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© 2015 Wiley Periodicals, Inc. Primary open-angle glaucoma is the most common optic neuropathy and an important cause of irreversible blindness worldwide. The optic nerve head or optic disc is divided in two parts: a central cup (without nerve fibers) surrounded by the neuroretinal rim (containing axons of the retinal ganglion cells). The International Glaucoma Genetics Consortium conducted a meta-analysis of genome-wide association studies consisting of 17,248 individuals of European ancestry and 6,841 individuals of Asian ancestry. The outcomes of the genome-wide association studies were disc area and cup area. These specific measurements describe optic nerve morphology in another way than the vertical cup-disc ratio, which is a clinically used measurement, and may shed light on new glaucoma mechanisms. We identified 10 new loci associated with disc area (CDC42BPA, F5, DIRC3, RARB, ABI3BP, DCAF4L2, ELP4, TMTC2, NR2F2, and HORMAD2) and another 10 new loci associated with cup area (DHRS3, TRIB2, EFEMP1, FLNB, FAM101, DDHD1, ASB7, KPNB1, BCAS3, and TRIOBP). The new genes participate in a number of pathways and future work is likely to identify more functions related to the pathogenesis of glaucoma.

© 2014 Macmillan Publishers Limited. All rights reserved. Glaucoma is characterized by irreversible optic nerve degeneration and is the most frequent cause of irreversible blindness worldwide. Here, the International Glaucoma Genetics Consortium conducts a meta-analysis of genome-wide association studies of vertical cup-disc ratio (VCDR), an important disease-related optic nerve parameter. In 21,094 individuals of European ancestry and 6,784 individuals of Asian ancestry, we identify 10 new loci associated with variation in VCDR. In a separate risk-score analysis of five case-control studies, Caucasians in the highest quintile have a 2.5-fold increased risk of primary open-angle glaucoma as compared with those in the lowest quintile. This study has more than doubled the known loci associated with optic disc cupping and will allow greater understanding of mechanisms involved in this common blinding condition.

This study examined cross-sectionally the association of dietary beta-carotene, vitamin C, and vitamin E with peripheral arterial disease in Rotterdam, the Netherlands (1990--1993). The 4,367 subjects from the Rotterdam Study were aged 55--94 years and had no previous cardiovascular disease at baseline. Diet was assessed with a food frequency questionnaire. Peripheral arterial disease was defined as an ankle-arm systolic blood pressure index (AAI) of < or = 0.9 and was present in 204 men and 370 women. In multivariate-adjusted logistic regression analyses, vitamin C intake was significantly inversely associated with peripheral arterial disease in women (highest vs. lowest quartile: relative risk = 0.64, 95% confidence interval (CI): 0.48, 0.89; p(trend) = 0.006), and a 100-mg increase in intake was associated with a 0.013 AAI increase (95% CI: 0.001, 0.025). In men, vitamin E intake was inversely associated with peripheral arterial disease (relative risk = 0.67, 95% CI: 0.44, 1.03; p(trend) = 0.067); a 10-mg increase in intake was associated with a 0.015 AAI increase (95% CI: 0.001, 0.031). Whether these differences in antioxidant intake and the risk of a low AAI and of peripheral arterial disease between sexes are attributable to a different food pattern for men compared with women remains to be elucidated.

Objective: To study associations between aspirin use and early and late aging macula disorder (AMD). Design: Population-based cross-sectional European Eye Study in 7 centers from northern to southern Europe. Participants: In total, 4691 participants 65 years of age and older, collected by random sampling. Methods: Aspirin intake and possible confounders for AMD were ascertained by a structured questionnaire. Ophthalmic and basic systemic measurements were performed in a standardized way. The study classified AMD according to the modified International Classification System on digitized fundus images at 1 grading center. Nonfasting blood samples were analyzed in a single laboratory. Associations were analyzed by logistic regression. Main Outcome Measures: Odds ratios (ORs) for AMD in aspirin users. Results: Early AMD was present in 36.4% of the participants and late AMD was present in 3.3% of participants. Monthly aspirin use was reported by 1931 (41.2%), at least once weekly by 7%, and daily use by 17.3%. For daily aspirin users, the ORs, adjusted for potential confounders, showed a steady increase with increasing severity of AMD grades. These were: grade 1, 1.26 (95% confidence interval [CI], 1.08-1.46; P

Purpose: Age-related macular degeneration (AMD) is a major cause of blindness in older adults and has a genetically complex background. This study examines the potential association between single nucleotide polymorphisms (SNPs) in the glucose transporter 1 (SLC2A1) gene and AMD. SLC2A1 regulates the bioavailability of glucose in the retinal pigment epithelium (RPE), which might influence oxidative stress-mediated AMD pathology. Methods: Twenty-two SNPs spanning the SLC2A1 gene were genotyped in 375 cases and 199 controls from an initial discovery cohort (the Amsterdam-Rotterdam-Netherlands study). Replication testing was performed in The Rotterdam Study (the Netherlands) and study populations from Wurzburg (Germany), the Age Related Eye Disease Study (AREDS; United States), Columbia University (United States), and Iowa University (United States). Subsequently, a meta-analysis of SNP association was performed. Results: In the discovery cohort, significant genotypic association between three SNPs (rs3754219, rs4660687, and rs841853) and AMD was found. Replication in five large independent (Caucasian) cohorts (4,860 cases and 4,004 controls) did not yield consistent association results. The genotype frequencies for these SNPs were significantly different for the controls and/or cases among the six individual populations. Meta-analysis revealed significant heterogeneity of effect between the studies. Conclusions: No overall association between SLC2A1 SNPs and AMD was demonstrated. Since the genotype frequencies for the three SLC2A1 SNPs were significantly different for the controls and/or cases between the six cohorts, this study corroborates previous evidence that population dependent genetic risk heterogeneity in AMD exists.

Objective: To investigate whether dietary nutrients can reduce the genetic risk of early age-related macular degeneration (AMD) conferred by the genetic variants CFH Y402H and LOC387715 A69S in a nested case-control study. Methods: For 2167 individuals (>= 55 years) from the population-based Rotterdam Study at risk of AMD, dietary intake was assessed at baseline using a semiquantitative food frequency questionnaire and genetic variants were determined using TaqMan assay. Incident early AMD was determined on fundus photographs at 3 follow-up visits (median follow-up, 8.6 years). The synergy index was used to evaluate biological interaction between risk factors; hazard ratios were calculated to estimate risk of early AMD in strata of nutrient intake and genotypes. Results: Five hundred seventeen participants developed early AMD. Significant synergy indices supported the possibility of biological interaction between CFH Y402H and zinc, beta-carotene, lutein/zeaxanthin, and eicosapentaenoic/docosahexaenoic acid (EPA/DHA) and between LOC387715 A69S and zinc and EPA/DHA (all P < .05). Homozygotes of CFH Y402H with dietary intake of zinc in the highest tertile reduced their hazard ratio of early AMD from 2.25 to 1.27. For intakes of beta-carotene, lutein/zeaxanthin, and EPA/DHA, these risk reductions were from 2.54 to 1.47, 2.63 to 1.72, and 1.97 to 1.30, respectively. Carriers of LOC387715 A69S with the highest intake of zinc and EPA/DHA reduced their risk from 1.70 to 1.17 and 1.59 to 0.95, respectively (all P trends

Purpose: Vascular endothelial growth factor (VEGF) is an important regulator of angiogenesis and a target for inhibition therapy in wet age-related macular degeneration (AMD). The purpose of this study was to examine whether genetic variation in the VEGF gene is associated with AMD and, especially, with its wet end stage. Design: Prospective population-based cohort study. Participants: Four thousand two hundred twenty-eight participants aged 55 years and older. Methods: AMD was classified according to a modified International Classification System using fundus color images. Genotypes and haplotypes were determined for 3 functional VEGF single nucleotide polymorphisms (SNPs): C-2578A, G-1154A, and G-634C. Cox proportional hazards regression analyses were used to investigate possible associations between the individual SNPs and incident AMD. The Haplo.Stats program was used to test the associations between VEGF gene haplotypes and incident AMD. Main Outcome Measure: AMD Results: Of 4228 participants at risk for incident early and late AMD for whom blood specimens were available for VEGF genotyping, incident early AMD developed in 514 and incident late AMD developed in 89 (35 dry and 54 wet) after a mean follow-up of 7.4 years. None of the SNPs showed a significant association with incident early or late AMD, especially not with incident wet AMD. Haplotype analyses also detected no associations. Conclusions: The a priori hypothesis that 3 common SNPs in the VEGF gene would be a risk factor for AMD, especially the wet form, could not be confirmed. Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references. Ophthalmology 2008; 115:1899-1903 (C) 2008 by the American Academy of Ophthalmology.

Objective: Retinal vessel diameters, in particular larger venular diameters, have been associated with cerebrovascular disease. Larger retinal venular diameters may reflect cerebral ischemia. The authors investigated whether arteriolar oxygen saturation (SaO(2)) and total cerebral blood flow (CBF), indicators of cerebral oxygen supply, are associated with retinal arteriolar or venular diameters. Design: Cross-sectional study performed within the population-based Rotterdam Study. Participants: Randomly selected participants aged 55 years or older (n = 696), who underwent both an eye examination and brain magnetic resonance imaging (MRI). Methods: Arteriolar oxygen saturation was determined by pulse oximetry on the right index finger. Cerebral blood flow was assessed using a phase-contrast MRI sequence that measured the flow in the basilar and both internal carotid arteries. Brain volume was measured to express CBF per 100 ml brain volume. Retinal arteriolar and venular diameters were measured on digitized fundus color transparencies on 1 eye of each participant. Regression models were used to investigate the association of SaO(2) and CBF with retinal vessel diameters. Main Outcome Measures: Mean retinal arteriolar and venular diameters (in micrometers). Results: Lower SaO(2) was associated with larger venular diameters. Persons with SaO(2) less than 96% (n 113) had on average 5 mu m larger venular diameters compared with those with SaO(2) of 96% or more (n = 583; age- and gender-adjusted mean difference, 5.6 mu m; 95% confidence interval, 1.2-10.0). Cerebral blood flow was not related to venular diameters when analyzed separately. Additional analyses showed that the association between SaO(2) and venular widening was confined to participants within the lowest tertile of CBF. No associations were found between SaO(2) or CBF and arteriolar diameters. Additional adjustment for established cardiovascular risk factors did not change the results. Conclusions: An association of lower SaO(2) with larger retinal venular diameters was observed, in particular in the presence of lower CBF. These findings suggest that venular widening may reflect a lower oxygen supply, especially to the brain.

Objective: To investigate whether polymorphisms in the estrogen receptor alpha (ESR1) and beta (ESR2) genes were a risk factor for open-angle glaucoma (OAG). Methods: Participants 55 years and older from the population-based Rotterdam Study underwent, at baseline and at follow-up, the same ophthalmic examination, including visual field screening and stereo optic disc photography. A diagnosis of OAG was based on an algorithm using optic disc measures and visual field loss. Haplotypes of the ESR1 and ESR2 genes were determined. Results: We diagnosed incident OAG in 87 of 3842 participants (2.3%) at risk after a mean follow-up of 6.5 years. We could not detect any association with ESR1 haplotypes. Haplotype 1 of ESR2 showed a 3.6-fold (95% confidence interval, 1.4-9.2) higher risk of incident OAG in men. In women, no association was found between ESR2 and incident OAG. Conclusion: Polymorphisms in the ESR1 gene are unrelated to OAG, but ESR2 polymorphisms seem to lead to increased risk of OAG in men.

Purpose: To determine the incidence of open–angle glaucoma (OAG) in a general elderly Caucasian population. Methods: Participants (n=3842) of the prospective population–based Rotterdam Study, aged 55 years and older and at risk for incident OAG, underwent at baseline and follow–up the same ophthalmic examination including measurement of intra–ocular pressure, visual field testing and stereo optic disc photography. The diagnosis of probable or definite OAG was made with an algorithm based on optic disc parameters and on glaucomatous visual field loss, independent of the intra–ocular pressure. The incidence was calculated in incidence rates and 5–year risks. Results:After a mean follow–up time of 6.5 years, probable or definite OAG developed in 87 persons. The 5–year risk rose threefold till 3.2% in men between ages 55 and 80 years and one and a half times till 2.3% in women. The odds ratio for men versus women was 1.3 (95% confidence interval: 0.9–2.0) Bilateral OAG occurred five times more often after than before age 75. In participants with prevalent OAG in one eye, the 5–year risk of OAG in the fellow eye was five times higher than in fellow eyes of non–OAG eyes. Only 37% of the incident cases received treatment for OAG. Conclusions:The incidence of OAG rose with age and more in men than in women. Bilateral incident OAG occurred more frequently among the eldest participants. The majority of the new cases was unaware of having OAG.

To investigate whether there is an association between the use of medication and the incidence of early age-related maculopathy (ARM). Pooled data from 3 prospective, population-based cohort studies. Subjects without early and late ARM at baseline who participated in the follow-up of the Beaver Dam Eye Study (n = 3012), the Rotterdam Study (n = 3434), and the Blue Mountains Eye Study (n = 2203). Stereoscopic color fundus photographs of all participants were graded according to a standardized protocol. At baseline, current use of prescription and over-the-counter medication was assessed by interview, and the drug name was confirmed at the research centers. Procedures and definitions were similar at both baseline and follow-up across the 3 study sites. Incidence of early ARM, defined as the presence at follow-up of either soft distinct drusen with pigmentary changes or soft indistinct or reticular drusen. In the pooled cohort, 53.3% of participants used at least one of the medications selected for this study. Within a mean period of 5.6 years, a total of 683 subjects developed early ARM. Users of antihypertensive medication in general, and beta-blockers in particular, had a borderline statistically significant increased risk of early ARM (odds ratio [OR] for beta-blockers, 1.3; 95% confidence interval [CI], 1.0-1.6) when adjusted for systolic (or diastolic) blood pressure and other confounders. A protective effect of borderline significance was found among women using hormone replacement therapy (OR, 0.6; 95% CI, 0.4-1.0) and in persons using tricyclic antidepressants (OR, 0.4; 95% CI, 0.2-1.0). In contrast with beta-blockers, the direction and magnitude of the association with hormone replacement therapy and tricyclic antidepressants were inconsistent among the 3 study populations. Pooled data from 3 population-based studies showed no strong associations between medication use and the incidence of early ARM. Of borderline significance were a slightly increased risk among users of beta-blockers and a reduced risk among users of hormone replacement therapy and users of tricyclic antidepressants. Although beta-blocker use could be a proxy for systemic hypertension, these findings warrant further investigations, preferably including information on the dosage and duration of drug exposure