Characteristics of pachychoroid neovasculopathy.

Recently, several research groups have reported a newly recognized clinical entity of choroidal neovascularization, termed pachychoroid neovasculopathy. However, its characteristics have yet to be well described. The purpose of this study was to investigate the clinical and genetic characteristics of pachychoroid neovasculopathy regardless of treatment modality. This study included 99 eyes of 99 patients with treatment-naïve pachychoroid neovasculopathy. Mean initial best-corrected visual acuity (BCVA) was 0.20 ± 0.32 logMAR, and did not change (P = 0.725) during follow-up period (mean ± SD, 37.0 ± 17.6 months). Subretinal hemorrhage (SRH) (≥ 4 disc areas in size) occurred in 20 eyes (20.2%) during follow-up. Age, initial BCVA, central retinal thickness, SRH (≥ 4 disc areas in size) and treatment (aflibercept monotherapy) were significantly associated with the final BCVA (P = 0.024, < 0.001, 0.031, < 0.001, and 0.029, respectively). Multiple regression analysis showed initial BCVA and presence of SRH to be significant predictors of final BCVA (both P < 0.001). Polypoidal lesions were more common in the SRH group than in the non-SRH group (85.0% vs 48.1%, P = 0.004). There was no significant difference in the frequency of the risk allele in ARMS2 A69S, CFH I62V, CFH Y402H between these groups (P = 0.42, 0.77, and 0.85, respectively). SRH (29.1% vs 9.1%, P = 0.014) and choroidal vascular hyperpermiability (65.5% vs 43.2%, P = 0.027) were seen more frequently in the polypoidal lesion (+) group than in the polypoidal lesion (-) group. There was considerable variation in lesion size and visual function in patients with pachychoroid neovasculopathy, and initial BCVA and presence of SRH at the initial visit or during the follow-up period were significant predictors of final BCVA.

Long Term Follow-Up of Prototheca keratitis: A Case Report.

BACKGROUND: Prototheca spp. are rare human pathogens, and only three cases of Prototheca keratitis have been reported. They were treated with anti-fungal drugs and surgical excision. Two of the three cases were successful, and the case of an immunocompromised patient was not successful. Thus, the best treatment of Prototheca keratitis is still undetermined, and further investigations are needed. The purpose of this report is to present our findings in a case of Prototheca keratitis that was successfully treated with topical medications without surgical excision. METHODS: This study was performed in accordance with the Declaration of Helsinki and was approved by the Ethics Committee of Hidaka Medical Center, Toyooka Hospital. A written informed consent was obtained from the patient before beginning the medical treatments. CASE REPORT: A 75-year-old man with a history of stage 4 prostate carcinoma and bilateral limbal stem cell deficiency had undergone keratoepithelioplasty on his left eye for the deficiency. Postoperatively, a greyish-white epithelial opacity was noted on the central cornea of his left eye, and he had been treated with topical fluorometholone and oral dexamethasone together with a therapeutic contact lens. Corneal smears and contact lens swabs were positive for Prototheca spp. He required a continuous treatment with amphotericin B (AMPH-B) ointment, topical fluconazole (FLCZ), and voriconazole (VRCZ). This treatment protocol was effective, but recurrences developed when his general condition worsened. CONCLUSION: Our findings indicate that Prototheca keratitis can be successfully treated but not cured with topical AMPH-B, FLCZ, and VRCZ without surgical treatment. However, recurrences can develop when the general condition of the patient worsens. Thus, continuous monitoring and treatment are necessary in cases of Prototheca keratitis.

Keratoconus-susceptibility gene identification by corneal thickness genome-wide association study and artificial intelligence IBM Watson.

Keratoconus is a common ocular disorder that causes progressive corneal thinning and is the leading indication for corneal transplantation. Central corneal thickness (CCT) is a highly heritable characteristic that is associated with keratoconus. In this two-stage genome-wide association study (GWAS) of CCT, we identified a locus for CCT, namely STON2 rs2371597 (P = 2.32 × 10-13), and confirmed a significant association between STON2 rs2371597 and keratoconus development (P = 0.041). Additionally, strong STON2 expression was observed in mouse corneal epithelial basal cells. We also identified SMAD3 rs12913547 as a susceptibility locus for keratoconus development using predictive analysis with IBM's Watson question answering computer system (P = 0.001). Further GWAS analyses combined with Watson could effectively reveal detailed pathways underlying keratoconus development.

Abnormal Outer Choroidal Vasculature in Amblyopia.

PURPOSE: Several studies have indicated morphological changes in the choroid in amblyopia cases. This study investigates whether choroidal vasculature was different among amblyopic and fellow eyes in unilateral amblyopia patients and healthy eyes, using en face images acquired via swept-source optical coherence tomography (SS-OCT). DESIGN: Prospective, observational case-control study. METHODS: This study included 14 consecutive patients with unilateral amblyopia and 22 age- and axial length-matched healthy eyes. Using SS-OCT, we obtained en face images of choroidal vasculature midway through the subfoveal inner and total choroid, corresponding to the vasculature of the choriocapillaris and Sattler's layer (inner choroid) and Haller's layer (outer choroid), respectively. We analyzed the en face images of the inner and outer choroidal vascular areas in 3 × 3 mm squares adjusted from 6 × 6 mm squares, using Littmann's magnification correction, after binarization of the images as a portion of the whole area. RESULTS: The outer choroidal vascular areas were larger in both amblyopic and fellow eyes than in healthy eyes (both P < 0.001), although there were no significant differences in inner (56.35 ± 2.46% and 56.27 ± 3.75%, respectively) or outer (61.49 ± 4.95% and 61.48 ± 3.73%, respectively) choroidal vascular area between amblyopic and fellow eyes (P=0.98 and 0.91, respectively). An outer choroidal vascular area of 59% was set as an appropriate cutoff value for distinguishing patients from controls. CONCLUSIONS: The outer choroidal vascular area was larger in both amblyopic eyes and fellow eyes compared to healthy eyes. Our findings may help clarify the etiology of amblyopia.

Five-year visual outcomes after anti-VEGF therapy with or without photodynamic therapy for polypoidal choroidal vasculopathy.

BACKGROUND/AIMS: To evaluate the 5-year visual and anatomical outcomes after anti-vascular endothelial growth factor (VEGF) therapy alone or in combination with photodynamic therapy (PDT), followed by pro re nata (PRN) anti-VEGF therapy with or without PDT, for polypoidal choroidal vasculopathy (PCV). METHODS: This retrospective, observational study included 61 consecutive patients with treatment-naïve symptomatic PCV who were followed for 5 years. Twenty eyes (20 patients) initially received PDT and intravitreal injection of ranibizumab (IVR), followed by a PRN regimen of anti-VEGF therapy with or without PDT (combination group), while 41 eyes (41 patients) initially received only IVR every 3 months, followed by a PRN regimen of anti-VEGF monotherapy (IVR group). Macular atrophy including the fovea was confirmed using colour fundus photography and spectral-domain optical coherence tomography. RESULTS: In both groups, the visual acuity (VA) at 1 year was better than the baseline VA, whereas the 3-year, 4-year and 5-year VA values were similar to the baseline VA. There was no significant difference in the 5-year VA, 5-year central retinal thickness and incidence of macular atrophy between the two groups (p=0.63, 0.72 and 0.06, respectively). In the combination group, the 5-year VA was correlated with the 5-year incidence of macular atrophy (p=0.02, r=0.51). CONCLUSIONS: A PRN regimen for PCV may have a limited effect for the long-term maintenance of improved VA. Macular atrophy may occur more frequently with combination therapy and is possibly associated with the 5-year VA. Thus, combination therapy should be carefully selected for patients susceptible to macular atrophy.

Pilot study assessing the structural changes in posttrabecular aqueous humor outflow pathway after trabecular meshwork surgery using swept-source optical coherence tomography.

This study evaluated the morphological change in aqueous humor outflow (AHO) pathways using swept-source optical coherence tomography (SS-OCT) volumetric scans in glaucoma patients before and after glaucoma surgery. In this prospective observational case series, 15 eyes (13 patients) with glaucoma were treated with 120-degree Trabectome or 360-degree suture trabeculotomy and followed up for 3 months. B-scan images of the posttrabecular AHO pathway were reconstructed and the pathway areas were evaluated, before and after surgery. Changes in posttrabecular AHO pathway were qualitatively classified as "increased", "non-significant change", and "decreased" on reconstructed B-scan images. Quantitative measurements of the posttrabecular AHO pathway areas were performed pre- and postoperatively. Factors associated with both qualitative and quantitative changes in AHO pathway were investigated. From 30 regions (15 nasal and 15 temporal regions) in the 15 eyes, AHO pathways were analyzable in 20 regions pre- and postoperatively. Qualitative assessments of the pathway changes were "increased" in 8 regions, "non-significant change" in 9 regions, and "decreased" in 3 regions. Quantitative assessments of the average pathway area did not change significantly (from 3155±1633 pixels preoperatively to 3212±1684 pixels postoperatively, P = 0.50). All parameters relating to intraocular pressure changes or the surgical location were not associated with postoperative AHO pathway change. The intrascleral AHO pathway could be well visualized in glaucoma patients pre- and postoperatively using swept-source optical coherence tomography. However, structural changes in the AHO pathway assessed by SS-OCT were not significant after trabecular-targeted glaucoma surgery. Functional assessments of AHO are needed in future studies.

CCDC102B confers risk of low vision and blindness in high myopia.

The incidence of high myopia is increasing worldwide with myopic maculopathy, a complication of myopia, often progressing to blindness. Our two-stage genome-wide association study of myopic maculopathy identifies a susceptibility locus at rs11873439 in an intron of CCDC102B (P = 1.77 × 10-12 and Pcorr = 1.61 × 10-10). In contrast, this SNP is not significantly associated with myopia itself. The association between rs11873439 and myopic maculopathy is further confirmed in 2317 highly myopic patients (P = 2.40 × 10-6 and Pcorr = 1.72 × 10-4). CCDC102B is strongly expressed in the retinal pigment epithelium and choroids, where atrophic changes initially occur in myopic maculopathy. The development of myopic maculopathy thus likely exhibits a unique background apart from the development of myopia itself; elucidation of the roles of CCDC102B in myopic maculopathy development may thus provide insights into preventive methods for blindness in patients with high myopia.

CFH and VIPR2 as susceptibility loci in choroidal thickness and pachychoroid disease central serous chorioretinopathy.

Central serous chorioretinopathy (CSC) is a common disease affecting younger people and may lead to vision loss. CSC shares phenotypic overlap with age-related macular degeneration (AMD). As recent studies have revealed a characteristic increase of choroidal thickness in CSC, we conducted a genome-wide association study on choroidal thickness in 3,418 individuals followed by TaqMan assays in 2,692 subjects, and we identified two susceptibility loci: CFH rs800292, an established AMD susceptibility polymorphism, and VIPR2 rs3793217 (P = 2.05 × 10-10 and 6.75 × 10-8, respectively). Case-control studies using patients with CSC confirmed associations between both polymorphisms and CSC (P = 5.27 × 10-5 and 5.14 × 10-5, respectively). The CFH rs800292 G allele is reportedly a risk allele for AMD, whereas the A allele conferred risk for thicker choroid and CSC development. This study not only shows that susceptibility genes for CSC could be discovered using choroidal thickness as a defining variable but also, deepens the understanding of differences between CSC and AMD pathophysiology.

Prevalence of posterior staphyloma and factors associated with its shape in the Japanese population.

Myopia is increasing rapidly worldwide. We performed a cross-sectional study to investigate the prevalence of posterior staphyloma, a complication of myopia, and its shape characteristics in relation to age, sex, and axial length (AL) in a Japanese community-based cohort. The right eyes of 3748 participants who underwent fundus photography and optical coherence tomography (OCT) examination were evaluated. Posterior staphyloma prevalence was evaluated using fundus photographs and OCT images. Furthermore, fundus shapes were analyzed by measuring local fundus curvatures on 6 mm cross-line OCT images at intervals of 1 µm. The mean and variance of the curvatures were calculated to represent the fundus shape of each eye for investigation of the relationship between fundus curvature and age, sex, and AL. Seventy-seven eyes (2.05%) had posterior staphyloma. The mean and variance of the fundus curvatures were significantly greater in women than in men and became greater with age, suggesting that the shape of the staphyloma was steeper and less smooth in women and elderly subjects. AL and mean curvature showed a significant correlation (P = 2 × 10-16, R = 0.480), which was significantly affected by age (P < 2 × 10-16). Quantitative analysis of fundus shapes was useful for statistical analysis of posterior staphyloma in relation to age, sex, and AL.

Genome-wide association study identifies seven novel susceptibility loci for primary open-angle glaucoma.

Primary open-angle glaucoma (POAG) is the leading cause of irreversible blindness worldwide for which 15 disease-associated loci had been discovered. Among them, only 5 loci have been associated with POAG in Asians. We carried out a genome-wide association study and a replication study that included a total of 7378 POAG cases and 36 385 controls from a Japanese population. After combining the genome-wide association study and the two replication sets, we identified 11 POAG-associated loci, including 4 known (CDKN2B-AS1, ABCA1, SIX6 and AFAP1) and 7 novel loci (FNDC3B, ANKRD55-MAP3K1, LMX1B, LHPP, HMGA2, MEIS2 and LOXL1) at a genome-wide significance level (P < 5.0×10-8), bringing the total number of POAG-susceptibility loci to 22. The 7 novel variants were subsequently evaluated in a multiethnic population comprising non-Japanese East Asians (1008 cases, 591 controls), Europeans (5008 cases, 35 472 controls) and Africans (2341 cases, 2037 controls). The candidate genes located within the new loci were related to ocular development (LMX1B, HMGA2 and MAP3K1) and glaucoma-related phenotypes (FNDC3B, LMX1B and LOXL1). Pathway analysis suggested epidermal growth factor receptor signaling might be involved in POAG pathogenesis. Genetic correlation analysis revealed the relationships between POAG and systemic diseases, including type 2 diabetes and cardiovascular diseases. These results improve our understanding of the genetic factors that affect the risk of developing POAG and provide new insight into the genetic architecture of POAG in Asians.

Association of Bruch's membrane opening and optic disc morphology to axial length and visual field defects in eyes with primary open-angle glaucoma.

PURPOSE: To examine the morphology of Bruch's membrane opening (BMO), optic disc, and peripapillary atrophy (PPA) by scanning laser ophthalmoscopy (SLO) and spectral-domain optical coherence tomography (SD-OCT), and to determine their association with the axial length and visual field defects. METHODS: This was a cross-sectional study of 94 eyes of 56 subjects; 77 eyes were diagnosed with primary open-angle glaucoma and 17 eyes as normal. The margins of the optic disc were determined in the SLO images, and that of the BMO in the SD-OCT images. The ovality and area of the BMO and the optic disc were measured. The beta and gamma-PPA areas were also measured. The association of each parameter with the axial length and the mean deviation (MD) of the visual field tests was determined by generalized estimating equations (GEEs). RESULTS: The optic disc ovality was associated with the axial length and the MD (ß = -0.47, P = 7.6 × 10-4 and ß = 0.12, P = 0.040). The BMO ovality was not significantly associated with the axial length and the MD. The BMO area was associated with the axial length (ß = 0.30, P = 0.029). A larger BMO area was associated with a thinner BMO-based neuroretinal rim width (BMO-MRW) after adjustments for the MD (ß = -0.30, P = 2.1 × 10-4). The beta- and gamma-PPA areas were associated with the axial length (ß = 0.50, P = 7.4 × 10-5 and ß = 0.62, P = 4.2 × 10-6). CONCLUSIONS: The optic disc ovality was associated with both the axial length and MD, whereas BMO ovality was not. Attention should be paid to the influence of the axial length-related enlargement of the BMO.

Age-related change and sex difference over 60s in disc-fovea angle in Japanese population: the Nagahama Study.

PURPOSE: To analyse the disc-fovea angle (DFA) by age group and to compare sex differences in each age group in a large cohort population. METHODS: This community-based cross-sectional cohort study included 9682 eyes of 9682 volunteers (aged 30-75 years). We measured the DFA, which is the angle between a horizontal line and a line connecting the fovea with the centroid of an optic disc on fundus photographs of the right eye. We manually marked the fovea and surrounded the optic disc. The centroid of an optic disc and the DFA was automatically calculated using originally developed software. We compared the DFA between age groups in 10-year increments and investigated sex differences of DFA in each age group. RESULTS: Overall mean DFA was 6.32 ± 3.53°. The DFA of older subjects was significantly larger than that of younger subjects (p < 0.001). The DFA of women was larger than that of men in their 60s and 70s (p < 0.001 for both), but not in subjects in their 30s, 40s and 50s. CONCLUSION: Larger DFA in women than in men in their 60s and 70s suggests the possibility that age-related excyclo-shift occurs more easily in postmenopausal women compared to men of the same age.

Pachychoroid Geographic Atrophy: Clinical and Genetic Characteristics.

PURPOSE: To describe the clinical and genetic characteristics of pachychoroid geographic atrophy (GA) and to compare them with those of conventional GA associated with age-related macular degeneration (AMD). DESIGN: Observational case series. PARTICIPANTS: Ninety-two eyes of 92 consecutive patients with GA who underwent a full ophthalmologic examination, including best-corrected visual acuity measurement, spectral-domain OCT, and fundus autofluorescence imaging. Their blood samples were genotyped for the major AMD-associated single nucleotide polymorphisms. METHODS: Pachychoroid GA was diagnosed if all of the following criteria were met: (1) GA in either eye; (2) clinical and anatomic features of the pachychoroid phenotype, such as reduced fundus tessellation and dilated choroidal vessels; and (3) no drusen in both eyes. Drusen-related GA was defined as conventional GA. MAIN OUTCOMES AND MEASURES: Comparison of clinical and genetic characteristics between pachychoroid GA and conventional GA. RESULTS: Twenty-one patients (22.8%) were diagnosed with pachychoroid GA. These patients were significantly younger than those with conventional GA (mean age, 70.5 vs. 78.5 years; P < 0.001), had a smaller GA area (mean, 0.9 mm2 vs. 4.0 mm2; P < 0.001, age-adjusted), had greater subfoveal choroidal thickness (mean, 353.3 µm vs. 175.6 µm; P = 0.009, age-adjusted), and were more likely to have choroidal vascular hyperpermeability (47.4% vs. 6.3%; P < 0.001). Pseudodrusen were found in 40 of 71 patients (56.3%) with conventional GA, but not in any of the patients with pachychoroid GA. The risk allele in ARMS2 A69S was less common in patients with pachychoroid GA than in those with conventional GA (31.6% vs. 68.8%; P < 0.001). The genetic risk score calculated from the single nucleotide polymorphisms of 11 AMD susceptibility genes indicated that patients with pachychoroid GA were less genetically prone to AMD than the conventional GA group (P = 0.001). CONCLUSIONS: Pachychoroid GA was diagnosed in 23% of patients with GA. Differences in the phenotypic and genetic characteristics of pachychoroid GA and conventional GA were identified. These 2 conditions should be differentiated when considering prevention and therapeutic strategies.

Choriocapillaris flow deficit in Bietti crystalline dystrophy detected using optical coherence tomography angiography.

BACKGROUND/AIMS: This study aimed to evaluate blood flow in the choriocapillaris in patients with Bietti crystalline dystrophy (BCD) with CYP4V2 mutations using optical coherence tomography angiography (OCTA), and to explore the parameters associated with visual function. METHODS: This prospective case-series study included 13 eyes of 13 consecutive patients with BCD with CYP4V2 mutations and 20 healthy eyes. Using OCTA, we obtained en face images of blood flow in the choriocapillaris. The residual choriocapillaris area on en face images in a 10°×10° macular cube was manually measured and graded according to whether the choriocapillaris remained at the subfovea. We also investigated factors associated with visual acuity (VA) and the mean deviation (MD) value using a Humphrey field analyser with a 10-2 Swedish Interactive Threshold Algorithm standard program among OCTA-derived parameters. RESULTS: Choriocapillaris blood flow deficit was observed in 12 eyes (92%), whereas this was observed in none of healthy eyes. The adjusted residual choriocapillaris area was 2.47±1.79 mm2. The presence of the choriocapillaris at the subfovea was significantly correlated with VA and the MD value (P=0.006, r=0.71; P=0.04, r=-0.59, respectively). CONCLUSIONS: Using OCTA, choriocapillaris blood flow deficit could be observed in most patients with BCD with CYP4V2 mutations. The presence of the choriocapillaris at the subfovea was significantly correlated with visual function in these patients. Analysis of choriocapillaris blood flow using OCTA allows non-invasive assessment of the patient's state.

Association of retinal vessel calibers and longitudinal changes in arterial stiffness: the Nagahama study.

OBJECTIVE: Morphological change in retinal vessel calibers has been reported as a marker of cardiovascular risk, but its association with arterial stiffening, a possible factor relating retinal vessel sings and cardiovascular outcomes, is not clear. The study aim was to clarify the relationship between retinal small vessel calibers and longitudinal change in large arterial stiffness in a sample of the general population. METHODS: The study included 6720 Japanese participants (52.1 ±â€Š12.8 years). Central retinal arteriolar equivalent (CRAE) and venular equivalent were measured by fundus photography. Arterial stiffness was evaluated by brachial-to-ankle pulse wave velocity (baPWV) at baseline and at 5 years. RESULTS: The overall change in baPWV (ΔbaPWV) during a mean follow-up 1814 ±â€Š136 days was 41 ±â€Š131 cm/s (3.4 ±â€Š9.9%), and was significantly increased in individuals with narrower CRAE (quartiles: Q1, 4.3 ±â€Š10.6%; Q2, 3.3 ±â€Š10.0%; Q3, 3.1 ±â€Š9.3%; Q4, 3.1 ±â€Š9.7%, P = 0.001). No significant association was observed with central retinal venular equivalent. Multivariate analysis identified CRAE as a significant inverse determinant of ΔbaPWV (ß = -0.033, P = 0.006) independent of possible covariates including age, sex, blood pressure, and baseline baPWV. The association between CRAE and ΔbaPWV was prominent in a middle-aged (age Q2, ß = -0.078, P = 0.002), but not younger (Q1, P = 0.232) or older (Q3, P = 0.427; Q4, P = 0.542) participants. CONCLUSION: Narrower CRAE in middle-age was associated with the long-term risk of arteriosclerosis in a general population sample.

Predictive factors for corrective effect of inferior rectus recession for congenital superior oblique palsy.

PURPOSE: To identify preoperative factors associated with the surgical corrective effect of contralateral inferior rectus recession (IRR) for vertical deviation in patients with congenital superior oblique palsy (SOP). METHODS: This retrospective study included 20 treatment-naïve patients with unilateral congenital SOP (age range, 6-79 years) who underwent contralateral IRR according to our basic policy to select IRR for paretic eye fixation. The corrective effect (°/mm) of IRR was defined as the difference in the vertical deviation at the primary gaze position between before and 6-18 months after surgery per distance of recession. We also measured the preoperative vertical deviation at primary and secondary gaze positions, and vertical deviation with head-tilting, and calculated the difference in vertical deviation between these positions. We analyzed the correlation between the corrective effect of IRR and these study parameters. RESULTS: The mean corrective effect of IRR was 2.4 ± 1.6°/mm, which had a significant correlation with preoperative differences in vertical deviation between the primary gaze position and the downward (P = 0.004, r = -0.61) and contralateral gaze positions (P = 0.03, r = -0.48); and the presence of preoperative stereopsis (P = 0.02, r = -0.51). After excluding a statistical outlier, the correlation between the corrective effect and the difference between the primary and contralateral gaze positions was no longer significant (P = 0.07), while the other two relationships remained significant. CONCLUSIONS: Our findings suggest that preoperative differences in vertical deviation between the primary and downward gaze positions and the presence of preoperative stereopsis are important considerations prior to performing IRR for congenital SOP, particularly with paretic eye fixation.

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.

Choroidal Vasculature in Bietti Crystalline Dystrophy With CYP4V2 Mutations and in Retinitis Pigmentosa With EYS Mutations.

Purpose: We compare the choroidal vascular area between Bietti crystalline dystrophy (BCD) patients with CYP4V2 mutations, retinitis pigmentosa (RP) patients with EYS mutations, and normal controls, and investigate the correlation between choroidal vascular area and associated parameters. Methods: This prospective case-series study included consecutive nine eyes of nine BCD patients with CYP4V2 mutations (BCD group), 16 eyes of 16 RP patients with EYS mutations (EYS-RP group), and 16 eyes of 16 normal volunteers matched for age and axial length (control group). Using swept-source optical coherence tomography, we obtained en face images of the choroidal vasculature at the midpoint of the choriocapillaris layer-Sattler's layer (inner choroid) and Haller's layer (outer choroid). After binarization, we compared the inner and outer choroidal vascular areas among the three groups and identified associated factors. Results: The outer choroidal vascular area was 43.34 ± 5.76%, 53.73 ± 4.92%, and 52.80 ± 4.10% in the BCD, EYS-RP, and control groups, respectively. This value was significantly smaller in the BCD group than in the EYS-RP and control groups (P < 0.001 in both; no significant difference between the EYS-RP and control groups). In the BCD group, the outer choroidal vascular area was correlated strongly with the subfoveal inner choroidal thickness (P = 0.001, r = 0.91, respectively). The inner choroidal vasculature could not be identified in eight of nine eyes in the BCD group. Conclusions: The outer choroidal vascular narrowing might progress with the inner choroidal thinning in BCD, and the inner choroidal vasculature might be extinguished in advanced-stage BCD. Our findings may help to clarify the etiology of BCD.

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.

Association of SIX1/SIX6 locus polymorphisms with regional circumpapillary retinal nerve fibre layer thickness: The Nagahama study.

SIX1 and SIX6 are glaucoma susceptibility genes. Previous reports indicate that the single nucleotide polymorphism (SNP) rs33912345 in SIX6 is associated with inferior circumpapillary retinal nerve fibre layer (cpRNFL) thickness (cpRNFLT). Although the region of visual field defect in glaucoma patients is directly related to cpRNFL thinning, a detailed sector analysis has not been performed in genetic association studies. In the present study, we evaluated 26 tagging SNPs in the SIX1/SIX6 locus ±50 kb region in a population of 2,306 Japanese subjects with 4- and 32-sector cpRNFLT analysis. While no SNPs showed a significant association with cpRNFLT in the 4-sectored analysis, the finer 32-sector assessment clearly showed a significant association between rs33912345 in the SIX1/SIX6 locus with inferior cpRNFL thinning at 292.5-303.8° (ß = -4.55, P = 3.0 × 10-5). Furthermore, the fine-sectored cpRNFLT analysis indicated that SIX1/SIX6 polymorphisms would affect cpRNFL thinning at 281.3-303.8°, which corresponds to parafoveal scotoma in a visual field test of glaucoma patients.