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Evaluation of: Klein ML, Francis PJ, Rosner B et al.: CFH and LOC387715/ARMS2 genotypes and treatment with antioxidants and zinc for age-related macular degeneration. Ophthalmology 115(6), 1019–1025 (2008). The late form of age-related macular degeneration (AMD) is a leading cause of irreversible vision loss in the elderly, with a complex etiology involving genetic and environmental factors. Recently, multiple distinct genetic susceptibility loci for AMD have been identified. Specifically, variations in the Complement Factor H (CFH) gene as well as the LOC387715/ARMS2 gene have been shown to be strongly associated with AMD. The Age-Related Eye Disease Study (AREDS) is a large multicenter, placebo-controlled, randomized clinical trial that showed that a combination of zinc and antioxidants reduced progression to late-stage AMD. In the present study, the authors found that within AREDS there was a significant interaction between zinc and CFH genotypes, indicating that CFH genotypes may be predictive of treatment response to zinc supplementation.

To determine whether there is an association between complement factor H (CFH) or LOC387715 genotypes and response to treatment with photodynamic therapy (PDT) for exudative age-related macular degeneration (AMD). Sixty-nine patients being treated for neovascular AMD with PDT were genotyped for the CFH Y402H and LOC387715 A69S polymorphisms by allele-specific digestion of PCR products. AMD phenotypes were characterized by clinical examination, fundus photography, and fluorescein angiography. Adjusting for age, pre-PDT visual acuity (VA), and lesion type, mean VA after PDT was significantly worse for the CFH TT genotype than for the TC or CC genotypes (P=0.05). Post-PDT VA was significantly worse for the CFH TT genotype in the subgroup of patients with predominantly classic choroidal neovascular lesions (P=0.04), but not for the patients with occult lesions (P=0.22). For the LOC387715 A69S variant, there was no significant difference among the genotypes in response to PDT therapy. The CFH Y402H variant was associated with a response to PDT treatment in this study. Patients with the CFH TT genotype fared significantly worse with PDT than did those with the CFH TC and CC genotypes, suggesting a potential relationship between CFH genotype and response to PDT.

Purpose To determine whether the complement factor H (CFH) Y402H variant is associated with specific age-related macular degeneration (AMD) clinical phenotypes. Design Retrospective, case-control study. Methods One hundred and eighty-eight white subjects with AMD and 189 control subjects were genotyped for the T-to-C polymorphism in exon 9 of the CFH gene by restriction-fragment length analysis and deoxyribonucleic acid (DNA) sequencing using genomic DNA from mouthwash samples. AMD phenotypes were characterized by clinical examination, fundus photography, and fluorescein angiography. Results Heterozygosity for the at-risk genotype (TC) increased the likelihood for AMD 2.1-fold (95% confidence interval [CI], 1.3 to 3.3), whereas homozygosity for the genotype (CC) increased the likelihood for AMD 6.5-fold (95% CI, 3.4 to 12.5) in our population. The C allele was associated significantly with predominantly classic choroidal neovascularization (odds ratio [OR], 2.01; 95% CI, 1.34 to 3.30). Neovascular lesion size was similar among the three genotypes ( P = .67). Conclusions The Y402H CFH variant carried a significantly increased risk for developing AMD in our population. Genotype and phenotype correlations regarding choroidal neovascular lesion type were observed.

Purpose To investigate whether there is an association between complement factor H (CFH) or LOC387715 genotypes with response to treatment with intravitreal bevacizumab for exudative age-related macular degeneration (AMD). Design Retrospective cohort study. Participants The study cohort consisted of 86 patients being treated for neovascular AMD with bevacizumab alone. Methods Genotype determination for the CFH Y402H and LOC387715 A69S polymorphisms was performed by allele-specific digestion of polymerase chain reaction products. All patients were treated with 1.25 mg intravitreal bevacizumab at 6-week intervals until choroidal neovascularization was no longer active. Main Outcome Measures CFH Y402H and LOC387715 A69S polymorphisms. Choroidal neovascular lesion characteristics were ascertained by fluorescein angiography. Snellen visual acuity (VA) was measured before and after treatment. Results For the CFH Y402H polymorphism, patients with the CFH TT genotype had the largest choroidal neovascular lesions ( P = 0.02). With treatment, VA improved from 20/248 to 20/166 for the CFH TT genotype and from 20/206 to 20/170 for the TC genotype, but fell from 20/206 to 20/341 for the CFH CC genotype ( P = 0.016). Only 10.5% of patients with the CFH CC genotype demonstrated improved VA with treatment, compared with 53.7% of CFH TT and TC genotypes ( P = 0.004). For the LOC387715 A69S variant, patients with the TT genotype had the largest choroidal neovascular lesions ( P = 0.012). There was no significant difference in response to bevacizumab treatment according to LOC387715 genotype. Conclusions The AMD-associated CFH Y402H and LOC387715 A69S variants were associated with differences in choroidal neovascular lesion size in this study. Patients with the CFH CC genotype fared significantly worse with intravitreal bevacizumab than did those with the CFH TC and TT genotypes, suggesting a potential pharmacogenetic relationship. Prospective studies to confirm or refute this observation should be considered.

Purpose To determine whether the duration of ischemic tolerance in the retina could be extended by repetitive presentations of the preconditioning stimulus and to begin to elucidate the mechanistic underpinnings of the resultant novel phenotype. Methods Adult male Swiss-Webster ND4 mice were repeatedly preconditioned with systemic hypoxia (RHP) over 12 days; 4 weeks later, the mice were subjected to 30 minutes of unilateral retinal ischemia. Protection was quantified morphologically and functionally 1 week after ischemia by histologic analyses and scotopic electroretinography, respectively. Temporal expression patterns of hypoxia-inducible factor (HIF)-1alpha and heme oxygenase (HO)-1 were measured in response to RHP and after retinal ischemia by immunoblot analysis and immunohistochemistry. Results Morphologic and functional protection against ischemia-induced reductions in retinal layer thicknesses and layer cell counts, and a- and b-wave amplitudes, was documented for at least 4 weeks after RHP. There was no evidence of tissue injury or dysfunction by RHP alone. Temporally associated with this period of long-term tolerance (LTT) to retinal ischemia were sustained increases in retinal levels of HIF-1alpha and HO-1 protein lasting at least 1 and 4 weeks, respectively, after the last RHP stimulus. Conclusions A novel form of sustained retinal ischemic tolerance is described, wherein endogenous adaptive responses triggered by repeated hypoxia afford protection against injury many weeks after the preconditioning stimulus. HIF-1alpha-mediated, long-lasting increases in retinal HO-1 expression may contribute to the LTT phenotype. Further elucidation of the genetic and molecular basis of such adaptive plasticity could provide therapeutic targets for preventing and/or treating a variety of ischemic retinopathies.

PURPOSE. To determine ( 1) clinical features that distinguish maculopathy due to the R345W substitution in fibulin- 3 from other forms of inherited or early- onset drusen, ( 2) the phenotypic variability, and ( 3) the extent of retinal disease in those with a positive molecular diagnosis.METHODS. Affected individuals underwent ophthalmic examination, digital color fundus photography, fundus autofluorescence ( AF) imaging, and psychophysical testing with automated photopic and dark- adapted perimetry and fine matrix mapping. Blood samples were taken for DNA extraction and screening for the R345W mutation in fibulin- 3. Patients were subsequently divided into mutation- positive and - negative groups, to compare the identified phenotypic findings in these two sets of subjects.RESULTS. Twenty- nine subjects from 19 families were ascertained with inherited or early- onset drusen. Twenty- four ( 83%) subjects from 15 families were found to harbor the R345W fibulin- 3 mutation. Peripapillary deposition and a radial distribution of macular drusen were consistent, distinguishing signs in the mutation- positive group. Subretinal neovascular membrane ( SRNVM) was a rare occurrence, affecting only 1 of 48 eyes, whereas hyperpigmentation and atrophy of the retinal pigment epithelium ( RPE) were common in older mutationpositive patients. Increased AF corresponding to the drusen was detected in both the mutation- positive and - negative groups. The phenotype in the group of patients positive for the R345W mutation was extremely variable, with evidence of interocular, intrafamilial, and interfamilial variability in visual loss, natural history, ophthalmoscopic findings, autofluorescence imaging, and psychophysical data. The novel finding of nonpenetrance was observed in a 62- year- old asymptomatic, mutation- positive man. The findings from detailed perimetry performed on a subset of subjects were consistent with the presence of widespread retinal dysfunction not isolated to the macula.CONCLUSIONS. Marked inter- and intrafamilial variation associated with the fibulin- 3 R345W mutation in terms of retinal appearance, severity, progression, and nonpenetrance were identified. It was noted that SRNVM is a rare occurrence in R345W fibulin- 3 maculopathy. These findings are helpful for advice regarding prognosis and for genetic counseling. The findings established that the presence of peripapillary deposit is highly likely to indicate that a patient carries the R345W mutation.

Aim: To investigate the association between posterior uveal melanoma and iris freckles, iris naevi, and choroidal naevi. Methods: Cross sectional study of 65 patients with posterior uveal melanoma and 218 controls. Iris colour, iris freckles, iris naevi, and choroidal naevi were recorded for each eye of each patient. Results: Iris freckles were present in 40 (61.5%) patients with melanoma and 135 (61.9%) controls (p = 0.494). Iris naevi were present in four (6.2%) patients with melanoma and nine (4.1%) controls (p = 0.955). Choroidal naevi were present in 12 (18.5%) patients with melanoma and 38 (17.4%) controls (p = 0.815). Conclusion: This study did not detect an association between posterior uveal melanoma and iris freckles, iris naevi, or choroidal naevi.

To examine the expression of proteins in the Rb and p53 tumor suppressor pathways in uveal melanomas following plaque radiotherapy.Immunohistochemistry and cell culture studies. Immunohistochemistry for Rb, p16, cyclin D1, p53, HDM2, and Bcl-2 was performed on twelve eyes containing posterior uveal melanomas that were enucleated following plaque radiotherapy. Cell culture studies were performed in three cases.The irradiated eyes were enucleated for radiation complications (five cases), local tumor recurrence (three cases), and other reasons (four cases). On histopathologic examination, all cases showed evidence of tumor cell loss. However, residual tumor cells were present in all cases, including those that were clinically regressed. Residual cells from three of the clinically regressed cases were cultured and demonstrated minimal cell division, marked cell death, and extensive chromosomal damage. Strong p53 staining was observed in six cases (50%) and was significantly associated with recent radiotherapy (P = .04). Abnormal cytoplasmic staining for Rb was observed in four cases (33%).Plaque radiotherapy of uveal melanomas induces DNA damage, inhibits cell division, and promotes cell death. These changes may be due, at least in part, to induction of p53, which activates genes involved in both cell cycle arrest and apoptosis. Plaque radiotherapy can also cause alterations in the expression of Rb, but the significance of this finding will require further study.

To determine if specific mitochondrial haplogroups associate with nonproliferative diabetic retinopathy (NPDR) and proliferative diabetic retinopathy (PDR).Deidentified medical records for Caucasian patients with diabetic retinopathy (DR; 153 NPDR and 138 PDR) were obtained from BioVU, Vanderbilt University's electronic, deidentified DNA databank. An independent cohort of Caucasian patients with DR (44 NPDR and 57 PDR) from the Vanderbilt Eye Institute (VEI) was used for validation. We tested for an association between mitochondrial haplogroups and PDR among patients with DR.In the BioVU cohort, PDR frequency among Caucasian DR patients differed significantly by mitochondrial haplogroup (P = 0.027). Replication in the VEI cohort confirmed this association (P = 0.0064). In the combined cohort, patients from the common haplogroup H were more likely to have PDR (odds ratio [OR] = 2.0 [95% confidence interval (CI) = 1.3-3.0], P = 0.0012), while patients from haplogroup Uk were less likely to have PDR (OR = 0.5 [95% CI = 0.3-0.8], P = 0.0049). In logistic regression analyses, the addition of diabetes duration, hemoglobin A1c (HgbA1c) levels, and hypertension had no effect on the associations of haplogroups H and Uk with PDR.In this study, DR patients from mitochondrial haplogroup H were more likely to have PDR, while DR patients from haplogroup Uk were less likely to have PDR. The association was independent of the major clinical variables affecting PDR. The mitochondrial haplogroups were as strong a risk factor for PDR as were elevated HgbA1c levels.

PURPOSE To test the hypothesis that primary open-angle glaucoma (POAG) patients have a systemic elevation of transforming growth factor β1 (TGFβ1). METHODS Plasma was prepared from blood samples drawn from patients of the Vanderbilt Eye Institute during clinic visits. Concentrations of total TGFβ1 and thrombospondin-1 (TSP1) in plasma were determined by ELISA. Statistical significance of differences between POAG and control samples was evaluated by Mann-Whitney test. Regression analysis was used to evaluate correlations between plasma TGFβ1 and patient age and between plasma TGFβ1 and TSP1. RESULTS Plasma samples were obtained from 148 POAG patients and 150 controls. Concentration of total TGFβ1 in the plasma of POAG patients (median = 3.25 ng/mL) was significantly higher (P < 0.0001) than in controls (median = 2.46 ng/mL). Plasma TGFβ1 was not correlated with age of patient (P = 0.17). Thrombospondin-1 concentration was also significantly higher (P < 0.0001) in POAG patients (median = 0.774 μg/mL) as compared to controls (median = 0.567 μg/mL). Plasma total TGFβ1 and TSP1 concentrations were linearly correlated (P < 0.0001). CONCLUSIONS Plasma samples from POAG patients display elevated total TGFβ1 compared to controls, consistent with elevated systemic TGFβ1 in POAG patients.

Retinoblastoma, a rare pediatric eye tumor, has served as an important model for the heritable predisposition to cancer. The retinoblastoma protein, Rb , functions as a tumor suppressor by controlling progression through the cell cycle. Rb function is regulated primarily by its phosphorylation state, which is determined by the complex interaction of multiple kinases and their inhibitors that together form the ‘Rb pathway’. This pathway has been found to be functionally inactivated in almost all types of cancer. Despite recent advances in our understanding of Rb function, the precise role of Rb loss in the development of retinoblastoma remains unclear. Recent work in genetically altered mice has suggested that an additional mutation in another gene is required for retinal tumor formation. An alternative model presented here is based on the noncell-autonomous functions of Rb contributing to tumorigenesis.

Purpose To compare plasma levels of oxidative stress biomarkers in patients with age-related macular degeneration (AMD) and controls and to evaluate a potential relationship between biochemical markers of oxidative stress and AMD susceptibility genotypes. Design Prospective case-control study. Methods Plasma levels of oxidative stress biomarkers were determined in 77 AMD patients and 75 controls recruited from a clinical practice. Cysteine, cystine (CySS), glutathione, isoprostane, and isofuran were measured, and participants were genotyped for polymorphisms in the complement factor H ( CFH ) and age-related maculopathy susceptibility 2 ( ARMS2 ) genes. Results CySS was elevated in cases compared with controls ( P = .013). After adjustment for age, sex, and smoking, this association was not significant. In all participants, CySS levels were associated with the CFH polymorphism rs3753394 ( P = .028) as well as an 8-allele CFH haplotype ( P = .029) after correction for age, gender, and smoking. None of the other plasma markers was related to AMD status in our cohort. Conclusions Our investigation of the gene–environment interaction involved in AMD revealed a relationship between a plasma biomarker of oxidative stress, CySS, and CFH genotype. These data suggest a potential association between inflammatory regulators and redox status in AMD pathogenesis.