Isao Nakata

Choroidal Thickness, Vascular Hyperpermeability, and Complement Factor H in Age-Related Macular Degeneration and Polypoidal Choroidal Vasculopathy

PURPOSE To investigate the relationship between subfoveal choroidal thickness, choroidal vascular hyperpermeability, and complement factor H (CFH) gene polymorphism in typical age-related macular degeneration (AMD) and polypoidal choroidal vasculopathy (PCV). METHODS Fifty-eight patients with typical AMD and 63 patients with PCV underwent fluorescein angiography, indocyanine green angiography (IA), and spectral-domain optical coherence tomography (OCT) using enhanced depth imaging (EDI). Subfoveal choroidal thickness was measured using EDI-OCT images, and choroidal hyperpermeability was evaluated using late-phase IA images. The major AMD-associated single-nucleotide polymorphisms were genotyped in 86 patients. RESULTS Mean subfoveal choroidal thickness was significantly lower in eyes with typical AMD than that in eyes with PCV (P = 0.025). Subfoveal choroidal thickness was greater in eyes with choroidal hyperpermeability than that in eyes without it in typical AMD (P < 0.001) and PCV (P = 0.020), and in the fellow eyes of typical AMD (P < 0.001) and PCV (P = 0.027). In eyes without choroidal hyperpermeability, the mean subfoveal choroidal thickness was greater in PCV than that in typical AMD (P = 0.001). Choroidal thickness decreased after photodynamic therapy combined with intravitreal ranibizumab in typical AMD (P = 0.016) and PCV (P = 0.036). In eyes with PCV, the I62V polymorphism in the CFH gene contributed to choroidal thickness (P = 0.043). CONCLUSIONS Choroidal thickness is related to the AMD subtypes, choroidal hyperpermeability, and I62V CFH gene polymorphism. In eyes without choroidal hyperpermeability, EDI-OCT is useful as an auxiliary measure for differentiating typical AMD and PCV.

CFH and ARMS2 variations in age-related macular degeneration, polypoidal choroidal vasculopathy, and retinal angiomatous proliferation.

PURPOSE To seek an association in Japanese individuals between the CFH polymorphisms Y402H and I62V and the ARMS2 polymorphism A69S and age-related macular degeneration (AMD) or its three subtypes: typical (t)AMD, polypoidal choroidal vasculopathy (PCV), and retinal angiomatous proliferation (RAP). METHODS The three polymorphisms were genotyped in a case-control study of 1351 control subjects and 962 patients with AMD. RESULTS The three polymorphisms correlated with AMD (Y402H, P = 1.54 × 10(-6); I62V, P =1.94 × 10(-29); and A69S, P = 9.56 × 10(-43)). The I62V and A69S polymorphisms were associated with all three subtypes: tAMD (P = 3.74 × 10(-18) and 1.37 × 10(-35), respectively), PCV (P = 3.18 × 10(-19) and 3.96 × 10(-18), respectively), and RAP (P = 0.034 and 2.49 × 10(-18), respectively). Y402H was associated with tAMD (P = 3.00 × 10(-5)) and with PCV (P = 9.73 × 10(-5)), but no association was found with RAP, possibly because of the small sample size and the rare minor allele. The risk allele contribution of A69S was stronger for RAP than for tAMD or PCV and was stronger for tAMD than for PCV. CONCLUSIONS CFH Y402H is associated with AMD, tAMD, and PCV, whereas I62V is associated with all three subtypes. ARMS2 A69S has a strong association with all three subtypes, with the association being strongest for RAP and weakest for PCV. PCV and RAP may thus be subtypes of AMD that are genetically distinct from tAMD.

Prevalence and Genomic Association of Reticular Pseudodrusen in Age-Related Macular Degeneration

PURPOSE To survey the prevalence of reticular pseudodrusen in late age-related macular degeneration (AMD) using multiple imaging methods, and to investigate the association between reticular pseudodrusen and polymorphisms in complement factor H (CFH) and age-related maculopathy susceptibility 2 (ARMS2) genes. DESIGN Retrospective case series. METHODS This study included 216 consecutive patients with late AMD (typical AMD, polypoidal choroidal vasculopathy [PCV], retinal angiomatous proliferation [RAP], or geographic atrophy). Eyes were assessed for reticular pseudodrusen using the blue channel of color fundus photography, infrared reflectance, fundus autofluorescence, and spectral-domain optical coherence tomography. The major AMD-associated single nucleotide polymorphisms (CFH Y402 rs1061170, CFH I62V rs800292, and ARMS2 A69S rs10490924) were genotyped. RESULTS Forty-nine eyes of 30 patients had a reticular pattern in ≥2 imaging modalities and were diagnosed with reticular pseudodrusen. Of these, 16 had bilateral late AMD, whereas 32 of 186 patients without reticular pseudodrusen had bilateral late AMD (P < .001). The prevalence of reticular pseudodrusen was 83% in RAP, 50% in geographic atrophy, 9% in typical AMD, and 2% in PCV. The frequency of the T allele in ARMS2 A69S in patients with and without reticular pseudodrusen was 78.6% and 59.9%, respectively (P=.007). CONCLUSIONS The prevalence of reticular pseudodrusen was low in PCV cases. About 50% of patients with reticular pseudodrusen had bilateral late AMD. The connection of ARMS2 risk allele and reticular pseudodrusen was confirmed in a Japanese population.

Factors Associated With the Response of Age-Related Macular Degeneration to Intravitreal Ranibizumab Treatment

PURPOSE To investigate factors affecting patient response to intravitreal ranibizumab treatment for age-related macular degeneration (AMD). DESIGN Retrospective chart review. METHODS We reviewed medical records of 105 consecutive eyes with AMD treated with intravitreal ranibizumab injections and followed for more than 1 year after treatment. Response to ranibizumab treatment was compared between typical neovascular AMD and polypoidal choroidal vasculopathy (PCV). Furthermore, we investigated associations of age, lesion size, and single nucleotide polymorphisms (SNPs) in CFH and ARMS2 genes with treatment response. RESULTS Forty-nine eyes were diagnosed with typical neovascular AMD and 56 eyes with PCV. Serous retinal detachment and retinal edema resolved similarly in both typical neovascular AMD and PCV after treatment. However, visual acuity (VA) significantly improved in eyes with PCV, whereas VA was maintained in typical neovascular AMD. At the third and twelfth months after injection, VA was better in PCV than in typical neovascular AMD (P = .027 and P = .044, respectively), although there were no differences in baseline VA between the 2 groups. Age and size of greatest linear dimension were significantly associated with visual prognosis in typical neovascular AMD but not in PCV. There was no clear association between 3 SNPs and responsiveness to ranibizumab treatment. CONCLUSIONS Although exudative changes were equivalent following ranibizumab treatment in both typical neovascular AMD and PCV, there was a significant increase in VA in PCV compared to typical neovascular AMD. Age and greatest linear dimension correlated with visual prognosis only in typical neovascular AMD and not in PCV.

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, β = −0.16 mm per minor allele, Pmeta = 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, Pmeta = 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.

Focal Choroidal Excavation in Eyes With Central Serous Chorioretinopathy

PURPOSE To study the prevalence and 3-dimensional (3-D) tomographic features of focal choroidal excavations in eyes with central serous chorioretinopathy (CSC) using swept-source optical coherence tomography (OCT). DESIGN Prospective, cross-sectional study. METHODS We examined 116 consecutive eyes with CSC with a prototype 3-D swept-source OCT. 3-D images of the shape of the macular area, covering 6 × 6 mm(2), were reconstructed by segmentation of the outer surface of the retinal pigment epithelium (RPE). RESULTS The 3-D swept-source OCT detected focal choroidal excavations in 9 eyes (7.8%). The 3-D scanning protocol, coupled with en face scans, allowed for clear visualization of the excavation morphology. In 5 eyes with focal excavations, unusual choroidal tissue was found beneath the excavation, bridging the bottom of the excavation and the outer choroidal boundary. Additionally, 3 of those 5 eyes showed a suprachoroidal space below the excavation, as if the outer choroidal boundary is pulled inward by this bridging tissue. The focal choroidal excavations were located within fluorescein leakage points and areas of choroidal hyperpermeability. Eyes with focal choroidal excavations were more myopic (-4.42 ± 2.92 diopters) than eyes without excavations (-0.27 ± 1.80 diopters, P = .001). Subfoveal choroidal thickness was significantly thinner (301.3 ± 60.1 μm) in eyes with focal excavations than in eyes without the excavations (376.6 ± 104.8 μm, P = .036). CONCLUSIONS Focal choroidal excavations were present in 7.8% of eyes with CSC. In these eyes, focal choroidal excavations may have formed from RPE retraction caused by focal scarring of choroidal connective tissue.

Prevalence and Characteristics of Age-Related Macular Degeneration in the Japanese Population: The Nagahama Study

PURPOSE To estimate the age- and sex-specific prevalence of early age-related macular degeneration (AMD; drusen and retinal pigment abnormalities) and late AMD (exudative AMD and geographic atrophy) in the Japanese population. DESIGN Community-based, cross-sectional study. METHODS The study was held in Nagahama, Japan, and included 6065 Japanese individuals (aged ≥50 years) recruited in 2008-2010. We graded fundus photographs of both eyes for the AMD phenotype based on drusen size, the presence of retinal pigment abnormalities, and late AMD. The associations between smoking and AMD phenotypes were also evaluated. RESULTS We assessed 5595 subjects (women, 65%) with a gradable macular condition. Early and late AMD prevalence increased from 16.1% and 0.27% at 50-59 years to 31.2% and 0.98%, respectively, at 70-74 years and was predominant in male subjects in each age group. Smoking was associated with both early and late AMD stages and retinal pigment abnormalities (P < .0001), but not with drusen (P = .305). The prevalence of retinal pigment abnormalities was significantly higher in men (P < .0001), which was associated with high rates of cigarette smoking. We found no sex difference for the prevalence of large drusen (P = .264). CONCLUSIONS The prevalence of early AMD among adult Japanese persons was similar to the rates in white populations. The prevalence of late AMD in Japanese people aged <70 years was similar to that observed in white populations, whereas that in Japanese people aged ≥70 years was relatively lower.

Significance of C2/CFB variants in age-related macular degeneration and polypoidal choroidal vasculopathy in a Japanese population

PURPOSE To determine whether genetic variants in the complement component 2 and factor B gene (C2/CFB) locus are associated with the risk for typical age-related macular degeneration (AMD) or polypoidal choroidal vasculopathy (PCV) in a Japanese population. METHODS Four single nucleotide polymorphisms (SNPs) were genotyped across the C2/CFB locus of patients with typical AMD (n = 455) or PCV (n = 581) and of 865 controls. Differences in the observed genotypic distribution between the case and control groups were tested by logistic regression analysis for age and sex adjustments. Significant associations were confirmed using a second control group of 336 cataract patients. A further model adjusting for age-related maculopathy susceptibility 2 (ARMS2) A69S, complement factor H (CFH) I62V, age, sex and smoking status was performed, to confirm their independent association from other covariates. RESULTS C2 rs547154 and CFB rs541862 were significantly associated with typical AMD and PCV in this Japanese sample (P < 0.05). These two SNPs were also significantly associated with typical AMD and PCV in evaluation of the second control cohort (P < 0.05). Furthermore, an independent association of C2/CFB variants was found for both typical AMD and PCV with age, sex, smoking, and genetic background of ARMS2 A69S and CFH I62V (vs. typical AMD: P = 0.0073, odds ratio [OR] = 0.47; vs. PCV: P = 0.0083, OR = 0.53). CONCLUSIONS C2/CFB variants play a protective role in the risk of developing neovascular AMD and PCV in the Japanese.

Association of Lesion Size and Visual Prognosis to Polypoidal Choroidal Vasculopathy

PURPOSE To investigate the progression of vascular lesions of polypoidal choroidal vasculopathy (PCV) as viewed with indocyanine green angiography and the visual prognosis of these eyes. DESIGN Retrospective case study. METHODS We reviewed retrospectively the medical records of 88 consecutive patients (88 eyes) with PCV who had been examined with indocyanine green angiography for more than 2 years. RESULTS Depending on the initial area of the vascular lesion, eyes were divided into smaller PCV (baseline area of lesion being < 1 disc area [DA], n = 22) and larger PCV (baseline area of lesion being ≥ 1 DA, n = 66). In larger PCV, the mean area of the lesion progressed significantly from 6.49 ± 8.96 mm(2) to 16.27 ± 14.19 mm(2) (P < .0001) with marked deterioration of visual acuity (P < .0001) during follow-up. In contrast, smaller PCV often showed minimal progression of the lesion, only limited exudative change, and the eyes maintained their initially good vision to the final visit. Smaller PCV lesions rarely progressed to extensive PCV lesions. Severe vision-threatening complications (ie, suprachoroidal hemorrhage, vitreous hemorrhage, and tears of the retinal pigment epithelium) were seen only in eyes with larger PCV, and in studying single nucleotide polymorphisms A69S of ARMS2 genes, there was a significant difference in T allele frequency between individuals with smaller PCV and those with larger PCV (20.2% vs 79.8%; P = .0235). CONCLUSIONS PCV with small vascular lesions shows minimal progression and no vision-threatening complications, and these eyes often maintain good visual acuity for a long time.

VEGF gene polymorphism and response to intravitreal bevacizumab and triple therapy in age-related macular degeneration

PurposeTo investigate the association between the vascular endothelial growth factor (VEGF) gene and response to either intravitreal bevacizumab (IVB) or photodynamic therapy with intravitreal triamcinolone acetonide and IVB (triple therapy) for neovascular age-related macular degeneration (AMD).MethodsThe study consisted of 94 patients with neovascular AMD who underwent IVB and 79 patients with neovascular AMD who underwent triple therapy. Genotypes were determined for four selected tagging single-nucleotide polymorphism (SNP)s of the VEGF gene.ResultsOf the four SNPs studied, one SNP (rs699946) was associated significantly with visual acuity (VA) changes 12 months after treatment—irrespective of whether they received IVB alone (P = 0.044) or triple therapy 0.010). Baseline VA was not significantly different among the three genotypes of rs699946 in either treatment group. There were no significant differences in the number of treatments, incidence of recurrence, or the period until the recurrence according to VEGF rs699946 genetic variant.ConclusionsThe VEGF gene SNP rs699946 was associated with response to IVB alone and to triple therapy in this study. The G allele in SNP rs699946 can thus be applied as a marker for better visual prognosis in patients with neovascular AMD who receive either IVB or triple therapy.