Macular Degeneration: Klein ML

Schultz DW, Weleber RG, Lawrence G, Barral S, Majewski J, Acott TS, Klein ML. · Macular Degeneration Center, Casey Eye Institute, Oregon Health & Science University, 3375 SW Terwilliger Boulevard, Portland, OR 97239-4197, U.S.A. · Ophthalmic Genet. · Pubmed #16020313 No free full text.

Abstract: Age-related macular degeneration (AMD) is the most common blinding disorder in the Western world. Similar to other common diseases in which age is a risk factor (e.g., type II diabetes or Alzheimer's disease), AMD is thought to have a complex etiology. Previously, a Gln5345Arg mutation in HEMICENTIN-1 was found to segregate with AMD in a large family. However, the population frequency of this allele is inconsistent with the large proportion of families shown by linkage studies to map near this gene at 1q31. This review summarizes current knowledge regarding the role of HEMICENTIN-1 in AMD, the results of association studies for the Gln5345Arg mutation, and the linkage evidence for an AMD locus on 1q31. The data can be reconciled through proposing both additional variants in HEMICENTIN-1 and a second genetic risk factor for AMD in the region.

Klein ML, Francis PJ. · Macular Degeneration Center, Casey Eye Institute, Department of Ophthalmology, Oregon Health and Sciences University, 3375 Southwest Terwilliger Boulevard, Portland, OR 97201, USA. · Ophthalmol Clin North Am. · Pubmed #14740997 No free full text.

Abstract: Gene discoveries will lead to more effective them pies for AMD by identifying specific underlying disease mechanisms that might be corrected by drugs or gene therapy. For example, investigations are currently being carried out using pigment epithelium-derived factor (FEDF). The gene for this potent inhibitor of angiogenesis has been incorporated into an adenoviral vector and delivered into the eye by intravitreal injection to inhibit growth of new blood vessels in eyes with neovascular AMD. In the future, as the genetics of this complex disease are unraveled, more effective treatments and preventative measures that target specific molecular defects underlying the development of AMD can be expected.

Campochiaro PA, Nguyen QD, Shah SM, Klein ML, Holz E, Frank RN, Saperstein DA, Gupta A, Stout JT, Macko J, DiBartolomeo R, Wei LL. · Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. · Hum Gene Ther. · Pubmed #16454650 No free full text.

Abstract: Twenty-eight patients with advanced neovascular age-related macular degeneration (AMD) were given a single intravitreous injection of an E1-, partial E3-, E4-deleted adenoviral vector expressing human pigment epithelium- derived factor (AdPEDF.11). Doses ranging from 10(6) to 10(9.5) particle units (PU) were investigated. There were no serious adverse events related to AdPEDF.11 and no dose-limiting toxicities. Signs of mild, transient intraocular inflammation occurred in 25% of patients, but there was no severe inflammation. Six patients experienced increased intraocular pressure that was easily controlled by topical medication. All adenoviral cultures were negative. At 3 and 6 months after injection, 55 and 50%, respectively, of patients treated with 10(6)-10(7.5) PU and 94 and 71% of patients treated with 10(8)-10(9.5) PU had no change or improvement in lesion size from baseline. The median increase in lesion size at 6 and 12 months was 0.5 and 1.0 disk areas in the low-dose group compared with 0 and 0 disk areas in the high-dose group. These data suggest the possibility of antiangiogenic activity that may last for several months after a single intravitreous injection of doses greater than 10(8) PU of AdPEDF.11. This study provides evidence that adenoviral vector-mediated ocular gene transfer is a viable approach for the treatment of ocular disorders and that further studies investigating the efficacy of AdPEDF.11 in patients with neovascular AMD should be performed.

Seddon JM, Gensler G, Milton RC, Klein ML, Rifai N. · Epidemiology Unit, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, Mass 02114, USA. · JAMA. · Pubmed #14871913 links to  free full text

Abstract: CONTEXT: C-reactive protein (CRP) is a systemic inflammatory marker associated with risk for cardiovascular disease (CVD). Some risk factors for CVD are associated with age-related macular degeneration (AMD), but the association between CRP and AMD is unknown. OBJECTIVE: To test the hypothesis that elevated CRP levels are associated with an increased risk for AMD. DESIGN, SETTING, AND PARTICIPANTS: A total of 930 (91%) of 1026 participants at 2 centers in the Age-Related Eye Disease Study (AREDS), a multicenter randomized trial of antioxidant vitamins and minerals, were enrolled in this case-control study. There were 183 individuals without any maculopathy, 200 with mild maculopathy, 325 with intermediate disease, and 222 with advanced AMD (geographic atrophy or neovascular AMD). The AMD status was assessed by standardized grading of fundus photographs, and stored fasting blood specimens drawn between January 1996 and April 1997 were analyzed for high-sensitivity CRP levels. MAIN OUTCOME MEASURE: Association between CRP and AMD. RESULTS: The CRP levels were significantly higher among participants with advanced AMD (case patients) than among those with no AMD (controls; median values, 3.4 vs 2.7 mg/L; P =.02). After adjustment for age, sex, and other variables, including smoking and body mass index, CRP levels were significantly associated with the presence of intermediate and advanced stages of AMD. The odds ratio (OR) for the highest vs the lowest quartile of CRP was 1.65 (95% confidence interval [CI], 1.07-2.55; P for trend =.02). The OR for CRP values at or above the 90th percentile (10.6 mg/L) was 1.92 (95% CI, 1.20-3.06), and the OR for CRP values at or above the mean plus 2 SDs (16.8 mg/L) was 2.03 (95% CI, 1.03-4.00). A trend for an increased risk for intermediate and advanced AMD with higher levels of CRP was seen for smokers (OR, 2.16; 95% CI, 1.33-3.49) and those who never smoked (OR, 2.03; 95% CI, 1.19-3.46) with the highest level of CRP. CONCLUSION: Our results suggest that elevated CRP level is an independent risk factor for AMD and may implicate the role of inflammation in the pathogenesis of AMD.

SanGiovanni JP, Arking DE, Iyengar SK, Elashoff M, Clemons TE, Reed GF, Henning AK, Sivakumaran TA, Xu X, DeWan A, Agrón E, Rochtchina E, Sue CM, Wang JJ, Mitchell P, Hoh J, Francis PJ, Klein ML, Chew EY, Chakravarti A. · National Eye Institute (NEI)/National Institutes of Health (NIH), Bethesda, Maryland, United States of America. · PLoS One. · Pubmed #19434233 links to  free full text

Abstract: BACKGROUND: Age-related macular degeneration (AMD), a chronic neurodegenerative and neovascular retinal disease, is the leading cause of blindness in elderly people of western European origin. While structural and functional alterations in mitochondria (mt) and their metabolites have been implicated in the pathogenesis of chronic neurodegenerative and vascular diseases, the relationship of inherited variants in the mitochondrial genome and mt haplogroup subtypes with advanced AMD has not been reported in large prospective cohorts. METHODOLOGY/PRINICIPAL FINDINGS: We examined the relationship of inherited mtDNA variants with advanced AMD in 1168 people using a three-stage design on samples from 12-year and 10-year prospective studies on the natural history of age-related eye disease. In Stage I we resequenced the entire genome in 99 elderly AMD-free controls and 215 people with advanced AMD from the 12-year study. A consistent association with AMD in 14 of 17 SNPs characterizing the mtDNA T haplogroup emerged. Further analysis revealed these associations were driven entirely by the T2 haplogroup, and characterized by two variants in Complex I genes (A11812G of MT-ND4 and A14233G of MT-ND6). We genotyped T haplogroups in an independent sample of 490 cases and 61 controls from the same study (Stage II) and in 56 cases and 246 controls from the 10-year study (Stage III). People in the T2 haplogroup were approximately 2.5 times more likely to have advanced AMD than their peers (odds ratio [OR] = 2.54, 95%CI 1.36-4.80, P<or=0.004) after considering the totality of evidence. Findings persisted after considering the impact of AMD-associated variants A69S and Y402H (OR = 5.19, 95%CI 1.19-22.69, P<or=0.029). CONCLUSION: Loci defining the mtDNA T2 haplogroup and Complex I are reasonable targets for novel functional analyses and therapeutic research in AMD.

Monson DM, Smith JR, Klein ML, Wilson DJ. · Casey Eye Institute, Portland, OR 97239-4197, USA. · Arch Ophthalmol. · Pubmed #19064845 No free full text.

Abstract: OBJECTIVES: To correlate clinical and histopathologic features of an eye with retinal angiomatous proliferation (RAP) secondary to age-related macular degeneration and to investigate the expression of von Willebrand factor (VWF) and vascular endothelial growth factor (VEGF) in this condition. METHODS: Histopathologic features from serial sections through the globe of an 87-year-old woman with RAP were studied and compared with fluorescein angiography and color fundus photographs obtained 4 months before death. Commercially available anti bodies were used to detect expression of VWF and VEGF in tissue sections. RESULTS: The pathologic correlate of RAP was a circumscribed intraretinal angiomatous complex within the outer part of the neurosensory retina overlying a large pigment epithelial detachment. There were no breaks in the Bruch membrane. No choroidal neovascularization was present. Endothelial cells within the RAP lesion immunostained positively for VWF and VEGF. The Bruch membrane expressed VWF adjacent to the RAP. CONCLUSIONS: Fundus examination and fluorescein angiography images of RAP in a patient with age-related macular degeneration correlated histopathologically with a neovascular intraretinal angiomatous complex, without the presence of sub-retinal pigment epithelial neovascularization. Immunostaining demonstrated that RAP expresses VWF and VEGF.

Francis PJ, Hamon SC, Ott J, Weleber RG, Klein ML. · Macular Degeneration Center, Casey Eye Institute, Oregon Health & Science University, Portland, Oregon 97239-4197, USA. · J Med Genet. · Pubmed #19015224 No free full text.

Abstract: BACKGROUND: Age related macular degeneration (AMD) is a leading cause of blindness. AMD is a complex disorder caused by genetic and environmental factors in which single nucleotide polymorphisms (SNPs) in the genes CFH and LOC387715/HTRA1/ARMS2 have prognostic importance for progression to advanced AMD (with visual loss). CFH may also have a pharmacogenetic role by affecting treatment response to widely used nutritional supplements. This paper examines other AMD susceptibility genes to determine if these genotypes influenced disease progression and treatment response. METHODS: Three cohorts, totalling 3137 individuals, were genotyped for SNPs in 13 genes previously published to be associated with advanced AMD (other than CFH and LOC387715/ARMS2/HTRA1). Those genes found associated were then evaluated for their involvement in disease progression. Interactions between the genes and with AREDS (Age-Related Eye Disease Study) nutritional supplements were investigated. RESULTS: Positive independent associations were noted in SNPs in the genes C2 (p = 0.0001, odds ratio (OR) 0.35, 95% confidence interval (CI) 0.2 to 0.6), CFB (p = 0.0001, OR 0.35, 95% CI 0.2 to 0.6), C3 (p = 0.0001, OR 3.91, 95% CI 1.94 to 7.88), APOE (epsilon4, p = 0.01, OR 0.50, 95% CI 0.29 to 0.86) and VEGFA (p = 0.01, OR 2.23, 95% CI 1.06 to 4.68). C2/CFB and C3 were independently related to progression from early/intermediate to advanced AMD with OR 0.32 (95% CI 0.14 to 0.73) and 3.32 (95% CI 1.46 to 7.59), respectively. Gene-gene and pharmacogenetic interactions were not observed. No preferential associations were observed with geographic atrophy or choroidal neovascularisation. CONCLUSION: This study provides insights into the genetic pathogenesis of AMD. Five genes have now been shown to be independently involved in progression from intermediate disease (before vision loss has occurred) to advanced disease in which blindness is frequent.

Yang Z, Stratton C, Francis PJ, Kleinman ME, Tan PL, Gibbs D, Tong Z, Chen H, Constantine R, Yang X, Chen Y, Zeng J, Davey L, Ma X, Hau VS, Wang C, Harmon J, Buehler J, Pearson E, Patel S, Kaminoh Y, Watkins S, Luo L, Zabriskie NA, Bernstein PS, Cho W, Schwager A, Hinton DR, Klein ML, Hamon SC, Simmons E, Yu B, Campochiaro B, Sunness JS, Campochiaro P, Jorde L, Parmigiani G, Zack DJ, Katsanis N, Ambati J, Zhang K. · Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, China. · N Engl J Med. · Pubmed #18753640 links to  free full text

Abstract: BACKGROUND: Age-related macular degeneration is the most common cause of irreversible visual impairment in the developed world. Advanced age-related macular degeneration consists of geographic atrophy and choroidal neovascularization. The specific genetic variants that predispose patients to geographic atrophy are largely unknown. METHODS: We tested for an association between the functional toll-like receptor 3 gene (TLR3) variant rs3775291 (involving the substitution of phenylalanine for leucine at amino acid 412) and age-related macular degeneration in Americans of European descent. We also tested for the effect of TLR3 Leu and Phe variants on the viability of human retinal pigment epithelial cells in vitro and on apoptosis of retinal pigment epithelial cells from wild-type mice and Tlr3-knockout (Tlr3(-/-)) mice. RESULTS: The Phe variant (encoded by the T allele at rs3775291) was associated with protection against geographic atrophy (P=0.005). This association was replicated in two independent case-control series of geographic atrophy (P=5.43x10(-4) and P=0.002). No association was found between TLR3 variants and choroidal neovascularization. A prototypic TLR3 ligand induced apoptosis in a greater fraction of human retinal pigment epithelial cells with the Leu-Leu genotype than those with the Leu-Phe genotype and in a greater fraction of wild-type mice than Tlr3(-/-) mice. CONCLUSIONS: The TLR3 412Phe variant confers protection against geographic atrophy, probably by suppressing the death of retinal pigment epithelial cells. Since double-stranded RNA (dsRNA) can activate TLR3-mediated apoptosis, our results suggest a role of viral dsRNA in the development of geographic atrophy and point to the potential toxic effects of short-interfering-RNA therapies in the eye.

Francis PJ, Zhang H, Dewan A, Hoh J, Klein ML. · Macular Degeneration Center, Casey Eye Institute, Oregon Health & Science University, Portland, OR, USA. · Mol Vis. · Pubmed #18682806 links to  free full text

Abstract: PURPOSE: To estimate the joint effects of single nucleotide polymorphisms (SNPs) in the genes complement factor H (CFH), HtrA serine peptidase 1 (HTRA1), and age-related maculopathy susceptibility 2 (LOC387715/ARMS2) in a Caucasian age related macular degeneration (AMD) case-control cohort. METHODS: We genotyped three SNPs, rs1061170 (exon 9, CFH), rs11200638 (HTRA1 promoter, -512 bp), and rs10490924 (6.6 kb upstream of HTRA1 in LOC387715/ARMS2) in 333 cases with advanced AMD (choroidal neovascularization [CNV] and geographic atrophy) and 171 age-matched examined controls. Association tests were performed for individual SNPs and jointly with the CFH SNP Y402H. Analyses for interaction were also performed. RESULTS: The linkage disequilibrium measure for two SNPs on 10q26, rs10490924 and rs11200638, is D'=0.8 and all four possible haplotypes of the two SNPs were detected in the samples. The allelic association test for rs11200638 on the promoter of HTRA1 yielded p-values less than 10(-10) for geographic atrophy, less than 10(-16) for neovascularization, and less than 10(-19) for the pooled phenotypes (with an odds ration [OR] of 3.973; 95% confidence interval [CI] 2.928, 5.390). Disease risk is conferred in a dosage-dependent fashion. Similar figures were observed for the LOC387715/ARMS2 SNP. No interaction was detected between either between the 10q26 SNPs or the CFH SNP. CONCLUSIONS: This is the first analysis to show that the two 10q26 SNPs are not in complete linkage disequilibrium. Our studies however show that both the HTRA1 and LOC387715/ARMS2 SNP appear to contribute equally to disease risk (both geographic atrophy and choroidal neovascularization) with no evidence of interaction with CFH.

Klein ML, Francis PJ, Rosner B, Reynolds R, Hamon SC, Schultz DW, Ott J, Seddon JM. · Macular Degeneration Center, Casey Eye Institute, Oregon Health & Science University, Portland, Oregon, USA. · Ophthalmology. · Pubmed #18423869 No free full text.

Abstract: OBJECTIVE: To determine if CFH and LOC387715/ARMS2 genotypes influence treatment response to AREDS-type nutritional supplementation with antioxidants and zinc. DESIGN: Retrospective analysis of participants in a randomized, controlled clinical trial, the Age-Related Eye Disease Study (AREDS). PARTICIPANTS AND/OR CONTROLS: Eight hundred seventy-six AREDS study participants who were considered at high risk for developing advanced age-related macular degeneration (AMD). METHODS: Using DNA extracted from venous blood of 876 white participants in AREDS categories 3 and 4, that is, those considered to be at high risk for progression to advanced AMD, the authors genotyped for the single nucleotide polymorphisms in the CFH (Y402H, rs1061170) and LOC387715/ARMS2 (A69S, rs10490924) genes. The authors performed adjusted unconditional logistic regression analysis and assessed interactions of these genotypes to determine the relationship between CFH and LOC387715/ARMS2 genotype and treatment with antioxidants plus zinc. MAIN OUTCOME MEASURES: Interaction between genetic variants and treatment response as determined by progression from high-risk to advanced AMD. RESULTS: Progression occurred in 264 of 876 patients from AREDS category 3 (intermediate AMD) to category 4 or 5 (unilateral or bilateral advanced AMD, respectively), or from category 4 to category 5. A treatment interaction was observed between the CFH Y402H genotype and supplementation with antioxidants plus zinc (CC; P = 0.03). An interaction (P = 0.004) was observed in the AREDS treatment groups taking zinc when compared with the groups taking no zinc, but not in groups taking antioxidants compared with those taking no antioxidants (P = 0.59). There were no significant treatment interactions observed with LOC387715/ARMS2. CONCLUSIONS: The findings of this study indicate that an individual's response to AREDS supplements may be related to CFH genotype. This could have clinical relevance by predicting treatment outcome and potentially preventing unwanted side effects in those who may not benefit. Corroboration of these analyses is needed before considering modification of current management. This is among the first pharmacogenetic studies to suggest interaction between genotype and treatment.

Francis PJ, Schultz DW, Hamon S, Ott J, Weleber RG, Klein ML. · Macular Degeneration Center, Casey Eye Institute, Oregon Health & Science University, Portland, Oregon, United States of America. · PLoS One. · Pubmed #18043728 links to  free full text

Abstract: BACKGROUND: Age-related macular degeneration (AMD), the leading cause of blindness in the Western world, is a complex disease that affects people over 50 years old. The complement factor H (CFH) gene has been repeatedly shown to be a major factor in determining susceptibility to the advanced form of the condition. We aimed to better understand the functional role of this gene in the AMD disease process and assess whether it is associated with earlier forms of the disease. METHODOLOGY/PRINCIPAL FINDINGS: WE genotyped SNPS at the cfh gene locus in three independent populations with AMD: (a) extended families where at least 3 family members had AMD; (b) sporadic cases of advanced AMD and (c) cases from the Age-Related Eye Disease Study (AREDS). We investigated polymorphisms and haplotypes in and around the CFH gene to assess their role in AMD. CFH is associated with early/intermediate and advanced AMD in both familial and sporadic cases. In our populations, the CFH SNP, rs2274700, is most strongly associated with AMD and when incorporated into a haplotype with the Y402H SNP and rs1061147, the strongest association is observed (p<10(-9)). CONCLUSIONS/SIGNIFICANCE: Our results, reproduced in three populations that represent the spectrum of AMD cases, provide evidence that the CFH gene is associated with drusen as well as with advanced AMD. We also identified novel susceptibility and protective haplotypes in the AMD populations.

Klein ML, Ferris FL, Armstrong J, Hwang TS, Chew EY, Bressler SB, Chandra SR, Anonymous00008. · Devers Eye Institute, Legacy Good Samaritan Hospital and Medical Center, Portland, Oregon, USA. · Ophthalmology. · Pubmed #17981333 No free full text.

Abstract: PURPOSE: To determine specific retinal precursor lesions and sequence of events preceding the onset of geographic atrophy (GA) in eyes with age-related macular degeneration (AMD). DESIGN: Retrospective review. PARTICIPANTS: All participants in the Age-Related Eye Disease Study (AREDS) at 2 clinical centers (Devers Eye Institute, Portland, Oregon, and University of Wisconsin, Madison, Wisconsin) in whom GA initially appeared in at least one eye a minimum of 4 years after the baseline study visit. METHODS: All stereoscopic fundus photographs taken before the appearance of GA in the involved (study) eye were reviewed. Fundus features at the site of future GA were graded and recorded. Three graders reviewed photographs, with independent grading and adjudication by mutual agreement. Features graded included drusen (classified by size and confluence), focal hyperpigmentation, hypopigmentation, and refractile deposits. The time between first appearance of these features and initial appearance of GA was recorded. MAIN OUTCOME MEASURE: Appearance of GA. RESULTS: Of all AREDS participants at the 2 sites, 95 eyes of 77 developed GA at least 4 years after entrance into the study. Average time from baseline to initial appearance of GA was 6.6 years (range, 4-11). Drusen were found in 100% of eyes at the site of later developing GA, drusen >125 mum in diameter in 96% of eyes, confluent drusen in 94%, hyperpigmentation in 96%, drusen > 250 mum in 83%, hypopigmentation in 82%, and refractile deposits in 23%. Time from lesion appearance to onset of GA varied by lesion type, ranging from 5.9 years for drusen confluence to 2.5 years for hypopigmentation or refractile deposits. Lesions generally followed a uniform sequence of appearance. CONCLUSIONS: By focusing on the location of initial GA appearance and then retrospectively analyzing prior photographs, we were able to identify specific precursor lesions and the most common sequence of events leading to GA formation in eyes with AMD. The progression was usually characterized by large drusen formation and development of hyperpigmentation, followed by regression of drusen, appearance of hypopigmentation, and ultimately development of GA, sometimes preceded by the appearance of refractile deposits.

LaRowe TL, Mares JA, Snodderly DM, Klein ML, Wooten BR, Chappell R, Anonymous00078. · Department of Family Medicine, University of Wisconsin-Madison, Madison, Wisconsin, USA. · Ophthalmology. · Pubmed #17868874 No free full text.

Abstract: PURPOSE: To examine the association between intermediate age-related macular degeneration (AMD) and the optical density of macular pigment (MPOD), which is composed of lutein and zeaxanthin from the diet. DESIGN: Cross-sectional cohort study. PARTICIPANTS: We included 1698 of 2005 women ages 54 to 86 years and participating in the Carotenoids in Age-Related Eye Disease Study, an ancillary study of the Women's Health Initiative. METHODS: The MPOD was measured noninvasively by heterochromatic flicker photometry. Fundus photographs were taken to document prevalent AMD. MAIN OUTCOME MEASURES: Intermediate AMD (n = 305) and two subtypes-large drusen (n = 233) and pigmentary abnormalities (n = 157). RESULTS: After adjusting for covariates, the odds ratio (OR) and 95% confidence interval (CI) for AMD among women in quintile (Q) 5 (n = 339) versus 1 (n = 340) for MPOD was 1.4 (0.9, 2.1). However, after excluding women with possible unstable diets and recent supplement use due to chronic disease history, associations reversed (OR Q2-5 vs. 1, 0.8; 95% CI, 0.5-1.2), but remained nonsignificant. Associations also differed between middle-aged (54-69 years) and older (> or =70 years) women (P-interaction = 0.09), but less so, after excluding women who were likely to have unstable diets: adjusted ORs (95% CI) were 0.5 (0.3-1.0; P = 0.08) for intermediate AMD among middle-aged women (n = 516) with MPOD in Q2 to Q5 versus 1 and 1.0 (0.5-2.0; P = 0.90) for older women (n = 422). CONCLUSIONS: The MPOD is not cross-sectionally associated with AMD. The inconsistency of relationships across age groups and in subgroups of women who are likely to have more stable diets suggests that cross-sectional associations may be biased and highlights the need to study these relationships prospectively.

Emerson GG, Flaxel CJ, Lauer AK, Stout JT, Emerson MV, Nolte S, Wilson DJ, Klein ML. · Casey Eye Institute, Oregon Health & Science University, Portland, OR, USA. · Retina. · Pubmed #17621181 No free full text.

Abstract: BACKGROUND: To evaluate macular thickness measured by optical coherence tomography (OCT) during pegaptanib therapy for neovascular age-related macular degeneration (AMD). METHODS: For this prospective, nonrandomized, observational case series, 41 eyes from 41 patients with neovascular AMD received intravitreous pegaptanib (1 mg) injections repeated every 6 weeks. The primary outcome measure was central foveal thickness measured by OCT. Secondary outcomes were fluorescein angiographic leakage and visual acuity. RESULTS: Mean thickness of the central area on OCT decreased from 340 +/- 24 microm to 299 +/- 14 microm after 12 weeks of pegaptanib injections. This represents a reduction in thickening of 32%. Fluorescein angiograms with definite leakage decreased from 100% to 81%, and mean visual acuity decreased from 20/116 to 20/120. CONCLUSIONS: Intravitreal injections of pegaptanib at 6-week intervals result in a moderate reduction of central foveal thickness in eyes with subfoveal neovascular AMD. This presents a modest effect relative to that reported with other anti-angiogenic agents.

Seddon JM, Francis PJ, George S, Schultz DW, Rosner B, Klein ML. · Ophthalmic Epidemiology and Genetics Service, Department of Ophthalmology, Tufts-New England Medical Center, Boston, MA 02111, USA. · JAMA. · Pubmed #17456821 links to  free full text

Abstract: CONTEXT: Studies have reported that single-nucleotide polymorphisms in the genes CFH and LOC387715 are associated with age-related macular degeneration (AMD). OBJECTIVE: To assess whether these genetic variants have prognostic importance for progression to advanced AMD and related visual loss. DESIGN, SETTING, AND PARTICIPANTS: Prospective analysis of 1466 white participants in the Age-Related Eye Disease Study (AREDS), a US multicenter clinical trial conducted from 1990 to 2001 with a mean follow-up time of 6.3 years. Age-related macular degeneration status was determined by grading of fundus photographs. Progression (n = 281) was defined as newly diagnosed advanced AMD (geographic atrophy, exudative disease, or AMD causing visual loss) in one or both eyes during the course of the study. Genotypic analysis was conducted in 2006. MAIN OUTCOME MEASURE: Incidence rates of dry and neovascular advanced AMD. RESULTS: The CFH Y402H and LOC387115 A69S polymorphisms were each independently related to progression from early or intermediate stages to advanced stages of AMD, controlling for demographic factors, smoking, body mass index, and AREDS vitamin-mineral treatment assignment, with odds ratios (ORs) of 2.6 (95% confidence interval [CI], 1.7-3.9) for CFH and 4.1 (95% CI, 2.7-6.3) for LOC387715 for the homozygous risk genotypes (P<.001 for trend for each additional risk allele for both genes). The effect of LOC387715 was stronger for progression to neovascular disease (OR, 6.1; 95% CI, 3.3-11.2) compared with geographic atrophy (OR, 3.0; 95% CI, 1.4-6.5) relative to no progression for the homozygous risk state. The presence of all adverse factors (both risk genotypes, smoking, and body mass index > or =25) increased risk 19-fold. Smoking and high body mass index increased odds of progression within each risk genotype. Genetic plus nongenetic risk scores provided an area under the receiver operating characteristic curve of up to 0.78. CONCLUSIONS: Common polymorphisms in the genes CFH and LOC387715 are independently related to AMD progression after adjustment for other known AMD risk factors. Presence of these polymorphisms plus smoking [corrected] and body mass index of 25 or higher, controlling for AREDS vitamin-mineral treatment, identifies [corrected] patients who are highly susceptible to developing advanced states [corrected] of this visually disabling disease.

Emerson MV, Lauer AK, Flaxel CJ, Wilson DJ, Francis PJ, Stout JT, Emerson GG, Schlesinger TK, Nolte SK, Klein ML. · Macular Degeneration Center, Casey Eye Institute, Oregon Health & Science University, Portland, Oregon, USA. · Retina. · Pubmed #17420695 No free full text.

Abstract: PURPOSE: To report the change in visual acuity and central retinal thickness by optical coherence tomography (OCT) after intravitreal injections of bevacizumab for the treatment of neovascular age-related macular degeneration (AMD). METHODS: A retrospective case series in a university-based practice evaluated patients with subfoveal choroidal neovascularization (CNV) due to AMD. Patients received intravitreal injections (1.25 mg) of bevacizumab and were monitored monthly with determination of best-corrected ETDRS visual acuity and OCT for persistence of retinal thickening. Eyes were retreated on an "as needed" basis, defined by presence of intraretinal or subretinal fluid. Patients were monitored every 2 months to 3 months for persistence of angiographic leakage. RESULTS: Seventy-nine eyes of 74 consecutive patients received the initial injection of bevacizumab between August 1, 2005, and January 30, 2006. Sixty-eight eyes (86%) of 64 patients had at least 3 months of follow-up. Mean central retinal thickness +/- SD decreased from 304 +/- 83 microm at baseline to 237 +/- 105 microm at 3 months (P = 0.00002). Mean ETDRS visual acuity gained 4 letters from 20/100 at baseline to 20/80-1 at 3 months (P = 0.040). Twenty eyes (25%) appeared to have a sustained response to a single injection and did not require further injections through 3 months. Two patients had a potentially drug-related adverse event (ischemic stroke and myocardial infarction). No serious injection-related adverse events occurred. CONCLUSIONS: Intravitreal bevacizumab injection affects a rapid decrease in retinal thickness to normal or near-normal levels and improvement in visual acuity in eyes with CNV due to AMD. The sustainability of changes in retinal thickness and visual acuity in response to bevacizumab treatment warrant further investigation and long-term follow-up.

Francis PJ, George S, Schultz DW, Rosner B, Hamon S, Ott J, Weleber RG, Klein ML, Seddon JM. · Macular Degeneration Center, Casey Eye Institute, Oregon Health and Science University, Portland, OR 97239, USA. · Hum Hered. · Pubmed #17347568 links to  free full text

Abstract: BACKGROUND AND AIMS: Age-related macular degeneration (AMD) is the leading cause of blindness in the Western World. It is now evident that both genetic and environmental factors contribute to disease susceptibility. We tested the hypotheses that (a) a common coding SNP in the LOC387715 gene is associated with advanced AMD (geographic atrophy or choroidal neovascularization), and (b) that modifiable environmental exposures alter AMD susceptibility associated with this SNP. METHODS: A case-control association analysis was performed on participants (530 advanced AMD cases and 280 controls) ascertained as part of the multi-center Age-Related Eye Disease Study. AMD status was determined by the reading center from fundus photographs using the AREDS AMD grading categorization. Environmental risk factor exposure data was collected from participants whose DNA was also genotyped for the LOC387715 gene SNP rs10490924. Multivariate logistic regression analyses were performed. RESULTS AND CONCLUSIONS: The number of risk alleles at the LOC387715 SNP was associated with advanced AMD, with odds ratios (OR) = 3.0 (95% confidence interval (CI) 2.1-4.3) for the GT heterozygous genotype and OR = 12.1 (5.6-26.5) for the homozygous TT risk genotype, after controlling for demographic and behavioral risk factors. The LOC387715 SNP was associated with both forms of advanced AMD. Current cigarette smoking and body mass index were independently related to AMD, controlling for genotype. However, there was no statistical interaction between LOC387715 genotype and smoking with regard to advanced AMD development.

Wang W, Connor SL, Johnson EJ, Klein ML, Hughes S, Connor WE. · Department of Medicine, Oregon Health and Science University, Portland, OR 97239-3098, USA. · Am J Clin Nutr. · Pubmed #17344498 links to  free full text

Abstract: BACKGROUND: Low dietary intakes and low plasma concentrations of lutein and zeaxanthin are associated with an increased risk of age-related macular degeneration (AMD). No studies have challenged AMD patients with a diet high in lutein and zeaxanthin. OBJECTIVE: The objective was to examine the effect of diets low or high in lutein and zeaxanthin on plasma carotenoids and their transport in AMD patients. DESIGN: Seven AMD patients and 5 control subjects were fed a low-lutein, low-zeaxanthin diet ( approximately 1.1 mg/d) for 2 wk, which was followed by a high-lutein, high-zeaxanthin diet ( approximately 11 mg/d) for 4 wk. Ten subjects continued the diet for 8 wk. Plasma and lipoprotein carotenoids were measured by HPLC. RESULTS: The high-lutein, high-zeaxanthin diet resulted in 2- to 3-fold increases in plasma concentrations of lutein and zeaxanthin and other carotenoids, except lycopene, in the AMD patients and the control subjects. With this diet, 52% of the lutein and 44% of the zeaxanthin were transported by HDL; approximately 22% of lutein and zeaxanthin was transported by LDL. Only 20-25% of alpha-carotene, beta-carotene, and lycopene was transported by HDL; 50-57% was transported by LDL. CONCLUSIONS: The AMD patients and control subjects responded similarly to a diet high in lutein and zeaxanthin; plasma carotenoid concentrations increased greatly in both groups, and the transport of carotenoids by lipoproteins was not significantly different between the groups. This finding suggests that abnormalities in the metabolism of lutein and zeaxanthin in AMD may reside in the uptake of lutein and zeaxanthin from the plasma and transport into the retina.

Barral S, Francis PJ, Schultz DW, Schain MB, Haynes C, Majewski J, Ott J, Acott T, Weleber RG, Klein ML. · Laboratory of Statistical Genetics, Rockefeller University, New York, New York, USA. · Invest Ophthalmol Vis Sci. · Pubmed #17122136 links to  free full text

Abstract: PURPOSE: To investigate further the genetic contribution to age-related macular degeneration (AMD), increasing the power of a previous analysis and reproducing the original findings. METHODS: A large cohort of families with this condition was assembled, and an expanded genome scan was performed with 556 microsatellite markers. In 2003, the results were reported of a genome-wide linkage analysis of 70 of these pedigrees. Members of 51 new families have now been ascertained and many of the original pedigrees expanded. Parametric and nonparametric linkage analyses were performed with a denser map of markers. In addition, analyses were performed with the sample stratified by age at ascertainment and by two major advanced phenotypes for the disease: neovascular AMD (choroidal neovascularization) and geographic atrophy. RESULTS: The results corroborate the macular degeneration-susceptibility loci consistently reported by the authors and others in genome-wide scans. New loci were identified, including the finding of a two-point HLOD of 3.70 at 6q25.2. CONCLUSIONS: The results suggest that the use of families enriched in predisposition to AMD has legitimacy. Genetic analyses of a genome-wide scan performed on our large cohort of families add further confirmatory evidence that susceptibility loci lie on 1q, 3p, 9q, and 10q. Furthermore, new loci have been identified, including a locus on 6q.

Mares JA, LaRowe TL, Snodderly DM, Moeller SM, Gruber MJ, Klein ML, Wooten BR, Johnson EJ, Chappell RJ, Anonymous00283. · Department of Ophthalmology and Visual Sciences, University of Wisconsin, Madison, WI, USA. · Am J Clin Nutr. · Pubmed #17093164 links to  free full text

Abstract: BACKGROUND: Lifestyle, diet, and physical and health predictors of xanthophyll carotenoids in the retina are poorly understood. OBJECTIVE: We aimed to investigate the predictors of the density of lutein and zeaxanthin in the macula of the retina. DESIGN: Macular pigment optical density (MPOD) was measured by heterochromatic flicker photometry. Relations to dietary lutein and zeaxanthin and to other predictors were measured in 1698 women aged 53-86 y. The women were members of observational study cohorts of the Women's Health Initiative at Iowa City, IA, Madison, WI, or Portland, OR, and participated in the Carotenoids in Age-Related Eye Disease Study (2001-2004). RESULTS: MPOD at 0.5 degrees from the foveal center was 30% higher in women in the highest quintile for lutein and zeaxanthin intake [x (+/-SD): 0.40 +/- 0.21] than in women in the lowest quintile (0.31 +/- 0.21) and 20% higher after adjustment for other predictors. Dietary intake of lutein, zeaxanthin, fiber, and polyunsaturated fatty acids (% of energy) together explained 3% of the variability in MPOD. Higher waist circumference and diabetes, which are related to lower MPOD, together with study site explained an additional 5% of variation. The total explained variability increased to 12% when lutein and zexanthin concentrations obtained from the serum, which were collected 4-7 y earlier, were added to the model. CONCLUSIONS: MPOD is directly related to dietary intake of lutein and zeaxanthin but even more strongly to serum concentrations, which may reflect unmeasured physical and medical factors that influence the uptake, distribution, and utilization of lutein and zeaxanthin. Higher abdominal body fat and diabetes are related to lower MPOD. Unknown predictors of retinal carotenoids remain.

Seddon JM, George S, Rosner B, Klein ML. · Epidemiology Unit, Massachusetts Eye and Ear Infirmary, Harvard Medical School, 243 Charles Street, Boston, MA 02114, USA. · Hum Hered. · Pubmed #16816528 links to  free full text

Abstract: OBJECTIVES: We tested the hypothesis that modifiable lifestyle factors alter the genetic susceptibility associated with a common coding variant in the complement factor H (CFH) gene, Y402H, for the leading cause of blindness among the elderly, age-related macular degeneration (AMD). METHODS: In this case-control association analysis, Caucasian participants in the multicenter Age-Related Eye Disease Study with advanced AMD (n = 574 cases) or no AMD (n = 280 controls) were evaluated. AMD status was determined by grading of fundus photographs. Risk factors including cigarette smoking and body mass index (BMI) were assessed and DNA specimens were genotyped for the variant in the CFH gene. Unconditional logistic regression analyses were performed. Attributable risks and multivariable AMD risk scores were calculated. RESULTS: The number of risk alleles for Y402H was associated with advanced AMD, with odds ratios (OR) of 2.7 (95% confidence interval (CI) 1.8-3.8) for the CT heterozygous genotype and OR 7.4 (4.7-11.8) for the homozygous CC risk genotype, after controlling for demographic and behavioral risk factors. Current cigarette smoking (OR 5.1) and high BMI > or =30 (OR 2.1) were independently related to AMD, controlling for genotype. The association between AMD and BMI varied dependent on genotype (P interaction = 0.006 for the CT vs. TT genotype). The CC genotype plus higher BMI (OR 5.9) or smoking (OR 10.2) conferred the greatest risks. Gene plus environment risk scores provided an area under the receiver operating characteristic (ROC) curve of 0.70-0.75. CONCLUSIONS: Genetic and environmental factors are independently related to advanced AMD, and modifiable factors alter genetic susceptibility. The AMD risk score identifies a highly susceptible population.

Seddon JM, Gensler G, Klein ML, Milton RC. · Epidemiology Unit, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA. · Nutrition. · Pubmed #16530626 No free full text.

Abstract: OBJECTIVE: We investigated whether age-related macular degeneration risk factors are associated with high-sensitivity C-reactive protein (CRP) and homocysteine (HCY), systemic biomarkers for cardiovascular disease. METHODS: Subjects with a range of age-related macular maculopathies or no maculopathy at two centers in the United States were evaluated. Risk factors and biomarkers were assessed by questionnaire, direct measurement, or analyses of blood specimens. RESULTS: Higher levels of serum antioxidants vitamin C and lutein/zeaxanthin and higher fish intake were associated with lower serum CRP levels, whereas serum vitamin E, smoking, and increased body mass index were associated with increased CRP. Serum vitamin E, serum alpha-carotene, and dietary intake of antioxidants and vitamin B6 were associated with lower levels of plasma HCY, whereas hypertension was associated with increased HCY. CONCLUSIONS: C-reactive protein and HCY levels are related to traditional dietary and behavioral factors associated with age-related macular degeneration.

Seddon JM, Gensler G, Klein ML, Milton RC. · Epidemiology Unit, Massachusetts Eye and Ear Infirmary, 243 Charles Street, Boston, MA 02114, USA. · Am J Ophthalmol. · Pubmed #16387004 No free full text.

Abstract: PURPOSE: To assess the relationship between plasma levels of homocysteine and age-related macular degeneration (AMD). DESIGN: Cross-sectional, case-control study. METHODS: Fasting plasma homocysteine levels were measured at two centers in 934 individuals who were participating in an ancillary study of the Age-Related Eye Disease Study. There were 547 cases and 387 control subjects, who were determined by fundus photography. Conditional logistic regression analyses were conducted to assess the association of homocysteine with AMD. RESULTS: Median values of homocysteine were higher among advanced AMD cases (9.51 mmol/l) compared with persons with no AMD (8.81 mmol/l; P = .01). Values of >12 mmol/l vs < or =12 mmol/l were also associated with an increased risk of AMD (P = .023), when controlled for other covariates. CONCLUSION: Results are consistent with a possible small, independent association between higher homocysteine levels and AMD. Homocysteine may be a modifiable risk factor for AMD.

Francis PJ, Schultz DW, Gregory AM, Schain MB, Barra R, Majewski J, Ott J, Acott T, Weleber RG, Klein ML. · Macular Degeneration Center, Casey Eye Institute, Oregon Health and Science University, 3375 SW Terwilliger Blvd, Portland, OR 97239-4197, USA. · Br J Ophthalmol. · Pubmed #16113362 links to  free full text

Abstract: BACKGROUND: The pattern dystrophies (PD) represent a clinically heterogeneous family of inherited macular diseases frequently caused by mutations in the peripherin/RDS gene. Most previous studies have detailed the clinical findings in single families, making it difficult to derive data from which progression and visual outcome can be generalised. METHODS: Families were ascertained and clinically evaluated including angiography and electrophysiology where appropriate. RESULTS: In each of the six families with autosomal dominant PD, a mutation in the peripherin/RDS gene was identified, including a novel Cys250Phe variant. These data suggest that the condition is characterised by the accumulation of yellow to grey subretinal flecks, followed by pigmentary change accompanied by patches of chorioretinal atrophy. Subsequently, 50% (16/32) of individuals with PD developed poor central vision because of chorioretinal geographic atrophy or subretinal neovascularisation. The risk of these complications appears to increase with age. CONCLUSION: PD should not necessarily be considered a benign condition. Instead, patients should be counselled that there is a significant chance of losing central vision in their later years. Some elderly patients with probands showing PD may be misdiagnosed with age related macular degeneration owing to the phenotypic similarities between these conditions in the advanced state.

Fisher SA, Abecasis GR, Yashar BM, Zareparsi S, Swaroop A, Iyengar SK, Klein BE, Klein R, Lee KE, Majewski J, Schultz DW, Klein ML, Seddon JM, Santangelo SL, Weeks DE, Conley YP, Mah TS, Schmidt S, Haines JL, Pericak-Vance MA, Gorin MB, Schulz HL, Pardi F, Lewis CM, Weber BH. · Department of Medical and Molecular Genetics, Guy's, King's and St Thomas' School of Medicine, King's College London, London SE1 9RT, UK. · Hum Mol Genet. · Pubmed #15987700 links to  free full text

Abstract: A genetic contribution to the development of age-related macular degeneration (AMD) is well established. Several genome-wide linkage studies have identified a number of putative susceptibility loci for AMD but only a few of these regions have been replicated in independent studies. Here, we perform a meta-analysis of six AMD genome screens using the genome-scan meta-analysis method, which allows linkage results from several studies to be combined, providing greater power to identify regions that show only weak evidence for linkage in individual studies. Results from non-parametric analysis for a broad AMD clinical phenotype (including two studies with quantitative traits) were extracted. For each study, 120 genomic bins of approximately 30 cM were defined and ranked according to maximum evidence for linkage within each bin. Bin ranks were weighted according to study size and summed across all studies; the summed rank (SR) for each bin was assessed empirically for significance using permutation methods. A high SR indicates a region with consistent evidence for linkage across studies. The strongest evidence for an AMD susceptibility locus was found on chromosome 10q26 where genome-wide significant linkage was observed (P=0.00025). Several other regions met the empirical significance criteria for bins likely to contain linked loci including adjacent pairs of bins on chromosomes 1q, 2p, 3p and 16. Several of the regions identified here showed only weak evidence for linkage in the individual studies. These results will help prioritize regions for future positional and functional candidate gene studies in AMD.