GENOTYPE-PHENOTYPE ASSOCIATIONS IN NEOVASCULAR AGE-RELATED MACULAR DEGENERATION.

PURPOSE:To examine associations between recognized genetic susceptibility loci and angiographic subphenotypes of the neovascular variant of age-related macular degeneration (nvAMD).METHODS:Participants (247 nvAMD, 52 early age-related macular degeneration [AMD], and 103 controls) were genotyped (complement factor H and ARMS2/HTRA1). nvAMD participants were assigned to one of two subcategories: mainly classic or mainly occult (based on the proportions of classic and occult choroidal neovascularization). nvAMD and early AMD were reassigned to two groups based on the extent and severity of drusen (retinal pigment epithelium dysfunction or not). Univariate and multivariate analysis were used to examine for associations between participant characteristics and genetic loci after adjusting for age, smoking status, and history of cardiovascular disease.RESULTS:Univariate analysis confirmed the known significant associations between AMD stage and age, hypertension, and a history of cardiovascular disease. Those with retinal pigment epithelium dysfunction (F = 5.46; P = 0.02) or a positive smoking history (F = 3.89; P = 0.05) were more likely to have been classified as having mainly an occult rather than a mainly classic lesion. Multivariate analysis showed that significant associations were noted with the number of ARMS2/HTRA1 risk alleles (P

Ranibizumab versus Bevacizumab to Treat Neovascular Age-related Macular Degeneration: One-Year Findings from the IVAN Randomized Trial.

Purpose
To compare the efficacy and safety of ranibizumab and bevacizumab intravitreal injections to treat neovascular age-related macular degeneration (nAMD).

Design
Multicenter, noninferiority factorial trial with equal allocation to groups. The noninferiority limit was 3.5 letters. This trial is registered (ISRCTN92166560).

Participants
People >50 years of age with untreated nAMD in the study eye who read =25 letters on the Early Treatment Diabetic Retinopathy Study chart.

Methods
We randomized participants to 4 groups: ranibizumab or bevacizumab, given either every month (continuous) or as needed (discontinuous), with monthly review.

Main Outcome Measures
The primary outcome is at 2 years; this paper reports a prespecified interim analysis at 1 year. The primary efficacy and safety outcome measures are distance visual acuity and arteriothrombotic events or heart failure. Other outcome measures are health-related quality of life, contrast sensitivity, near visual acuity, reading index, lesion morphology, serum vascular endothelial growth factor (VEGF) levels, and costs.

Results
Between March 27, 2008 and October 15, 2010, we randomized and treated 610 participants. One year after randomization, the comparison between bevacizumab and ranibizumab was inconclusive (bevacizumab minus ranibizumab -1.99 letters, 95% confidence interval [CI], -4.04 to 0.06). Discontinuous treatment was equivalent to continuous treatment (discontinuous minus continuous -0.35 letters; 95% CI, -2.40 to 1.70). Foveal total thickness did not differ by drug, but was 9% less with continuous treatment (geometric mean ratio [GMR], 0.91; 95% CI, 0.86 to 0.97; P = 0.005). Fewer participants receiving bevacizumab had an arteriothrombotic event or heart failure (odds ratio [OR], 0.23; 95% CI, 0.05 to 1.07; P = 0.03). There was no difference between drugs in the proportion experiencing a serious systemic adverse event (OR, 1.35; 95% CI, 0.80 to 2.27; P = 0.25). Serum VEGF was lower with bevacizumab (GMR, 0.47; 95% CI, 0.41 to 0.54; P<0.0001) and higher with discontinuous treatment (GMR, 1.23; 95% CI, 1.07 to 1.42; P = 0.004). Continuous and discontinuous treatment costs were £9656 and £6398 per patient per year for ranibizumab and £1654 and £1509 for bevacizumab; bevacizumab was less costly for both treatment regimens (P<0.0001).

Conclusions
The comparison of visual acuity at 1 year between bevacizumab and ranibizumab was inconclusive. Visual acuities with continuous and discontinuous treatment were equivalent. Other outcomes are consistent with the drugs and treatment regimens having similar efficacy and safety.

Financial Disclosure(s)
Proprietary or commercial disclosures may be found after the references.

Perception of patterns of musical beat distribution in phonological developmental dyslexia:significant longitudinal relations with word reading and reading comprehension

In a recent study, we reported that the accurate perception of beat structure in music ('perception of musical meter') accounted for over 40% of the variance in single word reading in children with and without dyslexia (Huss et al., 2011). Performance in the musical task was most strongly associated with the auditory processing of rise time, even though beat structure was varied by manipulating the duration of the musical notes.

Altered endothelin-1 induced contraction and second messenger generation in bovine retinal microvascular pericytes cultured in high glucose medium.

The effect of simulated hyperglycaemia on bovine retinal pericytes was studied following culture of these cells for 10 days under normal (5 mmol/l) and elevated (25 mmol/l) glucose conditions in the absence of endothelial cells. Pericytes cultured under high ambient glucose exhibited both a delayed and reduced contractile response following stimulation with endothelin-1. Stimulation with 10(-7) mol/l endothelin-1 for 30 s caused significant contraction in cells grown in both 5 mmol/l and 25 mmol/l glucose. The former also contracted significantly with 10(-8) mol/l endothelin-1. Further, at all concentrations tested, statistical comparison of the time course of contraction showed a significant difference (p 0.1) between bovine retinal pericytes grown for 10 days under normo- or hyperglycaemic conditions, it became apparent that the altered contractility in bovine retinal pericytes following culture in high glucose must be due to post-binding intracellular disturbance(s). Indeed, both basal and 15 s post-stimulation with 10(-8) mol/l endothelin-1, levels of inositol trisphosphate were significantly reduced (p

Common variants near FRK/COL10A1 and VEGFA are associated with advanced age-related macular degeneration

Despite significant progress in the identification of genetic loci for age-related macular degeneration (AMD), not all of the heritability has been explained. To identify variants which contribute to the remaining genetic susceptibility, we performed the largest meta-analysis of genome-wide association studies to date for advanced AMD. We imputed 6 036 699 single-nucleotide polymorphisms with the 1000 Genomes Project reference genotypes on 2594 cases and 4134 controls with follow-up replication of top signals in 5640 cases and 52 174 controls. We identified two new common susceptibility alleles, rs1999930 on 6q21-q22.3 near FRK/COL10A1 [odds ratio (OR) 0.87; P = 1.1 × 10(-8)] and rs4711751 on 6p12 near VEGFA (OR 1.15; P = 8.7 × 10(-9)). In addition to the two novel loci, 10 previously reported loci in ARMS2/HTRA1 (rs10490924), CFH (rs1061170, and rs1410996), CFB (rs641153), C3 (rs2230199), C2 (rs9332739), CFI (rs10033900), LIPC (rs10468017), TIMP3 (rs9621532) and CETP (rs3764261) were confirmed with genome-wide significant signals in this large study. Loci in the recently reported genes ABCA1 and COL8A1 were also detected with suggestive evidence of association with advanced AMD. The novel variants identified in this study suggest that angiogenesis (VEGFA) and extracellular collagen matrix (FRK/COL10A1) pathways contribute to the development of advanced AMD.

Carotenoids and co-antioxidants in age-related maculopathy:design and methods

Age-related macular degeneration (AMD), is the leading cause of blind registration in the Western World among individuals 65 years or older. Early AMD, a clinical state without overt functional loss, is said to be present clinically when yellowish deposits known as drusen and/or alterations of fundus pigmentation are seen in the macular retina. Although the etiopathogenesis of AMD remains uncertain, there is a growing body of evidence in support of the view that cumulative oxidative damage plays a causal role. Appropriate dietary antioxidant supplementation is likely to be beneficial in maintaining visual function in patients with AMD, and preventing or delaying the progression of early AMD to late AMD. The Carotenoids in Age-Related Maculopathy (CARMA) Study is a randomized and double-masked clinical trial of antioxidant supplementation versus placebo in 433 participants with either early AMD features of sufficient severity in at least one eye or any level of AMD in one eye with late AMD (neovascular AMD or central geographic atrophy) in the fellow eye. The aim of the CARMA Study is to investigate whether lutein and zeaxanthin, in combination with co-antioxidants (vitamin C, E, and zinc), has a beneficial effect on visual function and/or prevention of progression from early to late stages of disease. The primary outcome is improved or preserved distance visual acuity at 12 months. Secondary outcomes include improved or preserved interferometric acuity, contrast sensitivity, shape discrimination ability, and change in AMD severity as monitored by fundus photography. This article outlines the CARMA Study design and methodology, including its rationale.

Grading of age-related maculopathy:slit-lamp biomicroscopy versus an accredited grading center

To compare clinical age-related maculopathy (ARM) grading using slit-lamp biomicroscopy (SLB) versus photographic grading of stereoscopically captured fundus photographs (FP) using a high-resolution fundus camera.

AMD and micronutrient antioxidants

Age-related maculopathy (ARM) is a common clinical entity. The late-stage manifestations of ARM, which are known as age-related macular degeneration (AMD), have devastating consequences for vision. Various risk factors have been identified in the development of the condition, which are consistent with the premise that oxidative stress plays an important role in its pathogenesis. Thus, the possibility that antioxidant balance can be manipulated through diet or supplementation has created much interest. Associations between diet and nutrition and the clinical features of ARM have been described. Scrutiny of the literature shows consistency in the report of notable reductions in serum micronutrients in wet AMD, however, the evidence for causation is still circumstantial. In this comprehensive review of the clinical literature, we have assessed the evidence for a link between diet and nutrition as risk factors for the development of ARM and AMD. All published case control, population-based, and interventional studies on ARM were examined. Although initial support appeared to be moderate and somewhat contradictory, the evidence that lifetime oxidative stress plays an important role in the development of ARM is now compelling. The positive outcomes in the Age-Related Eye Diseases Study, a major controlled clinical trial, have given hope that modulation of the antioxidant balance through supplementation can help prevent progression of ARM to AMD.

Heritability and Genome-Wide Association Study to Assess Genetic Differences between Advanced Age-Related Macular Degeneration Subtypes

PURPOSE: To investigate whether the 2 subtypes of advanced age-related macular degeneration (AMD), choroidal neovascularization (CNV), and geographic atrophy (GA) segregate separately in families and to identify which genetic variants are associated with these 2 subtypes. DESIGN: Sibling correlation study and genome-wide association study (GWAS). PARTICIPANTS: For the sibling correlation study, 209 sibling pairs with advanced AMD were included. For the GWAS, 2594 participants with advanced AMD subtypes and 4134 controls were included. Replication cohorts included 5383 advanced AMD participants and 15 240 controls. METHODS: Participants had the AMD grade assigned based on fundus photography, examination, or both. To determine heritability of advanced AMD subtypes, a sibling correlation study was performed. For the GWAS, genome-wide genotyping was conducted and 6 036 699 single nucleotide polymorphisms (SNPs) were imputed. Then, the SNPs were analyzed with a generalized linear model controlling for genotyping platform and genetic ancestry. The most significant associations were evaluated in independent cohorts. MAIN OUTCOME MEASURES: Concordance of advanced AMD subtypes in sibling pairs and associations between SNPs with GA and CNV advanced AMD subtypes. RESULTS: The difference between the observed and expected proportion of siblings concordant for the same subtype of advanced AMD was different to a statistically significant degree (P = 4.2×10(-5)), meaning that in siblings of probands with CNV or GA, the same advanced subtype is more likely to develop. In the analysis comparing participants with CNV to those with GA, a statistically significant association was observed at the ARMS2/HTRA1 locus (rs10490924; odds ratio [OR], 1.47; P = 4.3×10(-9)), which was confirmed in the replication samples (OR, 1.38; P = 7.4×10(-14) for combined discovery and replication analysis). CONCLUSIONS: Whether CNV versus GA develops in a patient with AMD is determined in part by genetic variation. In this large GWAS meta-analysis and replication analysis, the ARMS2/HTRA1 locus confers increased risk for both advanced AMD subtypes, but imparts greater risk for CNV than for GA. This locus explains a small proportion of the excess sibling correlation for advanced AMD subtype. Other loci were detected with suggestive associations that differ for advanced AMD subtypes and deserve follow-up in additional studies. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Severity staging by early features of age-related maculopathy exhibits weak relationships with functional deficits on SWS grating acuity

To examine the relationship between short-wavelength-sensitive (SWS) resolution acuity and epidemiologically defined stages of early age-related maculopathy (ARM).

ARMS2 Increases the Risk of Early and Late Age-Related Macular Degeneration in the European Eye Study

OBJECTIVE:
To study associations between severity stages of early and late age-related macular degeneration (AMD) and genetic variations in age-related maculopathy susceptibility 2 (ARMS2) and complement factor H (CFH) and to investigate potential interactions between smoking and ARMS2.
DESIGN:
Population-based, cross-sectional European Eye Study in 7 countries in Europe.
PARTICIPANTS:
Four thousand seven hundred fifty participants, 65 years of age and older, recruited through random sampling.
METHODS:
Participants were classified on the basis of the more severely affected eye into 5 mutually exclusive AMD severity stages ranging from no AMD, 3 categories of early AMD, and late AMD. History of cigarette smoking was available and allowed classification into never, former, and current smokers, with the latter 2 groups combined into a single category of ever smokers for analysis. Genotyping was performed for single nucleotide polymorphisms rs10490924 and rs4146894 in ARMS2 and rs1061170 in CFH. Associations were analyzed by logistic regression.
MAIN OUTCOME MEASURES:
Odds ratios (ORs) for stage of AMD associated with genetic variations in ARMS2 and CFH and interactions between ARMS2 and smoking status.
RESULTS:
Early AMD was present in 36.4% and late AMD was present in 3.3% of participants. Data on both genotype and AMD were available for 4276 people. The ORs for associations between AMD stage and ARMS2 increased monotonically with more severe stages of early AMD and were altered little by adjustment for potential confounders. Compared with persons with no AMD, carriers of the TT genotype for rs10490924 in ARMS2 had a 10-fold increase in risk of late AMD (P<3 × 10(-20)). The ORs for associations with CFH were similar for stage 3 early AMD and late AMD. Interactions between rs10490924 in ARMS2 and smoking status were significant in both unadjusted and adjusted models (P = 0.001). The highest risk was observed in those doubly homozygous for rs10490924 and rs1061170 in CFH (OR, 62.3; 95% confidence interval, 16-242), with P values for trend ranging from 0.03 (early AMD, stage 1) to 1 × 10(-26) (late AMD).
CONCLUSIONS:
A strong association was demonstrated between all stages of AMD and genetic variation in ARMS2, and a significant gene-environment interaction with cigarette smoking was confirmed.

A posteriori-derived dietary patterns and retinal vessel caliber in an elderly population

Purpose. To examine the association between a posteriori–derived dietary patterns (DP) and retinal vessel caliber in an elderly population.

Methods. This was a cross-sectional study of 288 elderly adults (>65 years) who participated in the European Eye study (EUREYE) Northern Irish cohort. DP were extracted using principal component analysis from completed food frequency questionnaires. Semi-automated computer grading was used to determine the mean retinal vessel diameters (central retinal arteriole equivalent [CRAE] and central retinal venule equivalent [CRVE]) from digitized visual field one images using a standard measurement protocol.

Results. Three major DP were identified in this population, which accounted for 21% of the total variance: a “healthy” pattern with high factor loadings for oily fish, fruits and vegetables, and olive oil; an “unhealthy” pattern with high factor loadings for red and processed meat, refined grains, eggs, butter, sugar and sweets; and a “snack and beverage” pattern with high factor loading for pizza, nuts, and coffee. Multivariable linear regression analysis indicated no significant association between major identified DP and mean CRAE or CRVE in all models.

Conclusions. This is the first study to investigate associations between a posteriori–derived DP and retinal vessel caliber. There was no evidence of a relationship between extracted DP and retinal vessel measurements in this population. However, it is possible that potentially important relationships exist between single nutrients or foods and vessel diameters that cannot be identified using a DP approach. Further studies to examine the role of dietary factors in the microcirculation are required.

Alternative treatments to inhibit VEGF in age-related choroidal neovascularisation: 2-year findings of the IVAN randomised controlled trial

Background: Bevacizumab has been suggested to have similar effectiveness to ranibizumab for treatment of neovascular age-related macular degeneration. The Inhibition of VEGF in Age-related choroidal Neovascularisation (IVAN) trial was designed to compare these drugs and different regimens. Here, we report the findings at the prespecified 2-year timepoint. Methods: In a multicentre, 2×2 factorial, non-inferiority randomised trial, we enrolled adults aged at least 50 years with active, previously untreated neovascular age-related macular degeneration and a best corrected distance visual acuity (BCVA) of at least 25 letters from 23 hospitals in the UK. Participants were randomly assigned (1:1:1:1) to intravitreal injections of ranibizumab (0·5 mg) or bevacizumab (1·25 mg) in continuous (every month) or discontinuous (as needed) regimens, with monthly review. Study participants and clinical assessors were masked to drug allocation. Allocation to continuous or discontinuous treatment was masked up to 3 months, at which point investigators and participants were unmasked. The primary outcome was BCVA at 2 years, with a prespecified non-inferiority limit of 3·5 letters. The primary safety outcome was arterial thrombotic event or hospital admission for heart failure. Analyses were by modified intention to treat. This trial is registered, number ISRCTN92166560. Findings: Between March 27, 2008, and Oct 15, 2010, 628 patients underwent randomisation. 18 were withdrawn; 610 received study drugs (314 ranibizumab; 296 bevacizumab) and were included in analyses. 525 participants reached the visit at 2 years: 134 ranibizumab in continuous regimen, 137 ranibizumab in discontinuous regimen, 127 bevacizumab in continuous regimen, and 127 bevacizumab in discontinuous regimen. For BCVA, bevacizumab was neither non-inferior nor inferior to ranibizumab (mean difference -1·37 letters, 95% CI -3·75 to 1·01; p=0·26). Discontinuous treatment was neither non-inferior nor inferior to continuous treatment (-1·63 letters, -4·01 to 0·75; p=0·18). Frequency of arterial thrombotic events or hospital admission for heart failure did not differ between groups given ranibizumab (20 [6%] of 314 participants) and bevacizumab (12 [4%] of 296; odds ratio [OR] 1·69, 95% CI 0·80-3·57; p=0·16), or those given continuous (12 [4%] of 308) and discontinuous treatment (20 [7%] of 302; 0·56, 0·27-1·19; p=0·13). Mortality was lower with continuous than discontinuous treatment (OR 0·47, 95% CI 0·22-1·03; p=0·05), but did not differ by drug group (0·96, 0·46-2·02; p=0·91). Interpretation: Ranibizumab and bevacizumab have similar efficacy. Reduction in the frequency of retreatment resulted in a small loss of efficacy irrespective of drug. Safety was worse when treatment was administered discontinuously. These findings highlight that the choice of anti-VEGF treatment strategy is less straightforward than previously thought.