Luba Robman

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.

Vitamin E supplementation and macular degeneration: randomised controlled trial

Objective: To determine whether vitamin E supplementation influences the incidence or rate of progression of age related maculopathy (AMD). Design: Prospective randomised placebo controlled clinical trial. Setting: An urban study centre in a residential area supervised by university research staff. Participants: 1193 healthy volunteers aged between 55 and 80 years; 73% completed the trial on full protocol. Interventions: Vitamin E 500 IU or placebo daily for four years. Main outcome measures: Primary outcome: development of early age related macular degeneration in retinal photographs. Other measures included alternative definitions of age related macular degeneration, progression, changes in component features, visual acuity, and visual function Results: The incidence of early age related macular degeneration (early AMD 3) was 8.6% in those receiving vitamin E versus 8.1% in those on placebo (relative risk 1.05, 95% confidence interval 0.69 to 1.61). For late disease the incidence was 0.8% versus 0.6% (1.36, 0.67 to 2.77). Further analysis showed no consistent differences in secondary outcomes. Conclusion: Daily supplement with vitamin E supplement does not prevent the development or progression of early or later stages of age related macular degeneration.

Gene–environment interaction in progression of AMD: the CFH gene, smoking and exposure to chronic infection

A number of risk factors including the complement factor H (CFH) gene, smoking and Chlamydia pneumoniae have been associated with age-related macular degeneration (AMD). However, the mechanisms underlying how these risk factors might be involved in disease progression and disease aetiology is poorly understood. A cohort series of 233 individuals followed for AMD progression over a mean period of 7 years underwent a full eye examination, blood was taken for DNA and antibody titre and individuals completed a standard medical and general questionnaire. Y402H variants of the CFH gene were assessed with disease progression as well as examination of interaction between Y402H variants and smoking and Y402H variants and the pathogen C. pneumoniae. The CC risk genotype of Y402H was significantly associated with increased AMD progression [odds ratio (OR) 2.43, 95% confidence interval (95% CI) 1.07-5.49] as was smoking (OR 2.28, 95% CI 1.26-4.12). However, the risk of progression was greatly increased to almost 12-fold (OR 11.8, 95% CI 2.1-65.8) when, in addition to having the C risk allele, subjects also presented with the upper tertile of antibodies to the bacterial pathogen C. pneumoniae compared with those with the T allele of Y402H and the lowest antibody tertile. This demonstrates for the first time the existence of a gene environment-interaction between pathogenic load of C. pneumoniae and the CFH gene in the aetiology of AMD.

C-Reactive Protein Levels and Complement Factor H Polymorphism Interaction in Age-related Macular Degeneration and Its Progression

PURPOSE To determine the effect of elevated level of C-reactive protein (CRP) and its joint effect with the complement factor H (CFH) polymorphism on prevalent age-related macular degeneration (AMD) and its progression. DESIGN Two-arm case-control study: (a) Study on prevalent AMD cases and population-based controls; (b) longitudinal study on AMD progression, comparing those in whom AMD progressed with those with no progression. PARTICIPANTS (a) A cross-sectional sample of 544 participants, of whom 312 had features of early or late AMD and 232 were controls; (b) a sample of 254 early AMD cases, followed for 7 years. METHODS The study was conducted in Melbourne, Australia. Macular stereo photographs were graded for AMD according to the International Classification and Grading System. High-sensitivity CRP was measured in fresh serum, and genotyping was performed through the Australian Genome Research Facility. The association of CRP with outcomes was tested using multivariate logistic regression analysis adjusted for age, smoking, anti-inflammatory medications, and the CC genotype of the CFH gene. Risk factor interaction was explored using an additive model. MAIN OUTCOME MEASURES Prevalent early AMD, prevalent late AMD, progressed AMD, and measures of risk factor interaction. RESULTS Elevated CRP levels were associated with late AMD: odds ratio (OR), 3.12; 95% confidence interval (CI), 1.38-7.07. An association of elevated CRP with AMD progression was weaker: OR, 1.90 (95% CI, 0.88-4.10). A combination of elevated CRP and the CC (Y402H) genotype resulted in a super-additivity of the risks, with odds ratios of 19.3 (95% CI, 2.8-134) for late AMD, and 6.8 (95% CI, 1.2-38.8) for AMD progression, with the attributable proportion of risk owing to CRP-CFH interaction calculated at 26% for prevalent late AMD and 22% for AMD progression. CONCLUSIONS Synergistic influence of CRP levels and the at risk genotype of the CFH gene resulted in a super-additive risk for prevalent late AMD and AMD progression. Testing for the combination of these 2 risk factors to predict a high risk of AMD and its progression would allow for targeted trials of new intervention strategies.

Variants in the APOE Gene Are Associated with Improved Outcome after Anti-VEGF Treatment for Neovascular AMD

PURPOSE Anti-vascular endothelial growth factor (anti-VEGF) drugs have dramatically improved the treatment of neovascular AMD. In pivotal studies, almost 90% of patients maintain vision, with approximately 30% showing significant improvement. Despite these successes, 10% to 15% of patients continue to lose vision, even with treatment. It has been reported that variants in some AMD-associated genes influence treatment outcome. This study showed an association of treatment outcome with variants in the apolipoprotein E (APOE) gene. METHODS One hundred ninety-two patients receiving anti-VEGF treatment for subfoveal choroidal neovascularization secondary to AMD were enrolled. Information on demographics, lesion characteristics, delay until treatment, visual acuity (VA), and number of treatments was collected, and variants of APOE were assessed in all patients at baseline. Best corrected logarithm of the minimum angle of resolution (logMAR) VA was recorded in all patients. RESULTS The presence of the APOE ε4 allele was associated with improved treatment outcome at 3 (P = 0.02) and 12 (P = 0.06) months, compared with the presence of the ε2 allele, after adjustment for baseline acuity, treatment delay after first symptoms, age, and sex. Patients with an APOE ε4 allele had an odds ratio (OR) of 4.04 (95% confidence interval [CI], 1.11-14.70) for a 2-line gain in vision from baseline at 3 months (P = 0.03) and an OR of 2.54 (95% CI, 0.61-10.52; P = 0.20) at 12 months after treatment, based on multivariate analysis. CONCLUSIONS In patients with neovascular AMD, the presence of the APOE ε4 allele conferred significantly better visual outcomes after anti-VEGF treatment than did the ε2 allele. These findings suggest a possible role for a personalized approach to treatment with anti-VEGF.

Reticular Pseudodrusen and Their Association with Age-Related Macular Degeneration: The Melbourne Collaborative Cohort Study.

PURPOSE To determine the prevalence of reticular pseudodrusen (RPD) and its association with age-related macular degeneration (AMD) and AMD risk factors in a large sample. DESIGN Community-based cohort study in Melbourne, Victoria, Australia. PARTICIPANTS A total of 21,130 participants 48 to 86 years of age available for ophthalmic assessment at follow-up from 2003 through 2007. METHODS Lifestyle, diet, and anthropometric measurements were obtained at baseline and follow-up. At follow-up, digital macular color photographs were graded for early, intermediate, and late AMD as well as the presence of RPD. Data were analyzed using multinomial logistic regression controlling for age, gender, smoking, country of birth, and diet. MAIN OUTCOME MEASURES Detection of RPD based on color fundus photographs. RESULTS Prevalence of RPD was 0.41% (87 of 21,130 participants), with 51% having bilateral RPD. Patients with RPD were older compared with patients with large drusen (>125 μm; 76±4 vs. 68±9 years; P < 0.001). Increasing age, female gender, being a current smoker, as well as focal pigmentary abnormalities and large drusen (>125 μm) were associated with a higher prevalence of RPD. Presence of geographic atrophy (GA) was associated with the highest odds of having RPD (odds ratio [OR], 153; 95% confidence interval [CI], 53-442), followed by choroidal neovascularization (CNV; OR, 90; 95% CI, 26-310), intermediate AMD (OR, 33; 95% CI, 14-77), and early AMD (OR, 12; 95% CI, 5-31) compared with those with no AMD. The ARMS2 single nucleotide polymorphism (SNP) rs10490924, HTRA1 SNPs rs11200638 and rs3793917, and CFH SNPs rs393955, rs1061170, and rs2274700 were associated with increased prevalence of RPD (all P < 0.05). CONCLUSIONS Reticular pseudodrusen are highly concurrent with AMD and have similar associations with known AMD risk factors such as age, gender, smoking, and genetic risk factors. Reticular pseudodrusen are associated more strongly with GA than with CNV. Although RPD are not specific to AMD, they are likely to be a strong risk factor for progression to late-stage AMD, similar to focal pigmentary abnormalities and large drusen.

Comparison of Clinical and Digital Assessment of Nuclear Optical Density

To compare the standardised Nidek EAS-1000 densitometric analysis of the lens with clinical assessment of the nucleus at an early stage of cataract development, 1,200 eyes of 1,204 participants of the VECAT study were assessed at the baseline using both subjective and objective lens grading. Standardisation of the automatic slit image analysis was achieved using a custom-designed EAS-1000 Software version 3.01c. Among 6 measurements of nuclear optical density, the mean pixel luminescence of integrated anterior nuclear density correlated best with clinical assessment (R = 0.662, p < 0.001). Variance components that interfere with the assessment are defined.

The prevalence estimates of macular telangiectasia type 2: the Melbourne Collaborative Cohort Study.

Purpose: The purpose of this study was to determine the prevalence estimates of macular telangiectasia type 2 in an Australian population based on nonmydriatic digital fundus photography. Methods: Participants of the Melbourne Collaborative Cohort Study, initiated to investigate risk factors for common aging diseases, had nonmydriatic digital macular images taken from both eyes and graded for any macular abnormalities. Prevalence of the features suggestive of macular telangiectasia type 2 was assessed. Results: Macular images from the 22,062 subjects with a mean age of 64.96 years (range, 47–85 years) were assessed. Of these images, 43,234 images were gradable (21,708 images of the right eye and 21,526 images of the left eye). Using only the grading features of the macular images taken by the nonmydriatic digital fundus photography, 5 subjects with signs consistent with bilateral macular telangiectasia type 2 in this population were found by the authors. Based on the Gass-Blodi staging of this disease, all (5) were determined to be in stages 2 and 3. Conclusion: In an Australian population, the prevalence estimates of macular telangiectasia type 2 were found to be 1 of 22,062 to 5 of 22,062 or 5 to 23 cases per 100,000 people in which disease was at least at stages 2 and 3.

Iris colour, ethnic origin and progression of age-related macular degeneration

Aim: To investigate the relationship between iris colour, ethnic origin and the progression of age‐related macular degeneration (AMD).

Role of Flicker Perimetry in Predicting Onset of Late-Stage Age-Related Macular Degeneration

OBJECTIVE To investigate the longitudinal changes in flicker perimetry in patients with age-related macular degeneration (AMD) as the condition progresses from early AMD to geographic atrophy (GA) or choroidal neovascularization (CNV). METHODS Patients with AMD and control subjects were recruited from a longitudinal study of retinal function in early AMD consisting of 187 participants. Only those who completed at least 4 consecutive, 6-monthly flicker perimetry tests were selected for this study. Study groups consisted of everyone who went on to develop GA (n = 16) or CNV (n = 5), controls (n = 24), and the high-risk, early- AMD participants whose eyes did not progress to GA or CNV (drusen >125 μm; n = 18). The flicker sensitivity was determined, and its rate of change during the 18 months before the clinical detection of late AMD was calculated. RESULTS Eyes that went on to develop GA or CNV had a significantly reduced mean (SD) flicker sensitivity in the months before clinical detection of GA (15.8 [5.6] dB) or CNV (19.1 [3.8] dB) compared with control eyes (22.9 [3.0] dB) (P < .001) and with eyes that did not progress to GA or CNV (21.4 [3.4] dB) (P < .001). The rate of change in flicker sensitivity was significantly increased in GA eyes (-0.07 dB/mo) (P < .001) but not in CNV eyes (0.006 dB/mo) (P = .56) compared with the control eyes (-0.003 dB/mo). CONCLUSIONS Flicker sensitivity is reduced in eyes that go on to develop late AMD. The rate of change in flicker sensitivities over time was particularly useful in predicting eyes and areas within the eye that subsequently develop GA.