic ME. Metamorphopsia should be carefully considered when treating diabetic ME since its severity has been found to be independent of visual acuity and ME status.

Floating flap of internal limiting membrane in myopic macular hole surgery.

PURPOSE: To evaluate the surgical results of macular hole (MH) in patients with high myopia treated with pars plana vitrectomy (PPV) leaving the internal limiting membrane (ILM) flap floating in vitreous fluid at the edge of the MH. METHODS: Nine highly myopic eyes with MH of nine consecutive patients who underwent PPV were retrospectively evaluated. Three eyes were accompanied by retinal detachment (RD). ILM peeling was performed around the MH and some part of the ILM flap was left attached to the edge of the MH. Further manipulation of the ILM flap to cover the MH was not performed. Fluid-gas exchange was performed to the retinal vessel arcade level. Patients maintained a face down position for 3 to 7 days postoperatively. RESULTS: Complete MH closure was confirmed using optical coherence tomography in all eyes and three eyes with RD showed reattachment of the retina after the initial surgery. Visual acuity significantly improved (P = 0.02) and no eyes experienced MH reopening or RD occurrence during the follow-up period of 8.33 ± 3.61 months after the surgery. CONCLUSIONS: MH with or without RD in highly myopic eyes could be successfully treated with PPV leaving ILM flap floating in vitreous fluid at the edge of the MH. After the ILM peeling, further manipulation of the ILM flap to cover the MH would not be necessary for the treatment of MH in high myopia.

Disorganization of the Retinal Inner Layers after Anti-VEGF Treatment for Macular Edema due to Branch Retinal Vein Occlusion.

PURPOSE: To evaluate the association between disorganization of the retinal inner layers (DRIL) and visual acuity (VA) after anti-VEGF treatment for macular edema (ME) due to branch retinal vein occlusion (BRVO). METHODS: Sixty eyes of 60 patients were retrospectively investigated. Baseline characteristics and factors analyzed on optical coherence tomography (OCT) examination at the final visit were evaluated in association with VA at the final visit. RESULTS: DRIL was detected in 39 eyes at the final visit. The central subfield thickness was significantly higher in the eyes with DRIL. While DRIL length at the final visit showed a significant association with final VA on univariable analysis, only age and ellipsoid zone disruption on OCT at the final visit were found to be significantly associated with VA on multivariable analysis. CONCLUSIONS: DRIL had only a minor role in determining VA after anti-VEGF treatment for ME due to BRVO.

Diagnostic genetic testing for patients with bilateral optic neuropathy and comparison of clinical features according to OPA1 mutation status.

PURPOSE: Inherited optic neuropathy is genetically heterogeneous, and genetic testing has an important role in risk assessment and counseling. The purpose of this study is to determine the prevalence and spectrum of mutations in a group of patients referred for genetic testing to a tertiary center in the United States. In addition, we compared the clinical features of patients with and without mutations in OPA1, the gene most commonly involved in dominantly inherited optic atrophy. METHODS: Clinical data and genetic testing results were reviewed for 74 unrelated, consecutive patients referred with a history of insidious, relatively symmetric, bilateral visual loss secondary to an optic neuropathy. Patients were evaluated for disease-causing variants in OPA1, OPA3, WFS1, and the entire mitochondrial genome with DNA sequencing and copy number variation (CNV) testing. RESULTS: Pathogenic DNA variants were found in 25 cases, with the majority (24 patients) located in OPA1. Demographics, clinical history, and clinical features for the group of patients with mutations in OPA1 were compared to those without disease-causing variants. Compared to the patients without mutations, cases with mutations in OPA1 were more likely to have a family history of optic nerve disease (p = 0.027); however, 30.4% of patients without a family history of disease also had mutations in OPA1. OPA1 mutation carriers had less severe mean deviation and pattern standard deviation on automated visual field testing than patients with optic atrophy without mutations in OPA1 (p<0.005). Other demographic and ocular features were not statistically significantly different between the two groups, including the fraction of patients with central scotomas (42.9% of OPA1 mutation positive and 66.0% of OPA1 mutation negative). CONCLUSIONS: Genetic testing identified disease-causing mutations in 34% of referred cases, with the majority of these in OPA1. Patients with mutations in OPA1 were more likely to have a family history of disease; however, 30.4% of patients without a family history were also found to have an OPA1 mutation. This observation, as well as similar frequencies of central scotomas in the groups with and without mutations in OPA1, underscores the need for genetic testing to establish an OPA1 genetic diagnosis.

Genome-wide association study identifies ZFHX1B as a susceptibility locus for severe myopia.

Severe myopia (defined as spherical equivalent < -6.0 D) is a predominant problem in Asian countries, resulting in substantial morbidity. We performed a meta-analysis of four genome-wide association studies (GWAS), all of East Asian descent totaling 1603 cases and 3427 controls. Two single nucleotide polymorphisms (SNPs) (rs13382811 from ZFHX1B [encoding for ZEB2] and rs6469937 from SNTB1) showed highly suggestive evidence of association with disease (P < 1 × 10(-7)) and were brought forward for replication analysis in a further 1241 severe myopia cases and 3559 controls from a further three independent sample collections. Significant evidence of replication was observed, and both SNP markers surpassed the formal threshold for genome-wide significance upon meta-analysis of both discovery and replication stages (P = 5.79 × 10(-10), per-allele odds ratio (OR) = 1.26 for rs13382811 and P = 2.01 × 10(-9), per-allele OR = 0.79 for rs6469937). The observation at SNTB1 is confirmatory of a very recent GWAS on severe myopia. Both genes were expressed in the human retina, sclera, as well as the retinal pigmented epithelium. In an experimental mouse model for myopia, we observed significant alterations to gene and protein expression in the retina and sclera of the unilateral induced myopic eyes for Zfhx1b and Sntb1. These new data advance our understanding of the molecular pathogenesis of severe myopia.

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.

Two-year visual outcome of polypoidal choroidal vasculopathy treated with photodynamic therapy combined with intravitreal injections of ranibizumab.

PURPOSE: To investigate the 2-year outcomes of photodynamic therapy (PDT) combined with intravitreal injections of ranibizumab for polypoidal choroidal vasculopathy (PCV). METHODS: Ninety-five eyes with subfoveal PCV treated with combined therapy were followed for ≥24 months. The association between visual outcomes and single nucleotide polymorphisms in ARMS2 A69S and CFH I62V genes were examined without adjusting for multiple comparisons. RESULTS: Visual acuity (VA) improvement was observed at month 3 (P = 0.009). The improvement persisted until month 12 (P = 0.003), when VA began the decline back to baseline values at month 24. To investigate the factors associated with VA reduction during the second year, patients were divided into those with and those without a second-year VA reduction. Both patients with and without a second-year VA reduction showed similar VA changes over the first year. The first-year VA improvement was not predictive of the VA decline over the second year. Genetic analyses showed no significant difference in the frequency of the A risk allele of CFH I62V between patients with and without a second-year VA reduction. However, patients with the T risk allele of A69S had a higher rate of recurrence and were more likely to experience a reduction in VA during the second year when compared to patients without (P = 0.020 and P = 0.048, respectively). CONCLUSIONS: PDT combined therapy resulted in significant visual recovery in the first year, which was not sustained during the second year. VA reduction in the second year was affected by genetic factors.

Genetic variants on chromosome 1q41 influence ocular axial length and high myopia.

As one of the leading causes of visual impairment and blindness, myopia poses a significant public health burden in Asia. The primary determinant of myopia is an elongated ocular axial length (AL). Here we report a meta-analysis of three genome-wide association studies on AL conducted in 1,860 Chinese adults, 929 Chinese children, and 2,155 Malay adults. We identified a genetic locus on chromosome 1q41 harboring the zinc-finger 11B pseudogene ZC3H11B showing genome-wide significant association with AL variation (rs4373767, ß = -0.16 mm per minor allele, P(meta) =2.69 × 10(-10)). The minor C allele of rs4373767 was also observed to significantly associate with decreased susceptibility to high myopia (per-allele odds ratio (OR) =0.75, 95% CI: 0.68-0.84, P(meta) =4.38 × 10(-7)) in 1,118 highly myopic cases and 5,433 controls. ZC3H11B and two neighboring genes SLC30A10 and LYPLAL1 were expressed in the human neural retina, retinal pigment epithelium, and sclera. In an experimental myopia mouse model, we observed significant alterations to gene and protein expression in the retina and sclera of the unilateral induced myopic eyes for the murine genes ZC3H11A, SLC30A10, and LYPLAL1. This supports the likely role of genetic variants at chromosome 1q41 in influencing AL variation and high myopia.

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.

Long-term effect of intravitreal injection of anti-VEGF agent for visual acuity and chorioretinal atrophy progression in myopic choroidal neovascularization.

PURPOSE: To investigate the long-term visual prognosis and progression of chorioretinal atrophy in patients with myopic choroidal neovascularization (mCNV) treated with intravitreal injections of bevacizumab. METHODS: Hospital-based, retrospective, cross-sectional study. In total, 22 patients (22 eyes) with treatment-naïve mCNV who underwent intravitreal injection of bevacizumab and were followed up for more than 48 months were investigated. Visual acuity and fundus photographs before and 1, 2, 3, and 4 years after initial treatment in the clinics were compared and judged if chorioretinal atrophy (CRA) developed/enlarged or remained unchanged. The influence of clinical characteristics including age, sex, axial length, baseline visual acuity, CNV area, CNV location, and number of injections were investigated with logistic regression analysis. RESULTS: Mean logarithm of the minimum angle of resolution (logMAR) improved from 0.76 to 0.52 (P < .01), 0.48 (P < .01), and 0.54 (P < .05) after 1, 2, and 3 years, respectively. The effect slightly declined to marginally non-significant levels after 4 years (logMAR, 0.59; P = .07). CRA developed or enlarged in nine cases (41 %) in 1 year, reaching 16 cases (73 %) at the final visit. Those without CRA enlargement achieved better visual improvement. None of the aforementioned patient characteristics significantly affected CRA. CONCLUSIONS: Anti-VEGF therapy for mCNV is effective for vision improvement in the long term. On the other hand, development or enlargement of CRA frequently occurred, and affected visual improvement. Strategies to manage atrophy should be the next step in achieving better visual outcome upon mCNV treatment.

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.

Large scale international replication and meta-analysis study confirms association of the 15q14 locus with myopia. The CREAM consortium.

Myopia is a complex genetic disorder and a common cause of visual impairment among working age adults. Genome-wide association studies have identified susceptibility loci on chromosomes 15q14 and 15q25 in Caucasian populations of European ancestry. Here, we present a confirmation and meta-analysis study in which we assessed whether these two loci are also associated with myopia in other populations. The study population comprised 31 cohorts from the Consortium of Refractive Error and Myopia (CREAM) representing 4 different continents with 55,177 individuals; 42,845 Caucasians and 12,332 Asians. We performed a meta-analysis of 14 single nucleotide polymorphisms (SNPs) on 15q14 and 5 SNPs on 15q25 using linear regression analysis with spherical equivalent as a quantitative outcome, adjusted for age and sex. We calculated the odds ratio (OR) of myopia versus hyperopia for carriers of the top-SNP alleles using a fixed effects meta-analysis. At locus 15q14, all SNPs were significantly replicated, with the lowest P value 3.87 × 10(-12) for SNP rs634990 in Caucasians, and 9.65 × 10(-4) for rs8032019 in Asians. The overall meta-analysis provided P value 9.20 × 10(-23) for the top SNP rs634990. The risk of myopia versus hyperopia was OR 1.88 (95 % CI 1.64, 2.16, P < 0.001) for homozygous carriers of the risk allele at the top SNP rs634990, and OR 1.33 (95 % CI 1.19, 1.49, P < 0.001) for heterozygous carriers. SNPs at locus 15q25 did not replicate significantly (P value 5.81 × 10(-2) for top SNP rs939661). We conclude that common variants at chromosome 15q14 influence susceptibility for myopia in Caucasian and Asian populations world-wide.

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.

Genetic variants in pigment epithelium-derived factor influence response of polypoidal choroidal vasculopathy to photodynamic therapy.

PURPOSE: To investigate whether photodynamic therapy (PDT) outcomes of polypoidal choroidal vasculopathy (PCV) are related to baseline clinical characteristics, smoking history, or genetic factors by analyzing the retreatment-free period after the first PDT. DESIGN: Retrospective cohort study. PARTICIPANTS: The study consisted of 167 patients with PCV who underwent PDT as their first treatment. METHODS: We targeted 638 single nucleotide polymorphisms (SNPs) in 42 possible susceptible genes for age-related macular degeneration to evaluate their relation to the effectiveness of PDT for PCV. For this evaluation, we used 2 methods: (1) survival analysis, with the retreatment-free period as the target; and (2) logistic regression test between the need for additional therapy within 3 months after the first PDT and the genotypes, with age, gender, smoking status, and greatest linear dimension (GLD) at baseline as covariates. The contributions of smoking status and GLD at baseline for the retreatment-free period also were evaluated. Contributions of these factors to visual prognosis were evaluated for 1 year after PDT. MAIN OUTCOME MEASURES: Retreatment-free period after the first PDT for PCV. Secondary outcome measures included correlation of the susceptible factor to the retreatment requirement within the 3-month follow-up and the mean visual acuity change. RESULTS: In survival analyses, SERPINF1 rs12603825 showed a significant association with the retreatment-free period after the first PDT; those patients homozygous for the minor allele A of rs12603825 received additional treatment after PDT within significantly shorter times than those with other genotypes (P = 0.0038). There was no significant difference in the retreatment-free period between baseline GLD and smoking status. Retreatment within 3 months was required significantly more in patients with the AA genotype, even after taking into consideration the effect of clinical characteristics (age, gender), baseline PCV lesion size, and smoking status (P = 0.0027). Furthermore, patients with the AA genotype showed significantly worse visual prognosis after PDT (P = 0.013). CONCLUSIONS: Pigment epithelium-derived factor (SERPINF1 or PEDF) polymorphisms may influence the initial response to and visual prognosis after PDT for PCV. Our findings may lead to understanding the pathogenesis of PCV and modification of the effects of PDT.

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.

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.

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.