Atherosclerosis, C-reactive protein, and risk for open-angle glaucoma:The Rotterdam study

PURPOSE. To test the hypotheses that atherosclerosis and elevated serum C-reactive protein ( CRP) levels are risk factors for open-angle glaucoma ( OAG). METHODS. In a prospective, population-based cohort study, all participants 55 years and older and at risk for incident OAG underwent, at baseline ( 1990 - 1993) and at follow-up ( 1997 1999), the same ophthalmic examination, including visual field testing and optic disc photography. Baseline atherosclerosis was assessed by means of echography of the carotid arteries, abdominal x-ray examination, and ankle-arm index; baseline serum CRP levels were used in the analyses. The diagnosis of OAG was based on an algorithm using optic disc measures and visual field loss. Odds ratios of OAG were computed with logistic regression analyses. Risk factors were categorized in tertiles and according to standard deviation. RESULTS. After a mean follow-up of 6.5 years, incident OAG was diagnosed in 87 of 3842 ( 2.3%) participants at risk for OAG. Carotid artery plaques, carotid intima-media thickness, aortic calcifications, ankle-arm index, and CRP levels were not significant risk factors for OAG. The odds ratio, given for the highest and lowest tertiles, for carotid plaques was 1.43 ( 95% confidence interval [ CI], 0.68 - 2.99), for carotid intima-media thickness 0.86 ( 95% CI, 0.47 - 1.57), for aortic calcifications 1.02 ( 95% CI, 0.60 - 1.75), for ankle-arm index 0.69 ( 95% CI, 0.38 - 1.25), and for CRP 1.19 ( 95% CI, 0.68 - 2.07). CONCLUSIONS. In this prospective, population-based study, neither atherosclerosis nor serum CRP level was an important risk factor for OAG

Nutrient intake and risk of open-angle glaucoma: the Rotterdam Study

Open-angle glaucoma (OAG) is the commonest cause of irreversible blindness worldwide. Apart from an increased intraocular pressure (IOP), oxidative stress and an impaired ocular blood flow are supposed to contribute to OAG. The aim of this study was to determine whether the dietary intake of nutrients that either have anti-oxidative properties (carotenoids, vitamins, and flavonoids) or influence the blood flow (omega fatty acids and magnesium) is associated with incident OAG. We investigated this in a prospective population-based cohort, the Rotterdam Study. A total of 3502 participants aged 55 years and older for whom dietary data at baseline and ophthalmic data at baseline and follow-up were available and who did not have OAG at baseline were included. The ophthalmic examinations comprised measurements of the IOP and perimetry; dietary intake of nutrients was assessed by validated questionnaires and adjusted for energy intake. Cox proportional hazard regression analysis was applied to calculate hazard ratios of associations between the baseline intake of nutrients and incident OAG, adjusted for age, gender, IOP, IOP-lowering treatment, and body mass index. During an average follow-up of 9.7 years, 91 participants (2.6%) developed OAG. The hazard ratio for retinol equivalents (highest versus lowest tertile) was 0.45 (95% confidence interval 0.23–0.90), for vitamin B1 0.50 (0.25–0.98), and for magnesium 2.25 (1.16–4.38). The effects were stronger after the exclusion of participants taking supplements. Hence, a low intake of retinol equivalents and vitamin B1 (in line with hypothesis) and a high intake of magnesium (less unambiguous to interpret) appear to be associated with an increased risk of OAG

Comprehensive Analysis of the Candidate Genes CCL2, CCR2, and TLR4 in Age-Related Macular Degeneration

PURPOSE. To determine whether variants in the candidate genes TLR4, CCL2, and CCR2 are associated with age-related macular degeneration (AMD). METHODS. This study was performed in two independent Caucasian populations that included 357 cases and 173 controls from the Netherlands and 368 cases and 368 controls from the United States. Exon 4 of the TLR4 gene and the promoter, all exons, and flanking intronic regions of the CCL2 and CCR2 genes were analyzed in the Dutch study and common variants were validated in the U.S. study. Quantitative (q)PCR reactions were performed to evaluate expression of these genes in laserdissected retinal pigment epithelium from 13 donor AMD and 13 control eyes. RESULTS. Analysis of single nucleotide polymorphisms (SNPs) in the TLR4 gene did not show a significant association between D299G or T399I and AMD, nor did haplotypes containing these variants. Univariate analyses of the SNPs in CCL2 and CCR2 did not demonstrate an association with AMD. For CCR2, haplotype frequencies were not significantly different between cases and controls. For CCL2, one haplotype containing the minor allele of C35C was significantly associated with AMD (P ϭ 0.03), but this did not sustain after adjustment for multiple testing (q ϭ 0.30). Expression analysis did not demonstrate altered RNA expression of CCL2 and CCR2 in the retinal pigment epithelium from AMD eyes (for CCL2 P ϭ 0.62; for CCR2 P ϭ 0.97). CONCLUSIONS. No evidence was found of an association between TLR4, CCR2, and CCL2 and AMD, which implies that the common genetic variation in these genes does not play a significant role in the etiology of AMD. (Invest Ophthalmol Vis Sci

Cholesterol-Lowering Drugs and Incident Open-Angle Glaucoma: A Population-Based Cohort Study

Background: Open-angle glaucoma (OAG) is a progressive neurodegenerative disease that may lead to blindness. An elevated intraocular pressure (IOP) is its major risk factor. OAG treatment is currently exclusively directed towards the lowering of the IOP. IOP lowering does not prevent disease progression in all patients and thus other treatment modalities are needed. Earlier studies reported cholesterol-lowering drugs to have neuroprotective properties. The aim of this study was to determine the associations between the use of cholesterol-lowering drugs and incident OAG. Methodology/Principal Findings: Participants in a prospective population-based cohort study underwent ophthalmic examinations, including IOP measurements and perimetry, at baseline and follow-up. The use of statins and non-statin cholesterol-lowering drugs was monitored continuously during the study. Associations between the use of cholesterol-lowering drugs and incident OAG were analyzed with Cox regression; associations between cholesterol-lowering drugs and IOP at follow-up were analyzed with multiple linear regression. During a mean follow-up of 9.8 years, 108 of 3939 eligible participants (2.7%) developed OAG. The hazard ratio for statin use was 0.54 (95% confidence interval 0.31-0.96; P = 0.034) and for non-statin cholesterol-lowering drugs 2.07 (0.81-5.33; P = 0.13). The effect of statins was more pronounced with prolonged use (hazard ratio 0.

A Genetic Epidemiologic Study of Candidate Genes Involved in the Optic Nerve Head Morphology

PURPOSE. The size of the optic nerve head, referred to as disc area (DA), and the vertical cup-disc ratio (VCDR), are clinically relevant parameters for glaucomatous optic neuropathy. Although these measures have a high heritability, little is known about the underlying genes. Previously, the genes SALL1 and SIX1 were found to be genome-wide significantly associated with DA and VCDR. The purpose of the present study was to investigate whether genes encoding protein known to interact with protein encoded by SALL1 and SIX1 are also associated with either DA or VCDR. METHODS. A total of 38 candidate genes were chosen covering all known proteins interacting with SALL1 and SIX1. These were initially studied in the Rotterdam Study (RS)-I, including 5312 Caucasian subjects characterized for DA and VCDR. Positive findings were further investigated in two independent cohorts (RS-II and RS-III) and finally replicated in a fourth population (ERF). Bonferroni correction was applied to the meta-analyses. RESULTS. Three loci were found to be associated with DA. The only locus significant after correcting for multiple testing is located on chromosome 11p13. Three single nucleotide polymorphisms (SNPs) in ELP4, a gene which neighbors and plays a crucial role in the expression of PAX6, show association in meta-analysis of the four cohorts yielding P values of respectively 4.79 x 10(-6), 3.92 x 10(-6), and 4.88 x 10-6 which is below the threshold dictated by the most conservative Bonferroni correction (P = 5.2 x 10(-6)). CONCLUSIONS. This study suggests that the ELP4-PAX6 region plays a role in the DA. Further research to confirm this finding is needed. (Invest Ophthalmol Vis Sci. 2012;53:1485-1491) DOI:10.1167/iovs.11-738

Prevalence of Age-Related Macular Degeneration in Europe: The Past and the Future.

PURPOSE: Age-related macular degeneration (AMD) is a frequent, complex disorder in elderly of European ancestry. Risk profiles and treatment options have changed considerably over the years, which may have affected disease prevalence and outcome. We determined the prevalence of early and late AMD in Europe from 1990 to 2013 using the European Eye Epidemiology (E3) consortium, and made projections for the future. DESIGN: Meta-analysis of prevalence data. PARTICIPANTS: A total of 42 080 individuals 40 years of age and older participating in 14 population-based cohorts from 10 countries in Europe. METHODS: AMD was diagnosed based on fundus photographs using the Rotterdam Classification. Prevalence of early and late AMD was calculated using random-effects meta-analysis stratified for age, birth cohort, gender, geographic region, and time period of the study. Best-corrected visual acuity (BCVA) was compared between late AMD subtypes; geographic atrophy (GA) and choroidal neovascularization (CNV). MAIN OUTCOME MEASURES: Prevalence of early and late AMD, BCVA, and number of AMD cases. RESULTS: Prevalence of early AMD increased from 3.5% (95% confidence interval [CI] 2.1%-5.0%) in those aged 55-59 years to 17.6% (95% CI 13.6%-21.5%) in those aged ≥85 years; for late AMD these figures were 0.1% (95% CI 0.04%-0.3%) and 9.8% (95% CI 6.3%-13.3%), respectively. We observed a decreasing prevalence of late AMD after 2006, which became most prominent after age 70. Prevalences were similar for gender across all age groups except for late AMD in the oldest age category, and a trend was found showing a higher prevalence of CNV in Northern Europe. After 2006, fewer eyes and fewer ≥80-year-old subjects with CNV were visually impaired (P = 0.016). Projections of AMD showed an almost doubling of affected persons despite a decreasing prevalence. By 2040, the number of individuals in Europe with early AMD will range between 14.9 and 21.5 million, and for late AMD between 3.9 and 4.8 million. CONCLUSION: We observed a decreasing prevalence of AMD and an improvement in visual acuity in CNV occuring over the past 2 decades in Europe. Healthier lifestyles and implementation of anti-vascular endothelial growth factor treatment are the most likely explanations. Nevertheless, the numbers of affected subjects will increase considerably in the next 2 decades. AMD continues to remain a significant public health problem among Europeans

The structure of the tetrasialoganglioside from human brain

Autosomal dominant retinal vasculopathy with cerebral leukodystrophy is a microvascular endotheliopathy with middle- age onset. In nine families, we identified heterozygous C- terminal frameshift mutations in TREX1, which encodes a 3'-5' exonuclease. These truncated proteins retain exonuclease activity but lose normal perinuclear localization. These data have implications for the maintenance of vascular integrity in the degenerative cerebral microangiopathies leading to stroke and dementias

Common genetic determinants of intraocular pressure and primary open-angle Glaucoma

10.1371/journal.pgen.1002611PLoS Genetics85

Genome-Wide Association Study of Retinopathy in Individuals without Diabetes

10.1371/journal.pone.0054232PLoS ONE82