Complement factor H and high-temperature requirement A-1 genotypes and treatment response of age-related macular degeneration.

PURPOSE: To determine whether there is an association between complement factor H (CFH), high-temperature requirement A-1 (HTRA1), vascular endothelial growth factor (VEGF), and pigment epithelium-derived factor (PEDF) genotypes and response to treatment with photodynamic therapy (PDT) for age-related macular degeneration (AMD) in a Japanese population. DESIGN: Prospective, case-control study. PARTICIPANTS: One hundred ten patients with exudative AMD treated by verteporfin PDT were recruited prospectively at the Department of Ophthalmology, Saitama Medical University Hospital, Saitama, Japan. METHODS: The patients were genotyped for 4 single nucleotide polymorphisms (SNPs; rs800292, rs1061170, rs1410996, rs2274700) in the CFH gene, a rs11200638-SNP in the HTRA1 gene, 3 SNPs (rs699947, rs1570360, rs2010963) in the VEGF gene, and 4 SNPs (rs12150053, rs12948385, rs9913583, rs1136287) in the PEDF gene using a TaqMan assay. MAIN OUTCOME MEASURES: The treatment outcomes and genotypes of CFH, HTRA1, VEGF, and PEDF polymorphisms. RESULTS: Best-corrected visual acuity 1 year after PDT was significantly increased in patients with the HTRA1-rs11200638 GG genotype as compared with patients with the GA or AA genotypes (P = 2.9 × 10⁻², 7.0 × 10⁻4, respectively). The rate of recurrence in the 12-month period after PDT was also associated with HTRA1-rs11200638 genotype (P = 3.12 × 10⁻²). Patients with the AA genotype of HTRA1-rs11200638 had an approximately 6-fold greater risk of the recurrence than patients with the GG genotype (P = 5.58 × 10⁻³). Significant differences were demonstrated in the mean time interval from the initial treatment to the time of recurrence for the genotypes of CFH-rs1410996/-rs2274700 (P = 8.50 × 10⁻³). CONCLUSIONS: The HTRA1-rs11200638 and CFH-rs1410996/-rs2274700 variants were associated with response to PDT in this study population. These variants may be used for genetic biomarkers to estimate visual outcomes and recurrences in the response to PDT with significant predictive power.

[Outcome of photodynamic therapy for exudative age-related macular degeneration with good visual acuity].

PURPOSE: To evaluate visual outcome one year after photodynamic therapy (PDT) in patients with exudative age-related macular degeneration (AMD) showing good visual acuity (VA). SUBJECTS AND METHODS: One hundred and thirteen patients with AMD who received PDT therapy were recruited for this study. The study subjects were divided into two groups : those having a better visual acuity than 0.6 (n = 34), and those with VA worse than 0.5 (n = 79). All patients were examined by corrected visual acuity, fundus biomicroscopy, and optical coherence tomography (OCT) before, 1 month, 3 months, and 12 months after PDT. RESULTS: Visual acuity at 12 months was either at baseline visual acuity or improved in 82% of the better vision group. Foveal retinal thickness was significantly reduced with PDT in both the better vision and the worse vision groups (p = 0.04, 0.008, respectively). The greatest linear dimension (GLD) was significantly associated with significant vision decline among baseline factors (p = 0.049)such as gender and age. CONCLUSIONS: PDT is an effective adjunct for AMD patients even when they have good baseline vision. To perform PDT safely for AMD in patients with good vision, both larger GLD and retinal pigment epithelial detachment have to be considered as a risk factor.

Photodynamic effects on retinal oxygen saturation, blood flow, and electrophysiological function in patients with neovascular age-related macular degeneration.

PURPOSE: To evaluate the effect of photodynamic therapy (PDT) on retinal functions, such as oxygen saturation, blood flow, and electrophysiological function using Fourier transform-based spectral retinal imaging (SRI), Heidelberg retinal flowmeter (HRF), and multifocal electroretinogram (mfERG). METHODS: This was a prospective interventional case series. Twenty-two patients with age-related macular degeneration (AMD) with unilateral choroidal neovascularization (CNV) were examined using SRI, HRF, and mfERG before and 1 week and 1 month after PDT. Eleven fellow eyes without CNV and 11 control eyes of 11 age-matched healthy volunteers were also investigated. Eleven of 22 patients with neovascular AMD were retreated using verteporfin PDT and examined using a protocol similar to the one used for the first treatment. RESULTS: Oxygen saturation levels in the macula of eyes with neovascular AMD were significantly higher than those in normal control eyes (P = 0.026) but were not significantly higher in eyes with nonneovascular AMD. Oxygen saturation levels decreased 1 week after a single treatment (P = 4.59 x 10(-3)) and retreatment (P = 0.0134) and recovered to baseline levels at 1 month follow-up (P > 0.05). HRF demonstrated reduced mean blood flow at 1 week after single treatment (P = 9.22 x 10(-4)) and retreatment (P = 0.0307). One month after PDT, mean blood flow tended to show recovery. There was a similar decrease in mfERG amplitude 1 week after treatment, but the logarithm of minimum angular resolution (logMAR) vision was stable or improved throughout follow-up. CONCLUSION: Oxygen saturation levels, mean blood flow, and mfERG amplitude decreased 1 week after PDT treatment in both single treatment and retreatment groups. Although logMAR vision is stable or improved, our data showed transient functional deterioration in the retina after PDT treatment.

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.

Prognostic phenotypic and genotypic factors associated with photodynamic therapy response in patients with age-related macular degeneration.

BACKGROUND: This study aimed to demonstrate the phenotypic and genotypic factors associated with photodynamic therapy (PDT) for age-related macular degeneration (AMD). METHODS: The study included 149 patients with exudative AMD treated by PDT. Eight phenotypic factors and ten genotypic factors for three single nucleotide polymorphisms (SNPs; rs800292, rs1061170, rs1410996) in the complement factor H (CFH) gene, rs 11200638-SNP in the high temperature requirement A-1 (HTRA1) gene, two SNPs (rs699947, rs2010963) in the vascular endothelial growth factor (VEGF) gene, and four SNPs (rs12948385, rs12150053, rs9913583, rs1136287) in the pigment epithelium-derived factor (PEDF) gene were evaluated. RESULTS: A significant association with best-corrected visual acuity change was demonstrated in the greatest linear dimension, presence or absence of pigment epithelial detachment, and HTRA1-rs11200638 genotype statistically (P=3.67×10(-4), 1.95×10(-2), 1.24×10(-3), respectively). Best-corrected visual acuity in patients with AA genotype of HTRA1-rs11200638 significantly decreased compared with that in patients with GG genotype (P=1.33×10(-3)). Logistic regression analyses demonstrated HTRA1-rs11200638 genotype was most strongly associated with best-corrected visual acuity outcome from baseline at 12 months after photodynamic therapy (P=4.60×10(-3); odds ratio 2.363; 95% confidence interval 1.303-4.285). CONCLUSION: The HTRA1-rs11200638 variant showed the most significant association. Therefore, this variant may be used as a prognostic factor to estimate the PDT response with significant predictive power.

Five-year results of photodynamic therapy with verteporfin for Japanese patients with neovascular age-related macular degeneration.

PURPOSE: To describe the treatment outcome of photodynamic therapy (PDT) in Japanese patients with age-related macular degeneration (AMD) followed for 5 years. PATIENTS AND METHODS: We retrospectively reviewed clinical charts of 51 patients with AMD. Thirty-one eyes of typical AMD (tAMD) and 20 eyes of polypoidal choroidal vasculopathy (PCV) were evaluated. RESULTS: The mean logarithm of the minimum angle of resolution (logMAR) vision of all AMD patients was 0.807 at the baseline examination and 0.937 at the 5 year examination. Mean visual acuity letter score loss is similar between patients with tAMD (-7.25) and with PCV (-5.36) at the month 60 examination. The patients with lesions of classic choroidal neovascularization (CNV) had 10.0 letters loss, but the patients with lesions of occult CNV had only 1.43 letters loss. The number of retreatments peaked in year 1 and declined immediately for patients with tAMD, but patients with PCV had significantly more frequent retreatments in the years 3 and 4 than patients with tAMD (P = 1.48 × 10(-2), 5.96 × 10(-3), respectively). CONCLUSION: Visual outcomes in patients with Japanese patients with AMD treated with PDT after 5-year follow up were worse than that in short-term follow up reported previously. In addition, the difference in visual prognosis between tAMD and PCV was not demonstrated after long-term follow-up.

Association of elastin gene polymorphism to age-related macular degeneration and polypoidal choroidal vasculopathy.

PURPOSE: To see if there is an association in Japanese between elastin gene (ELN) polymorphisms and neovascular age-related macular degeneration (AMD) or its subtypes, typical AMD (tAMD) and polypoidal choroidal vasculopathy (PCV). METHODS: The authors genotyped five single nucleotide polymorphisms (SNPs), rs2301995, rs2856728, rs868005, rs884843, and rs13239907, at Kyoto University and Saitama Medical University. A case-control study was performed on 1296 patients with AMD and 478 controls. RESULTS: A statistically significant association was detected between the rs2301995 SNP and AMD (P = 0.018). Furthermore, subtype analysis revealed a significant association of rs2301995 with tAMD (P = 0.0018), but not with PCV. The genotype distribution of rs2301995 also differed significantly between tAMD and PCV (P = 0.00030). The trend in genotype distribution of rs2301995 was similar between the Kyoto and the Saitama studies. The A allele frequency was higher in tAMD, whereas it was similar in PCV and in controls, which is opposite to that reported in a previous study that the A allele frequency is higher in PCV, whereas it is similar in tAMD and in controls. Haplotype analysis also showed that the ELN polymorphism is significantly associated with tAMD (P = 0.0055), but not with PCV. CONCLUSIONS: ELN is associated with AMD in Japanese. Furthermore, the findings suggest that ELN is a susceptibility gene for tAMD but not for PCV, which is opposite to that reported in a previous study that ELN is the susceptibility gene for PCV but not for tAMD.

Genome-wide association study identifies two susceptibility loci for exudative age-related macular degeneration in the Japanese population.

Age-related macular degeneration (AMD), the leading cause of irreversible blindness in the world, is a complex disease caused by multiple environmental and genetic risk factors. To identify genetic factors that modify the risk of exudative AMD in the Japanese population, we conducted a genome-wide association study and a replication study using a total of 1,536 individuals with exudative AMD and 18,894 controls. In addition to CFH (rs800292, P = 4.23 × 10(-15)) and ARMS2 (rs3750847, P = 8.67 × 10(-29)) loci, we identified two new susceptibility loci for exudative AMD: TNFRSF10A-LOC389641 on chromosome 8p21 (rs13278062, combined P = 1.03 × 10(-12), odds ratio = 0.73) and REST-C4orf14-POLR2B-IGFBP7 on chromosome 4q12 (rs1713985, combined P = 2.34 × 10(-8), odds ratio = 1.30). Fine mapping revealed that rs13278062, which is known to alter TNFRSF10A transcriptional activity, had the most significant association in 8p21 region. Our results provide new insights into the pathophysiology of exudative AMD.

Midperipheral mottling pigmentation with familial choroidal osteoma.

PURPOSE: To describe a rare presentation of familial choroidal osteoma in two siblings. METHODS: The clinical findings in two siblings over 4 years' follow-up. RESULTS: Two brothers (15 and 12 years old) had bilateral choroidal osteomas. Both had bilateral peripapillary yellowish-white lesions and midperipheral mottling pigment appearance, which are not seen in sporadic cases. Extensive midperipheral area with mottling pigment appearance was noted by fluorescein angiography (FA) as scattered multiple hyperfluorescent dots. The yellowish-white lesions showed diffuse hyperfluorescence with FA and hypofluorescence with indocyanine green angiography (ICG). ICG also revealed irregular hyperfluorescent areas within the tumor, indicating abnormal choroidal vessels on the tumor. In the left eye of the younger brother, the subretinal fibrosis due to choroidal neovascularization superior to the macula extended down toward the foveal region over 2 years, resulting in visual deterioration. CONCLUSION: The midperipheral mottling pigment appearance of familial choroidal osteoma cases is unique and different from most sporadic cases, suggesting that familial choroidal osteoma might have separate etiologic or modified factors.