Purpose To describe associations of serum lipid levels and lipid pathway genes to the incidence of age-related macular degeneration (AMD). Design Meta-analysis. Methods setting : Three ...population-based cohorts. population : A total of 6950 participants from the Beaver Dam Eye Study (BDES), Blue Mountains Eye Study (BMES), and Rotterdam Study (RS). observation procedures : Participants were followed over 20 years and examined at 5-year intervals. Hazard ratios associated with lipid levels per standard deviation above the mean or associated with each additional risk allele for each lipid pathway gene were calculated using random-effects inverse-weighted meta-analysis models, adjusting for known AMD risk factors. main outcome measures : Incidence of AMD. Results The average 5-year incidences of early AMD were 8.1%, 15.1%, and 13.0% in the BDES, BMES, and RS, respectively. Substantial heterogeneity in the effect of cholesterol and lipid pathway genes on the incidence and progression of AMD was evident when the data from the 3 studies were combined in meta-analysis. After correction for multiple comparisons, we did not find a statistically significant association between any of the cholesterol measures, statin use, or serum lipid genes and any of the AMD outcomes in the meta-analysis. Conclusion In a meta-analysis, there were no associations of cholesterol measures, history of statin use, or lipid pathway genes to the incidence and progression of AMD. These findings add to inconsistencies in earlier reports from our studies and others showing weak associations, no associations, or inverse associations of high-density lipoprotein cholesterol and total cholesterol with AMD.
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Generalized retinal arteriolar narrowing is an important sign of systemic hypertension, and a lower arteriolar:venular diameter ratio predicts the risk of hypertension. We investigated whether this ...association was based on arteriolar or venular diameters or both. This study was based on the prospective population-based Rotterdam Study (1990–1993) and included 1900 participants (≥55 years of age) of whom 739 persons had normal blood pressure (systolic <120 mm Hg and diastolic <80 mm Hg) and 1161 prehypertension (systolic 120 to 139 mm Hg or diastolic 80 to 89 mm Hg). For each participant, retinal arteriolar and venular diameters were measured on digitized images of 1 eye. After a mean follow-up of 6.6 years, 808 persons developed hypertension, defined as either systolic blood pressure ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg or use of antihypertensive medication. Adjusted for age, gender, follow-up time, body mass index, smoking, diabetes mellitus, total and high-density lipoprotein cholesterol, C-reactive protein, and intima-media thickness, arteriolar narrowing was associated with an increased risk of hypertension (odds ratio per SD1.38; 95% CI, 1.23 to 1.55); for venular narrowing this was less striking (OR1.17; 95% CI, 1.04 to 1.32). Each SD decrease in the arteriolar:venular diameter ratio significantly increased the risk of hypertension by 24%. To examine the effect of baseline blood pressure, we stratified persons into those with “normal blood pressure” or “prehypertension.” Within these strata, arteriolar narrowing was still related to incident hypertension. These data show that both retinal arteriolar and venular narrowing may precede the development of systemic hypertension.
Genome-wide association studies and targeted sequencing studies of candidate genes have identified common and rare variants that are associated with age-related macular degeneration (AMD). ...Whole-exome sequencing (WES) studies allow a more comprehensive analysis of rare coding variants across all genes of the genome and will contribute to a better understanding of the underlying disease mechanisms. To date, the number of WES studies in AMD case-control cohorts remains scarce and sample sizes are limited. To scrutinize the role of rare protein-altering variants in AMD cause, we performed the largest WES study in AMD to date in a large European cohort consisting of 1125 AMD patients and 1361 control participants.
Genome-wide case-control association study of WES data.
One thousand one hundred twenty-five AMD patients and 1361 control participants.
A single variant association test of WES data was performed to detect variants that are associated individually with AMD. The cumulative effect of multiple rare variants with 1 gene was analyzed using a gene-based CMC burden test. Immunohistochemistry was performed to determine the localization of the Col8a1 protein in mouse eyes.
Genetic variants associated with AMD.
We detected significantly more rare protein-altering variants in the COL8A1 gene in patients (22/2250 alleles 1.0%) than in control participants (11/2722 alleles 0.4%; P = 7.07×10–5). The association of rare variants in the COL8A1 gene is independent of the common intergenic variant (rs140647181) near the COL8A1 gene previously associated with AMD. We demonstrated that the Col8a1 protein localizes at Bruch’s membrane.
This study supported a role for protein-altering variants in the COL8A1 gene in AMD pathogenesis. We demonstrated the presence of Col8a1 in Bruch’s membrane, further supporting the role of COL8A1 variants in AMD pathogenesis. Protein-altering variants in COL8A1 may alter the integrity of Bruch’s membrane, contributing to the accumulation of drusen and the development of AMD.
To determine whether blood pressure and subclinical atherosclerosis are associated with incident age-related maculopathy (ARM).
The study was performed within the Rotterdam Study, a population-based, ...prospective cohort study in Rotterdam, The Netherlands. A total of 4822 subjects who at baseline were aged 55 years more, were free of ARM, and participated in at least one of two follow-up examinations after a mean of 2 and 6.5 years, were included in the study. At baseline, blood pressure and the presence of atherosclerosis were determined. ARM was assessed according to the International Classification and Grading System and defined as large, soft drusen with pigmentary changes; indistinct drusen; or atrophic or neovascular age-related macular degeneration.
After a mean follow-up of 5.2 years, incident ARM was diagnosed in 417 subjects. Increased systolic blood pressure or pulse pressure was associated with a higher risk of ARM. Adjusted for age, gender, smoking, total and high-density lipoprotein cholesterol, body mass index, and diabetes mellitus, odds ratios (OR) per 10-mm Hg increase were 1.08 (95% confidence interval CI: 1.03-1.14) and 1.11 (95% CI: 1.04-1.18), respectively. Moreover, different measures of atherosclerosis were associated with the risk of ARM. An increase in carotid wall thickness (OR per 1 SD, 1.15; 95% CI: 1.03-1.28) increased the risk of ARM. The lowest compared with the highest tertile of ankle-arm index had an OR of 1.32 (95% CI: 1.00-1.75). A weak association was found between aortic calcifications and the risk of ARM.
Elevated systolic blood or pulse pressure or the presence of atherosclerosis may increase the risk of development of ARM.
Abstract
Purpose: To describe methods to harmonize the classification of age-related macular degeneration (AMD) phenotypes across four population-based cohort studies: the Beaver Dam Eye Study ...(BDES), the Blue Mountains Eye Study (BMES), the Los Angeles Latino Eye Study (LALES), and the Rotterdam Study (RS).
Methods: AMD grading protocols, definitions of categories, and grading forms from each study were compared to determine whether there were systematic differences in AMD severity definitions and lesion categorization among the three grading centers. Each center graded the same set of 60 images using their respective systems to determine presence and severity of AMD lesions. A common 5-step AMD severity scale and definitions of lesion measurement cutpoints and early and late AMD were developed from this exercise.
Results: Applying this severity scale changed the age-sex adjusted prevalence of early AMD from 18.7% to 20.3% in BDES, from 4.7% to 14.4% in BMES, from 14.1% to 15.8% in LALES, and from 7.5% to 17.1% in RS. Age-sex adjusted prevalences of late AMD remained unchanged. Comparison of each center's grades of the 60 images converted to the consortium scale showed that exact agreement of AMD severity among centers varied from 61.0-81.4%, and one-step agreement varied from 84.7-98.3%.
Conclusion: Harmonization of AMD classification reduced categorical differences in phenotypic definitions across the studies, resulted in a new 5-step AMD severity scale, and enhanced similarity of AMD prevalence among the four cohorts. Despite harmonization it may still be difficult to remove systematic differences in grading, if present.
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CONTEXT Age-related macular degeneration (AMD) is the most prevalent cause of irreversible blindness in developed countries. Recently, high-dose supplementation with beta carotene, vitamins C and E, ...and zinc was shown to slow the progression of AMD. OBJECTIVE To investigate whether regular dietary intake of antioxidants is associated with a lower risk of incident AMD. DESIGN Dietary intake was assessed at baseline in the Rotterdam Study (1990-1993) using a semiquantitative food frequency questionnaire. Incident AMD until final follow-up in 2004 was determined by grading fundus color transparencies in a masked way according to the International Classification and Grading System. SETTING Population-based cohort of all inhabitants aged 55 years or older in a middle-class suburb of Rotterdam, the Netherlands. PARTICIPANTS Of 5836 persons at risk of AMD at baseline, 4765 had reliable dietary data and 4170 participated in the follow-up. MAIN OUTCOME MEASURE Incident AMD, defined as soft distinct drusen with pigment alterations, indistinct or reticular drusen, geographic atrophy, or choroidal neovascularization. RESULTS Incident AMD occurred in 560 participants after a mean follow-up of 8.0 years (range, 0.3-13.9 years). Dietary intake of both vitamin E and zinc was inversely associated with incident AMD. The hazard ratio (HR) per standard deviation increase of intake for vitamin E was 0.92 (95% confidence interval CI, 0.84-1.00) and for zinc was 0.91 (95% CI, 0.83-0.98). An above-median intake of all 4 nutrients, beta carotene, vitamin C, vitamin E, and zinc, was associated with a 35% reduced risk (HR, 0.65; 95% CI, 0.46-0.92) of AMD. Exclusion of supplement users did not affect the results. CONCLUSION In this study, a high dietary intake of beta carotene, vitamins C and E, and zinc was associated with a substantially reduced risk of AMD in elderly persons.
To assess the 5-year progression from unilateral to bilateral age-related macular degeneration (AMD) and associated risk factors.
Pooled data analyses of three prospective population-based cohorts, ...the Blue Mountains Eye Study, Beaver Dam Eye Study and Rotterdam Study.
Retinal photography and interview with comprehensive questionnaires were conducted at each visit of three studies. AMD was assessed following the modified Wisconsin AMD grading protocol. Progression to bilateral any (early and late) or late AMD was assessed among participants with unilateral involvement only. Factors associated with the progression were assessed using logistic regression models while simultaneously adjusting for other significant risk factors.
In any 5-year duration, 19-28% of unilateral any AMD cases became bilateral and 27-68% of unilateral late AMD became bilateral. Factors associated with the progression to bilateral involvement of any AMD were age (per year increase, adjusted OR 1.07), carrying risk alleles of the
and
genes (compared with none, OR 1.76 for 1 risk allele and OR 3.34 for 2+ risk alleles), smoking (compared with non-smokers, OR 1.64 for past and OR 1.67 for current smokers), and the presence of large drusen area or retinal pigmentary abnormalities in the first eye.
One in four to one in five unilateral any AMD cases, and up to one in two unilateral late AMD cases, progressed to bilateral in 5 years. Known AMD risk factors, including smoking, are significantly associated with the progression to bilateral involvement.
Prediction models for age-related macular degeneration (AMD) based on case-control studies have a tendency to overestimate risks. The aim of this study is to develop a prediction model for late AMD ...based on data from population-based studies.
Three population-based studies: the Rotterdam Study (RS), the Beaver Dam Eye Study (BDES), and the Blue Mountains Eye Study (BMES) from the Three Continent AMD Consortium (3CC).
People (n = 10,106) with gradable fundus photographs, genotype data, and follow-up data without late AMD at baseline.
Features of AMD were graded on fundus photographs using the 3CC AMD severity scale. Associations with known genetic and environmental AMD risk factors were tested using Cox proportional hazard analysis. In the RS, the prediction of AMD was estimated for multivariate models by area under receiver operating characteristic curves (AUCs). The best model was validated in the BDES and BMES, and associations of variables were re-estimated in the pooled data set. Beta coefficients were used to construct a risk score, and risk of incident late AMD was calculated using Cox proportional hazard analysis. Cumulative incident risks were estimated using Kaplan-Meier product-limit analysis.
Incident late AMD determined per visit during a median follow-up period of 11.1 years with a total of 4 to 5 visits.
Overall, 363 participants developed incident late AMD, 3378 participants developed early AMD, and 6365 participants remained free of any AMD. The highest AUC was achieved with a model including age, sex, 26 single nucleotide polymorphisms in AMD risk genes, smoking, body mass index, and baseline AMD phenotype. The AUC of this model was 0.88 in the RS, 0.85 in the BDES and BMES at validation, and 0.87 in the pooled analysis. Individuals with low-risk scores had a hazard ratio (HR) of 0.02 (95% confidence interval CI, 0.01-0.04) to develop late AMD, and individuals with high-risk scores had an HR of 22.0 (95% CI, 15.2-31.8). Cumulative risk of incident late AMD ranged from virtually 0 to more than 65% for those with the highest risk scores.
Our prediction model is robust and distinguishes well between those who will develop late AMD and those who will not. Estimated risks were lower in these population-based studies than in previous case-control studies.
The optic nerve head is involved in many ophthalmic disorders, including common diseases such as myopia and open-angle glaucoma. Two of the most important parameters are the size of the optic disc ...area and the vertical cup-disc ratio (VCDR). Both are highly heritable but genetically largely undetermined. We performed a meta-analysis of genome-wide association (GWA) data to identify genetic variants associated with optic disc area and VCDR. The gene discovery included 7,360 unrelated individuals from the population-based Rotterdam Study I and Rotterdam Study II cohorts. These cohorts revealed two genome-wide significant loci for optic disc area, rs1192415 on chromosome 1p22 (p = 6.72x10(-19)) within 117 kb of the CDC7 gene and rs1900004 on chromosome 10q21.3-q22.1 (p = 2.67x10(-33)) within 10 kb of the ATOH7 gene. They revealed two genome-wide significant loci for VCDR, rs1063192 on chromosome 9p21 (p = 6.15x10(-11)) in the CDKN2B gene and rs10483727 on chromosome 14q22.3-q23 (p = 2.93x10(-10)) within 40 kbp of the SIX1 gene. Findings were replicated in two independent Dutch cohorts (Rotterdam Study III and Erasmus Rucphen Family study; N = 3,612), and the TwinsUK cohort (N = 843). Meta-analysis with the replication cohorts confirmed the four loci and revealed a third locus at 16q12.1 associated with optic disc area, and four other loci at 11q13, 13q13, 17q23 (borderline significant), and 22q12.1 for VCDR. ATOH7 was also associated with VCDR independent of optic disc area. Three of the loci were marginally associated with open-angle glaucoma. The protein pathways in which the loci of optic disc area are involved overlap with those identified for VCDR, suggesting a common genetic origin.
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