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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

New loci and coding variants confer risk for age-related macular degeneration in East Asians.

Age-related macular degeneration (AMD) is a major cause of blindness, but presents differently in Europeans and Asians. Here, we perform a genome-wide and exome-wide association study on 2,119 patients with exudative AMD and 5,691 controls, with independent replication in 4,226 patients and 10,289 controls, all of East Asian descent, as part of The Genetics of AMD in Asians (GAMA) Consortium. We find a strong association between CETP Asp442Gly (rs2303790), an East Asian-specific mutation, and increased risk of AMD (odds ratio (OR)=1.70, P=5.60 × 10(-22)). The AMD risk allele (442Gly), known to protect from coronary heart disease, increases HDL cholesterol levels by 0.17 mmol l(-1) (P=5.82 × 10(-21)) in East Asians (n=7,102). We also identify three novel AMD loci: C6orf223 Ala231Ala (OR=0.78, P=6.19 × 10(-18)), SLC44A4 Asp47Val (OR=1.27, P=1.08 × 10(-11)) and FGD6 Gln257Arg (OR=0.87, P=2.85 × 10(-8)). Our findings suggest that some of the genetic loci conferring AMD susceptibility in East Asians are shared with Europeans, yet AMD in East Asians may also have a distinct genetic signature.

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.

Comprehensive replication of the relationship between myopia-related genes and refractive errors in a large Japanese cohort.

PURPOSE: We investigated the association between refractive error in a Japanese population and myopia-related genes identified in two recent large-scale genome-wide association studies. METHODS: Single-nucleotide polymorphisms (SNPs) in 51 genes that were reported by the Consortium for Refractive Error and Myopia and/or the 23andMe database were genotyped in 3712 healthy Japanese volunteers from the Nagahama Study using HumanHap610K Quad, HumanOmni2.5M, and/or HumanExome Arrays. To evaluate the association between refractive error and recently identified myopia-related genes, we used three approaches to perform quantitative trait locus analyses of mean refractive error in both eyes of the participants: per-SNP, gene-based top-SNP, and gene-based all-SNP analyses. Association plots of successfully replicated genes also were investigated. RESULTS: In our per-SNP analysis, eight myopia gene associations were replicated successfully: GJD2, RASGRF1, BICC1, KCNQ5, CD55, CYP26A1, LRRC4C, and B4GALNT2.Seven additional gene associations were replicated in our gene-based analyses: GRIA4, BMP2, QKI, BMP4, SFRP1, SH3GL2, and EHBP1L1. The signal strength of the reported SNPs and their tagging SNPs increased after considering different linkage disequilibrium patterns across ethnicities. Although two previous studies suggested strong associations between PRSS56, LAMA2, TOX, and RDH5 and myopia, we could not replicate these results. CONCLUSIONS: Our results confirmed the significance of the myopia-related genes reported previously and suggested that gene-based replication analyses are more effective than per-SNP analyses. Our comparison with two previous studies suggested that BMP3 SNPs cause myopia primarily in Caucasian populations, while they may exhibit protective effects in Asian populations.

Choroidal neovascularization in eyes with choroidal vascular hyperpermeability.

PURPOSE: We describe the clinical and genetic characteristics of choroidal neovascularization (CNV) in eyes with choroidal vascular hyperpermeability (CVH). METHODS: This cross-sectional study consisted of 438 consecutive patients who underwent fluorescein and indocyanine green angiography for macular disease. We used the genotypes of 1576 age-related macular degeneration (AMD) cases and 3248 general population controls as reference groups for genetic association analyses. RESULTS: Of 871 eyes (438 patients) examined, CVH was found in 227 eyes (26.1%). Of these 227 eyes, 52 (22.6%) had CNV in the macular area. The proportion of patients with drusen and the choroidal thickness were not different between eyes with and without CNV, after adjusting for age (P = 0.21 and 0.95). Of the 52 eyes with CNV, 51 had type 1 CNV and only one eye had pure type 2 CNV. Of the 51 eyes with type 1 CNV, polypoidal lesions were observed in 17 eyes (33.3%). Genotype distributions of ARMS2 (A69S) and CFH (I62V) in patients with CVH and type 1 CNV significantly differed from those of AMD cases (P = 0.0014 and 0.0098, respectively), but not from general population controls (P = 0.33 and 0.82, statistical power of 88.5% and 72.9%, respectively). CONCLUSIONS: In patients with CVH, type 1 CNV may occur frequently and sometimes accompanies type 2 CNV or polypoidal lesions. In terms of ARMS2 and CFH, genetic background of patients with CVH and type 1 CNV was different from those with AMD, but rather similar to the general Japanese population.

Multimodal evaluation of macular function in age-related macular degeneration.

OBJECTIVE: To evaluate macular function using multimodality in eyes with age-related macular degeneration (AMD) at various stages. METHODS: Macular function in 20 control eyes (20 subjects), 17 eyes (17 patients) with large drusen, 18 eyes (18 patients) with drusenoid pigment epithelial detachment (PED), and 19 eyes (19 patients) with neovascular AMD was examined using a Landolt chart for visual acuity; retinal sensitivity was measured by microperimetry; and focal macular electroretinography (fmERG) was performed. In all of these eyes, retinal morphology was examined using optical coherence tomography. RESULTS: Eyes with neovascular AMD showed morphologic changes in the neurosensory retina as well as marked deterioration of macular function in all parameters measured with a Landolt chart, fmERG, and microperimetry. Eyes with large drusen showed only minimal morphologic changes in the neurosensory retina. In this large drusen group, although retinal sensitivity at the central point was significantly decreased (P = 0.0063), the other parameters of macular function were well preserved. In eyes with drusenoid PED, the structure of the neurosensory retina was well preserved, while the foveal thickness was significantly increased (P = 0.013). The macular function of these eyes was significantly deteriorated, with the VA, amplitude of the a-wave and b-wave, and retinal sensitivity being markedly decreased. In addition, the area of PED correlated with the latency of the a-wave and b-wave and with the retinal sensitivity within the central 4° or 8° region. CONCLUSION: Multimodal evaluation demonstrated a significant decrease in macular function in drusenoid PED and in neovascular 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.

Association between ZIC2, RASGRF1, and SHISA6 genes and high myopia in Japanese subjects.

PURPOSE: We investigated the association of genetic variations, which were identified recently in a large-scale genome-wide association study (GWAS) to confer risk of refractive error and common myopia in Caucasians, with high myopia in Japanese subjects. METHODS: The 5 single-nucleotide polymorphisms (SNPs) from the 5 genes TOX, RDH5, ZIC2, RASGRF1, and SHISA6, were genotyped in 1339 unrelated highly myopic Japanese patients and 3248 healthy Japanese participants in the Nagahama Study. In addition, genotypes were compared between high myopia patients without choroidal neovascularization (CNV) and patients with myopic CNV. RESULTS: Significant associations between rs8000973 near ZIC2 (P = 7.16 × 10(-7)), rs4778879 in RASGRF1 (P = 3.40 × 10(-7)), and rs2969180 in SHISA6 (P = 0.033) and high myopia were observed. Odds ratios (95% confidence intervals) were 1.33 (1.19-1.49), 0.78 (0.71-0.86), and 1.11 (1.01-1.22) for the rs8000973 C allele, rs4778879 A allele, and rs2969180 G allele, respectively. The effect of the rs2969180 allele G contrasted with that observed in the original report, whereas the effect of the other 2 SNPs agreed. Further analysis using controls with -1.0 diopter (D) ≤ spherical equivalent ≤ +1.0 D showed a significant association between ZIC2 and RASGRF1, but not SHISA6. Among the patients with high myopia, 516 had myopic CNV in either eye, while 823 patients did not have myopic CNV in eyes. No evaluated genes showed a significant association with the development of myopic CNV. CONCLUSIONS: ZIC2 and RASGRF1 are susceptibility genes, not only for common myopia, but also for high myopia.