Blue Light Exposure: Ocular Hazards and Prevention-A Narrative Review.

INTRODUCTION: Exposure to blue light has seriously increased in our environment since the arrival of light emitting diodes (LEDs) and, in recent years, the proliferation of digital devices rich in blue light. This raises some questions about its potential deleterious effects on eye health. The aim of this narrative review is to provide an update on the ocular effects of blue light and to discuss the efficiency of methods of protection and prevention against potential blue light-induced ocular injury. METHODS: The search of relevant English articles was conducted in PubMed, Medline, and Google Scholar databases until December 2022. RESULTS: Blue light exposure provokes photochemical reactions in most eye tissues, in particular the cornea, the lens, and the retina. In vitro and in vivo studies have shown that certain exposures to blue light (depending on the wavelength or intensity) can cause temporary or permanent damage to some structures of the eye, especially the retina. However, currently, there is no evidence that screen use and LEDs in normal use are deleterious to the human retina. Regarding protection, there is currently no evidence of a beneficial effect of blue blocking lenses for the prevention of eye diseases, in particular age-related macular degeneration (AMD). In humans, macular pigments (composed of lutein and zeaxanthin) represent a natural protection by filtering blue light, and can be increased through increased intake from foods or food supplements. These nutrients are associated with lower risk for AMD and cataract. Antioxidants such as vitamins C, E, or zinc might also contribute to the prevention of photochemical ocular damage by preventing oxidative stress. CONCLUSION: Currently, there is no evidence that LEDs in normal use at domestic intensity levels or in screen devices are retinotoxic to the human eye. However, the potential toxicity of long-term cumulative exposure and the dose-response effect are currently unknown.

Associations Between Vitamin D Intake and Progression to Incident Advanced Age-Related Macular Degeneration.

Purpose: There is growing evidence of the importance of nutrition in age-related macular degeneration (AMD), but no prospective studies have explored the impact of vitamin D. We evaluated the association between vitamin D intake and progression to advanced AMD. Methods: Among 2146 participants (3965 eyes), 541 (777 eyes) progressed from early or intermediate AMD to advanced disease (mean follow-up: 9.4 years) based on ocular imaging. Nutrients were log transformed and calorie adjusted. Survival analysis was used to assess associations between incident advanced disease and vitamin D intake. Neovascular disease (NV) and geographic atrophy (GA) were evaluated separately. Combined effects of dietary vitamin D and calcium were assessed based on high or low consumption of each nutrient. Results: There was a lower risk of progression to advanced AMD in the highest versus lowest quintile of dietary vitamin D intake after adjustment for demographic, behavioral, ocular, and nutritional factors (hazard ratio [HR]: 0.60; 95% confidence interval [CI]: 0.43-0.83; P trend = 0.0007). Similar results were observed for NV (HR: 0.59; 95% CI: 0.39-0.89; P trend = 0.005) but not GA (HR: 0.83; 95% CI: 0.53-1.30; P trend = 0.35). A protective effect was observed for advanced AMD among participants with high vitamin D and low calcium compared to the group with low levels for each nutrient (HR: 0.67; 95% CI: 0.50-0.88; P = 0.005). When supplement use was considered, the effect was in the protective direction but was not significant. Conclusions: A diet rich in vitamin D may prevent or delay progression to advanced AMD, especially NV. Additional exploration is needed to elucidate the potential protective role of vitamin D and its contribution to reducing visual loss.

Response to AREDS supplements according to genetic factors: survival analysis approach using the eye as the unit of analysis.

BACKGROUND/AIMS: The Age-Related Eye Disease Study (AREDS) reported the beneficial impact of antioxidant and zinc supplements on the risk of progression to advanced stages of age-related macular degeneration (AMD). We evaluated the role of genetic variants in modifying the relationship between supplementation and progression to advanced AMD. METHODS: Among 4124 eyes (2317 subjects with a genetic specimen), 882 progressed from no AMD, early or intermediate AMD to overall advanced disease, including geographic atrophy (GA) and neovascular disease (NV) over the course of the clinical trial. Survival analysis using individual eyes as the unit of analysis was used to assess the effect of supplementation on AMD outcomes, with adjustment for demographic, environmental, ocular and genetic covariates. Interaction effects between supplement groups and individual complement factor H (CFH) Y402H and age-related maculopathy susceptibility 2 (ARMS2) genotypes, and composite genetic risk groups combining the number of risk alleles for both loci, were evaluated for their association with progression. RESULTS: Among antioxidant and zinc supplement users compared with the placebo group, subjects with a non-risk genotype for CFH (TT) had a lower risk of progression to advanced AMD (HR: 0.55, 95% CI 0.32 to 0.95, p=0.033). No significant treatment effect was apparent among subjects who were homozygous for the CFH risk allele (CC). A protective effect was observed among high-risk ARMS2 (TT) carriers (HR: 0.52, 95% CI 0.33 to 0.82, p=0.005). Similar results were seen for the NV subtype but not GA. CONCLUSIONS: The effectiveness of antioxidant and zinc supplementation appears to differ by genotype. Further study is needed to determine the biological basis for this interaction. TRIAL REGISTRATION NUMBER: NCT00594672, pre-results.

Dietary omega-3 fatty acids, other fat intake, genetic susceptibility, and progression to incident geographic atrophy.

OBJECTIVE: To investigate associations between dietary omega-3 fatty acids and other fat intake, genes related to age-related macular degeneration (AMD), and progression to geographic atrophy (GA). DESIGN: Observational analysis of a prospective cohort. PARTICIPANTS: A total of 2531 individuals from the Age-Related Eye Disease Study, among which 525 eyes progressed to GA and 4165 eyes did not. METHODS: Eyes without advanced AMD at baseline were evaluated for progression to GA. Behavioral data, including smoking and body mass index measurements, were collected at baseline using questionnaires. Dietary data were collected from food frequency questionnaires (FFQs) at baseline. Omega-3 fatty acids (docosahexaenoic acid [DHA] and eicosapentaenoic acid [EPA]), omega-6 fatty acids, monounsaturated, saturated, polyunsaturated, and total fat were adjusted for sex and calories and divided into quintiles (Q). Eight single nucleotide polymorphisms in 7 genes (CFH, ARMS2/HTRA1, CFB, C2, C3, CFI, and LIPC) were genotyped. Cox proportional hazards models were used to test for associations between incident GA and intake of dietary lipids and interaction effects between dietary fat intake and genetic variation on risk of GA. MAIN OUTCOME MEASURES: Associations between dietary fat intake reported from FFQs, genetic variants, and incident GA. RESULTS: Increased intake of DHA was significantly associated with reduced risk of progression to GA in models with behavioral factors (model A) plus genetic variants (model B) (P trend = 0.01 and 0.03, respectively). Total omega-3 long chain polyunsaturated (DHA + EPA) fatty acid intake was significantly associated with reduced risk of progression in model B (P trend = 0.02). Monounsaturated fat was associated with increased risk in model A (P trend = 0.05). DHA intake was significantly associated with reduced risk of incident GA among those with the ARMS2/HTRA1 homozygous risk genotype (hazard ratio [HR] Q5 vs Q1, 0.4; P = 0.002; P for interaction between gene and fat intake = 0.05). DHA was not associated with reduced risk of GA among those with the homozygous ARMS2/HTRA1 nonrisk genotype (HR, 1.0; P = 0.90). CONCLUSIONS: Increased self-reported dietary intake of omega-3 fatty acids is associated with reduced risk of GA and may modify genetic susceptibility for progression to GA. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

C-reactive protein and CFH, ARMS2/HTRA1 gene variants are independently associated with risk of macular degeneration.

PURPOSE: Genetic variants CFH and ARMS2/HTRA1 gene regions as well as high-sensitivity C-reactive protein (CRP) levels are related to age-related macular degeneration (AMD). We evaluated their independent and combined effects on risk of AMD, as well as their interactions. DESIGN: Case-control study. PARTICIPANTS: Subjects with AMD (n = 244) or no or minimal maculopathy (n = 209) in the Age Related Eye Disease Ancillary Study. METHODS: Risk factors, genotypes, and biomarkers were assessed by questionnaire, direct measurement, and analyses of blood specimens. The independent and joint effects of serum CRP and CFH (rs1061170) and ARMS2/HTRA1 (rs10490924) genotypes were assessed using logistic regression analyses, adjusting for age, gender, education, smoking, body mass index, and vitamin/mineral supplementation. MAIN OUTCOME MEASURES: We defined AMD as large drusen, geographic atrophy, or neovascular disease. RESULTS: Higher CRP levels were associated with a higher risk of AMD, controlling for genotype and demographic and behavioral risk factors, with odds ratio 2.6 for levels of 3.0 mg/L and above versus below 1.0 mg/L (95% confidence interval, 1.01-6.7). Single nucleotide polymorphisms (SNPs) in both genes were also independently associated with risk of AMD, controlling for the level of CRP and other factors. Presence of both highest level of CRP together with risk genotypes for both SNPs, conferred the highest risk of AMD (OR 5.4, 95% CI 1.4-21.1). CONCLUSIONS: High-sensitivity CRP and polymorphisms in the CFH and ARMS2/HTRA1 genes are independently associated with risk of AMD. Higher CRP level tends to confer a higher risk of AMD within most genotype groups.

The relationship of dietary omega-3 long-chain polyunsaturated fatty acid intake with incident age-related macular degeneration: AREDS report no. 23.

OBJECTIVE: To examine the association of dietary omega-3 long-chain polyunsaturated fatty acid and fish intake with incident neovascular age-related macular degeneration (AMD) and central geographic atrophy (CGA). METHODS: Multicenter clinic-based prospective cohort study from a clinical trial including Age-Related Eye Disease Study (AREDS) participants with bilateral drusen at enrollment. Main outcome measures were incident neovascular AMD and CGA, ascertained from annual stereoscopic color fundus photographs (median follow-up, 6.3 years). We estimated nutrient and food intake from a validated food frequency questionnaire (FFQ) at baseline, with intake of docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), combined EPA and DHA, and fish as primary exposures. RESULTS: After controlling for known covariates, we observed a reduced likelihood of progression from bilateral drusen to CGA among people who reported the highest levels of EPA (odds ratio [OR], 0.44; 95% confidence interval [CI], 0.23-0.87) and EPA+DHA (OR, 0.45; 95% CI, 0.23-0.90) consumption. Levels of DHA were associated with CGA in age-, sex-, and calorie-adjusted models (OR, 0.51; 95% CI, 0.26-1.00); however, this statistical relationship did not persist in multivariable models. CONCLUSIONS: Dietary lipid intake is a modifiable factor that may influence the likelihood of developing sight-threatening forms of AMD. Our findings suggest that dietary omega-3 long-chain polyunsaturated fatty acid intake is associated with a decreased risk of progression from bilateral drusen to CGA.

CFH and LOC387715/ARMS2 genotypes and treatment with antioxidants and zinc for age-related macular degeneration.

OBJECTIVE: To determine if CFH and LOC387715/ARMS2 genotypes influence treatment response to AREDS-type nutritional supplementation with antioxidants and zinc. DESIGN: Retrospective analysis of participants in a randomized, controlled clinical trial, the Age-Related Eye Disease Study (AREDS). PARTICIPANTS AND/OR CONTROLS: Eight hundred seventy-six AREDS study participants who were considered at high risk for developing advanced age-related macular degeneration (AMD). METHODS: Using DNA extracted from venous blood of 876 white participants in AREDS categories 3 and 4, that is, those considered to be at high risk for progression to advanced AMD, the authors genotyped for the single nucleotide polymorphisms in the CFH (Y402H, rs1061170) and LOC387715/ARMS2 (A69S, rs10490924) genes. The authors performed adjusted unconditional logistic regression analysis and assessed interactions of these genotypes to determine the relationship between CFH and LOC387715/ARMS2 genotype and treatment with antioxidants plus zinc. MAIN OUTCOME MEASURES: Interaction between genetic variants and treatment response as determined by progression from high-risk to advanced AMD. RESULTS: Progression occurred in 264 of 876 patients from AREDS category 3 (intermediate AMD) to category 4 or 5 (unilateral or bilateral advanced AMD, respectively), or from category 4 to category 5. A treatment interaction was observed between the CFH Y402H genotype and supplementation with antioxidants plus zinc (CC; P = 0.03). An interaction (P = 0.004) was observed in the AREDS treatment groups taking zinc when compared with the groups taking no zinc, but not in groups taking antioxidants compared with those taking no antioxidants (P = 0.59). There were no significant treatment interactions observed with LOC387715/ARMS2. CONCLUSIONS: The findings of this study indicate that an individual's response to AREDS supplements may be related to CFH genotype. This could have clinical relevance by predicting treatment outcome and potentially preventing unwanted side effects in those who may not benefit. Corroboration of these analyses is needed before considering modification of current management. This is among the first pharmacogenetic studies to suggest interaction between genotype and treatment.

The relationship of dietary lipid intake and age-related macular degeneration in a case-control study: AREDS Report No. 20.

OBJECTIVE: To evaluate the association of lipid intake with baseline severity of age-related macular degeneration (AMD) in the Age-Related Eye Disease Study (AREDS). METHODS: Age-Related Eye Disease Study participants aged 60 to 80 years at enrollment (N = 4519) provided estimates of habitual nutrient intake through a self-administered semiquantitative food frequency questionnaire. Stereoscopic color fundus photographs were used to categorize participants into 4 AMD severity groups and a control group (participants with <15 small drusen). RESULTS: Dietary total omega-3 long-chain polyunsaturated fatty acid (LCPUFA) intake was inversely associated with neovascular (NV) AMD (odds ratio [OR], 0.61; 95% confidence interval [CI], 0.41-0.90), as was docosahexaenoic acid, a retinal omega-3 LCPUFA (OR, 0.54; 95% CI, 0.36-0.80), comparing highest vs lowest quintile of intake, after adjustment for total energy intake and covariates. Higher fish consumption, both total and broiled/baked, was also inversely associated with NV AMD (OR, 0.61; 95% CI, 0.37-1.00 and OR, 0.65; 95% CI, 0.45-0.93, respectively). Dietary arachidonic acid was directly associated with NV AMD prevalence (OR, 1.54; 95% CI, 1.04-2.29). No statistically significant relationships existed for the other lipids or AMD groups. CONCLUSION: Higher intake of omega-3 LCPUFAs and fish was associated with decreased likelihood of having NV AMD.

Multivitamin-multimineral supplements and eye disease: age-related macular degeneration and cataract.

The prevalence and effects of age-related macular degeneration (AMD) and cataract are increasing dramatically as the proportion of elderly in our population continues to rise. A multivitamin-multimineral supplement with a combination of vitamin C, vitamin E, beta-carotene, and zinc (with cupric oxide) is recommended for AMD but not cataract. Weak support exists for multivitamins or other vitamin supplements from observational studies of cataract. The results of observational studies suggest that a healthy lifestyle with a diet containing foods rich in antioxidants, particularly lutein and zeaxanthin, as well as n-3 fatty acids, appears beneficial for AMD and possibly cataract. The Age-Related Eye Disease Study II will evaluate some of these additional nutrients as dietary supplements in a randomized trial.

Cigarette smoking, fish consumption, omega-3 fatty acid intake, and associations with age-related macular degeneration: the US Twin Study of Age-Related Macular Degeneration.

OBJECTIVE: To evaluate modifiable risk and protective factors for age-related macular degeneration (AMD) among elderly twins. METHODS: The US Twin Study of Age-Related Macular Degeneration comprises elderly male twins from the National Academy of Sciences-National Research Council World War II Veteran Twin Registry. To determine genetic and environmental risk factors for AMD, twins were surveyed for a prior diagnosis of AMD and underwent an eye examination, fundus photography, and food frequency and risk factor questionnaires. This environmental component of the study includes 681 twins: 222 twins with AMD (intermediate or late stages) and 459 twins with no maculopathy or early signs. Risk for AMD according to cigarette smoking and dietary fat intake was estimated using logistic regression analyses. RESULTS: Current smokers had a 1.9-fold increased risk (95% confidence interval, 0.99-3.68, P = .06) of AMD while past smokers had about a 1.7-fold increased risk (95% confidence interval, 1.2-2.6, P = .009). Increased intake of fish reduced risk of AMD, particularly for 2 or more servings per week (P trend = .04). Dietary omega-3 fatty intake was inversely associated with AMD (odds ratio, 0.55; 95% confidence interval, 0.32-0.95) comparing the highest vs lowest quartile. Reduction in risk of AMD with higher intake of omega-3 fatty acids was seen primarily among subjects with low levels (below median) of linoleic acid intake, an omega-6 fatty acid (P trend<.001). The attributable risk percentage was 32% for smoking and the preventive fraction was 22% for higher omega-3 intake. CONCLUSIONS: This study of twins provides further evidence that cigarette smoking increases risk while fish consumption and omega-3 fatty acid intake reduce risk of AMD.

Risk factors for the incidence of Advanced Age-Related Macular Degeneration in the Age-Related Eye Disease Study (AREDS) AREDS report no. 19.

PURPOSE: To describe the association of demographic, behavioral, medical, and nonretinal ocular factors with the incidence of neovascular age-related macular degeneration (AMD) and central geographic atrophy (CGA) in the Age-Related Eye Disease Study (AREDS), a randomized trial of antioxidants and zinc supplementation prophylaxis for development of advanced AMD. DESIGN: Clinic-based prospective cohort study. PARTICIPANTS: Of individuals with early or intermediate AMD at baseline with a median follow-up of 6.3 years, 788 were at risk of developing advanced AMD in one eye (the fellow eye had advanced AMD), and 2506 were at risk in both eyes. METHODS: The incidence of neovascular AMD and CGA was assessed from stereoscopic color fundus photographs taken at baseline and at annual visits beginning at year 2. MAIN OUTCOME MEASURES: Neovascular AMD was defined as photocoagulation for choroidal neovascularization, or photographic documentation at the reading center of any of the following: nondrusenoid retinal pigment epithelial detachment, serous or hemorrhagic retinal detachment, hemorrhage under the retina or the retinal pigment epithelium, and subretinal fibrosis. Central geographic atrophy was defined as geographic atrophy involving the center of the macula. RESULTS: In multivariable models, in persons at risk of advanced AMD in both eyes, while controlling for age, gender, and AREDS treatment group, the following variables were statistically significantly associated with the incidence of neovascular AMD: race (odds ratio [OR], white vs. black, 6.77; 95% confidence interval [CI], 1.24-36.9) and larger amount smoked (OR, >10 vs. < or =10 pack-years [a pack-year is an average of 1 pack of cigarette smoked per day for a year], 1.55; 95% CI, 1.15-2.09). The following were statistically significantly associated with the incidence of CGA: less education (OR, high school graduate or less vs. college graduate, 1.75; 95% CI, 1.10-2.78), greater body mass index (BMI) (OR, obese vs. nonobese, 1.93; 95% CI, 1.25-2.65), larger amount smoked (OR, >10 pack-years vs. < or =10 pack-years, 1.82; 95% CI, 1.25-2.65), and antacid use (OR, 0.29; 95% CI, 0.09-0.91). In persons at risk of developing advanced AMD in one eye, the incidence of neovascular AMD was associated with diabetes (OR, 1.88; 95% CI, 1.07-3.31), and the incidence of CGA was associated with use of antiinflammatory medications (OR, 0.22; 95% CI, 0.08-0.59). CONCLUSIONS: Results suggest that, among persons with early or intermediate AMD, smoking and BMI are modifiable factors associated with progression to advanced AMD, and suggest other associations (e.g., use of antacids and antiinflammatory medications) that warrant further study. This article contains additional online-only material available at http://www.ophsource.org/periodicals/ophtha. .

Association between C-reactive protein and age-related macular degeneration.

CONTEXT: C-reactive protein (CRP) is a systemic inflammatory marker associated with risk for cardiovascular disease (CVD). Some risk factors for CVD are associated with age-related macular degeneration (AMD), but the association between CRP and AMD is unknown. OBJECTIVE: To test the hypothesis that elevated CRP levels are associated with an increased risk for AMD. DESIGN, SETTING, AND PARTICIPANTS: A total of 930 (91%) of 1026 participants at 2 centers in the Age-Related Eye Disease Study (AREDS), a multicenter randomized trial of antioxidant vitamins and minerals, were enrolled in this case-control study. There were 183 individuals without any maculopathy, 200 with mild maculopathy, 325 with intermediate disease, and 222 with advanced AMD (geographic atrophy or neovascular AMD). The AMD status was assessed by standardized grading of fundus photographs, and stored fasting blood specimens drawn between January 1996 and April 1997 were analyzed for high-sensitivity CRP levels. MAIN OUTCOME MEASURE: Association between CRP and AMD. RESULTS: The CRP levels were significantly higher among participants with advanced AMD (case patients) than among those with no AMD (controls; median values, 3.4 vs 2.7 mg/L; P =.02). After adjustment for age, sex, and other variables, including smoking and body mass index, CRP levels were significantly associated with the presence of intermediate and advanced stages of AMD. The odds ratio (OR) for the highest vs the lowest quartile of CRP was 1.65 (95% confidence interval [CI], 1.07-2.55; P for trend =.02). The OR for CRP values at or above the 90th percentile (10.6 mg/L) was 1.92 (95% CI, 1.20-3.06), and the OR for CRP values at or above the mean plus 2 SDs (16.8 mg/L) was 2.03 (95% CI, 1.03-4.00). A trend for an increased risk for intermediate and advanced AMD with higher levels of CRP was seen for smokers (OR, 2.16; 95% CI, 1.33-3.49) and those who never smoked (OR, 2.03; 95% CI, 1.19-3.46) with the highest level of CRP. CONCLUSION: Our results suggest that elevated CRP level is an independent risk factor for AMD and may implicate the role of inflammation in the pathogenesis of AMD.

Potential public health impact of Age-Related Eye Disease Study results: AREDS report no. 11.

OBJECTIVE: To estimate the potential public health impact of the findings of the Age-Related Eye Disease Study (AREDS) on reducing the number of persons developing advanced age-related macular degeneration (AMD) during the next 5 years in the United States. METHODS: The AREDS clinical trial provides estimates of AMD progression rates and of reduction in risk of developing advanced AMD when a high-dose nutritional supplement of antioxidants and zinc is used. These results are applied to estimates of the US population at risk, to estimate the number of people who would potentially avoid advanced AMD during 5 years if those at risk were to take a supplement such as that used in AREDS. RESULTS: An estimated 8 million persons at least 55 years old in the United States have monocular or binocular intermediate AMD or monocular advanced AMD. They are considered to be at high risk for advanced AMD and are those for whom the AREDS formulation should be considered. Of these people, 1.3 million would develop advanced AMD if no treatment were given to reduce their risk. If all of these people at risk received supplements such as those used in AREDS, more than 300,000 (95% confidence interval, 158,000-487,000) of them would avoid advanced AMD and any associated vision loss during the next 5 years. CONCLUSION: If people at high risk for advanced AMD received supplements such as those suggested by AREDS results, the potential impact on public health in the United States would be considerable during the next 5 years.