Risk Of Age-related Macular Degeneration Research Articles

MP11-04 ANDROGEN-DEPRIVATION THERAPY AND THE RISK OF NEWLY DEVELOPED NEOVASCULAR AGE-RELATED MACULAR DEGENERATION IN PATIENTS WITH PROSTATE CANCER: A NESTED CASE-CONTROL STUDY

You have accessJournal of UrologyCME1 Apr 2023MP11-04 ANDROGEN-DEPRIVATION THERAPY AND THE RISK OF NEWLY DEVELOPED NEOVASCULAR AGE-RELATED MACULAR DEGENERATION IN PATIENTS WITH PROSTATE CANCER: A NESTED CASE-CONTROL STUDY Jee Soo Ha, Hye Sun Lee, Soyoung Jeon, Jinhyung Jeon, Hyunho Han, Jong Cheol Ko, Daeho Kim, June Seok Kim, Min Kim, and Kang Su Cho Jee Soo HaJee Soo Ha More articles by this author , Hye Sun LeeHye Sun Lee More articles by this author , Soyoung JeonSoyoung Jeon More articles by this author , Jinhyung JeonJinhyung Jeon More articles by this author , Hyunho HanHyunho Han More articles by this author , Jong Cheol KoJong Cheol Ko More articles by this author , Daeho KimDaeho Kim More articles by this author , June Seok KimJune Seok Kim More articles by this author , Min KimMin Kim More articles by this author , and Kang Su ChoKang Su Cho More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003226.04AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: We evaluated the association between newly developed neovascular age-related macular degeneration (AMD) and androgen deprivation therapy (ADT) in patients with prostate cancer. METHODS: A nested case-control study was performed. From the nationwide claims database in the Republic of Korea, 228,803 men with prostate cancer were identified between August 1, 2009 and December 31, 2018, and followed through April 2021. After applying the exclusion criteria, 193,090 patients were included in the final analysis. Cases were defined as those who were newly diagnosed neovascular AMD during follow-up and 1,751 patients were identified. Cases were matched with controls based on age, index date, and duration of follow-up with a a case to control ratio of 1:4 cases. Adjusted odd ratios (aORs) of incident neovascular AMD associated with ADT use were estimated using conditional logistic regression. RESULTS: The main analysis included 1,700 cases and 6,800 controls with a median follow-up of 3.42 years. The use of ADT was associated with a reduced risk of incident neovascular AMD in patients with prostate cancer compared with that of non-ADT users (aOR=0.840; 95% confidence interval [CI], 0.743-0.951; P=0.0058) in multivariable analysis. An accumulated dose of ADT less than 1 year was associated with a reduced risk of neovascular AMD (aOR=0.727; 95% CI, 0.610-0.866; p=0.0004), however, no association was observed in the duration of ADT between 1 and 2 years (aOR=0.862; 95% CI, 0.693-1.074; p=0.1854) and more than 2 years (aOR=1.009; 95% CI, 0.830-1.226; p=0.9304). CONCLUSIONS: In prostate cancer patients, androgen suppression was associated with a reduced risk of incident neovascular AMD. A relatively short duration of ADT of less than 1 year was associated with a reduced risk of incident neovascular AMD, but this association disappeared as the longer duration of ADT. These results suggest that androgen may be involved in the pathogenesis of neovascular AMD. Source of Funding: This study was supported by the 2021 Research Grant of the Korean Urological Association © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e124 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Jee Soo Ha More articles by this author Hye Sun Lee More articles by this author Soyoung Jeon More articles by this author Jinhyung Jeon More articles by this author Hyunho Han More articles by this author Jong Cheol Ko More articles by this author Daeho Kim More articles by this author June Seok Kim More articles by this author Min Kim More articles by this author Kang Su Cho More articles by this author Expand All Advertisement PDF downloadLoading ...

RISK OF EXUDATIVE AGE-RELATED MACULAR DEGENERATION IN PATIENTS WITH CENTRAL SEROUS CHORIORETINOPATHY: A Nationwide Cohort Study.

In Brief We read with interest the article entitled “Risk of exudative age-related macular degeneration in patients with central serous chorioretinopathy: A Nationwide Cohort Study” recently published in Retina Journal. However, we believe that the authors failed to define exudative AMD and differentiate it from choroidal neovascularization complicating CSC (i.e., pachychoroid neovasculopathy).

The zeaxanthin present in a tomato line rich in this carotenoid is as bioavailable as that present in the food sources richest in this xanthophyll

It is strongly suspected that, like lutein, zeaxanthin (ZEA) plays a biological role in the human eye. Many studies also suggest that it could reduce the risk of age-related macular degeneration and improve cognition. Unfortunately, it is only present in a very limited number of foods. This is why a new tomato line, named “Xantomato”, whose fruits can synthesize this compound, was generated. However, whether ZEA in Xantomato is bioavailable enough for Xantomato to qualify as a nutritionally relevant ZEA source is not known. The objective was to compare the bioaccessibility and intestinal cell uptake efficiency of ZEA from Xantomato to that present in the richest sources of this compound. Bioaccessibility was assessed using in vitro digestions and uptake efficiency using Caco-2 cells. Xantomato ZEA bioaccessibility was not statistically different from that of common fruits and vegetables rich in this compound. Xantomato ZEA uptake efficiency (7.8%) was lower (P < 0.05) than that of orange pepper (10.6%) but not different from that of corn (6.9%). Therefore, the results of the in vitro digestion/Caco-2 cell model suggest that Xantomato ZEA could be as bioavailable as that found in common food sources of this compound.

PENTOSAN POLYSULFATE SODIUM (ELMIRON) MACULOPATHY: A Genetic Perspective.

To assess genetic associations for pentosan polysufate sodium maculopathy. Genetic testing for inherited retinal dystrophy genes using exome testing and for 14 age-related macular degeneration-associated single nucleotide polymorphisms (SNPs) using panel testing were performed. In addition, full-field electroretinograms (ffERG) were obtained to identify any cone-rod dystrophy. Eleven of 15 patients were women, with a mean age of 69 (range 46-85). Inherited retinal dystrophy exome testing in five patients revealed six pathogenic variants, but failed to confirm inherited retinal dystrophy in any patient genetically. FfERG performed in 12 patients demonstrated only nonspecific a- and b-wave abnormalities in 11 cases and was normal in one case. For age-related macular degeneration single nucleotide polymorphisms, CFH rs3766405 ( P = 0.003) and CETP ( P = 0.027) were found to be statistically significantly associated with pentosan polysulfate maculopathy phenotype compared with the control population. Pentosan polysulfate maculopathy is not associated with Mendelian inherited retinal dystrophy genes. However, several age-related macular degeneration risk alleles were identified to be associated with maculopathy compared with their frequency in the normal population. This suggests a role for genes in disease pathology, particularly the alternative complement pathway. These findings would benefit from further investigation to understand the risk of developing maculopathy in taking pentosan polysulfate.

The Role of the Complement Pathway in Clinical Progression of Geographic Atrophy: Analysis of the Phase III Chroma and Spectri Trials

To investigate the relationship between complement pathway activities and progression of geographic atrophy (GA) secondary to age-related macular degeneration in samples collected from patients enrolled in the Chroma and Spectri trials. Chroma and Spectri were phase III, double-masked, and sham-controlled, 96-week trials. Aqueous humor (AH) samples collected at baseline and week 24 visits from 81 patients with bilateral GA across all 3 treatment groups (intravitreal lampalizumab 10 mg every 6 weeks, every 4 weeks, or corresponding sham procedures) were tested, along with patient-matched plasma samples collected at baseline. Antibody capture assays using the Simoa platform were used to measure the levels of complement factor B, the Bb fragment of complement factor B, intact complement component 3 (C3), processed C3, intact complement C4, and processed C4. Complement factor D levels were measured using enzyme-linked immunosorbent assay. Correlations of complement levels and activities (i.e., processed:intact ratio of complement component) in AH and plasma with baseline GA lesion size and growth rate. In baseline AH, there were strong correlations (Spearman's rho ≥ 0.80) between intact complement proteins, between processed complement proteins, and between linked processed and intact complement proteins; weak correlations (rho ≤ 0.24) were found between complement pathway activities. There were no strong correlations between complement protein levels and activities measured in AH and plasma at baseline (rho ≤ 0.37). Baseline complement levels and activities in AH and plasma did not correlate with baseline GA lesion size or change from baseline in GA lesion area at week 48 (i.e., annualized growth rate). There were no strong correlations between changes in complement levels/activities in the AH from baseline to week 24 and annualized GA lesion growth rate. Genotype analysis did not reveal a meaningful correlation between complement-related, age-related macular degeneration risk single-nucleotide polymorphisms and complement levels and activities. Complement levels or activities in AH and plasma did not correlate with GA lesion size or growth rate. This suggests that local complement activation as measured in AH does not appear to be related to GA lesion progression. Proprietary or commercial disclosure may be found after the references.

Association between glycemic status and age-related macular degeneration: A nationwide population-based cohort study

AimThe risk of dry and wet age-related macular degeneration (AMD) based on fasting glucose levels and disease duration of type 2 diabetes was investigated. MethodsUsing a health insurance claims database and the results of health examinations in South Korea, we conducted a retrospective, population-based cohort study of 2,103,604 adults ≥ 45 years of age who were AMD-free based on health checkups in 2009 and observed from January 1, 2011, to December 31, 2018. Glycemic status was classified into five groups: normal, impaired fasting glucose, new-onset diabetes (fasting glucose level ≥ 126 mg/dl but no diabetes diagnosis or diabetes medication), diabetes diagnosis < 5 years, and diabetes ≥ 5 years. According to the presence and absence of choroidal neovascularization, AMD was classified as wet AMD and dry AMD, respectively. Adjusted hazard ratios (HRs) of AMD occurrence were estimated in each category. ResultsFor dry AMD (n = 36,271, 1.72%), the HR was 1.192 (1.141–1.245) among subjects with diabetes < 5 years and 1.294 (1.242–1.349) among subjects with diabetes ≥ 5 years compared with subjects with normal glycemic status after adjusting for age, sex, body mass index, lifestyle, and medical history. For wet AMD (n = 12,912, 0.61%), the HR was 1.103 (1.011–1.203) among subjects with new-onset diabetes, 1.252 (1.167–1.344) among subjects with diabetes < 5 years, and 1.506 (1.413–1.605) among subjects with diabetes ≥ 5 years. The HR of AMD was significantly increased among participants ≤ 65 years old and those who did not have hypertension. ConclusionsThe incidence of dry and wet AMD increased among diabetes patients compared to the normal glycemic status group. These risks increased when the duration of diabetes was 5 years or more. The risk of wet AMD was increased among new-onset diabetes patients. These results suggest that high blood glucose levels without treatment might induce the vision-threatening condition of wet AMD, emphasizing the importance of early blood glucose management.

Association between oral metformin use and the risk of age-related macular degeneration: A systematic review with meta-analysis.

Rodent studies demonstrate that oral metformin use may reduce chronic low-grade inflammation, downregulate apoptosis and extend life span. Emerging epidemiological evidence suggests that oral metformin use may protect against development of age-related macular degeneration (AMD) in humans. In this study, we systematically reviewed the literature on the association between oral metformin use and AMD in patients with type 2 diabetes and conducted a quantitative meta-analysis to provide a summary estimate of the association. We searched 12 literature databases on 10 August 2022 and identified nine eligible studies with data on a total of 1427 074 individuals with diabetes. We found that patients with diabetes using metformin had a significantly lower odds ratio (OR) of having or developing AMD (OR 0.63; 95% CI: 0.46-0.86; p=0.004). Our analyses also revealed that although the findings were robust in the sensitivity analysis, the Funnel plot indicated a certain publication bias towards finding a protective effect. Results of individual studies suggested inconsistent findings, as some studies found lower risk of AMD from higher total metformin exposure, whereas other studies found a higher risk of AMD from higher total metformin exposure. Taken together, there may be a link between metformin use and lower risk of AMD, but the relationship is only studied in observational studies, various sources of bias can be speculated to influence, and careful interpretation is warranted.

Abstract P551: Genetic Variants in the Adenosine Triphosphate-Binding Cassette Transporter A1 and Risk of Age-Related Macular Degeneration

Objective: Genetic variants in the adenosine triphosphate-binding cassette transporter A1( ABCA1 ) is associated with higher concentrations of high-density lipoprotein (HDL) cholesterol. Higher HDL cholesterol concentrations are observationally and genetically associated with higher risk of age-related macular degeneration (AMD). However, whether amino acid changing genetic variants in ABCA1 associated with high HDL cholesterol concentrations confer a higher risk of AMD in the general population is currently unknown. We tested this hypothesis. Methods: We genotyped all amino acid changing ABCA1 variants with a minor allele frequency above 0.002, measured plasma HDL cholesterol and other plasma lipids, and used Cox regression to assess risk of AMD. We created an HDL cholesterol weighted allele score and tested the association with risk of AMD on a continuous scale and in tertiles. Further, we performed mediation analyses. Main outcome measures: 1,554 AMD events. Median follow-up of 10 years. Results: Of 90,344 study participants, 55% were women. Median age was 58 (interquartile range: 47-67) years. On a continuous scale, higher concentrations of genetically determined HDL cholesterol were associated with higher risk of all-cause AMD, dry AMD, and wet AMD both in an age- and sex adjusted model and in a multivariable adjusted model (See Figure). The ABCA1 allele score for the third versus the first tertile was associated with HRs (95% confidence intervals (CIs)) of 1.30 (1.14-1.49) for all-cause AMD, 1.26 (1.06-1.50) for dry AMD, and 1.31 (1.12-1.53) for wet AMD in a multivariable adjusted model. 6-8% of the effect was mediated through HDL cholesterol. There was no interaction between weighted allele score tertiles and confounding factors on risk of AMD. Conclusions: Amino acid changing genetic variants in ABCA1 which were associated with higher HDL cholesterol concentrations, were also associated with higher risk of AMD, both on a weighted allele score continuously and when divided into tertiles.

Serum 25-Hydroxyvitamin D Is Differentially Associated with Early and Late Age-Related Macular Degeneration in the United States Population.

Age-related macular degeneration (AMD) has been the leading cause of irreversible blindness in industrialized countries. Emerging data suggest that serum vitamin D levels may be associated with AMD but show mixed results. National-level population data on the relationship between vitamin D and AMD severities are still lacking. We used data from the National Health and Nutrition Examination Survey (NHANES) 2005 to 2008. Retinal photographs were taken and graded for AMD stage. The odds ratio (OR) of AMD and its subtype was calculated after adjusting for confounding factors. Restricted cubic spline (RCS) analyses were used to explore potential non-linear relations. A total of 5041 participants with a mean age of 59.6 years were included. After adjusting for covariates, participants with higher level of serum 25-hydroxyvitamin D [25(OH)D] had significantly greater odds of early AMD (OR, 1.65; 95% CI, 1.08-2.51) and decreased risk of late AMD (OR, 0.29; 95% CI, 0.09-0.88). When stratified by age, a positive association between the level of serum 25(OH)D and early AMD was present in the <60 years group (OR, 2.79; 95% CI, 1.08-7.29), whereas a negative relation between the level of serum 25(OH)D and late AMD was detected in the ≥60 years group (OR, 0.24; 95% CI, 0.08-0.76). A higher level of serum 25(OH)D was related to increased risk of early AMD in those <60 years and decreased risk of late AMD in those ≥60 years.

Genome-wide association study and identification of systemic comorbidities in development of age-related macular degeneration in a hospital-based cohort of Han Chinese.

Background: Age-related macular degeneration (AMD) is the main cause of severe vision loss in elderly populations of the developed world with limited therapeutic medications available. It is a multifactorial disease with a strong genetic susceptibility which exhibits the differential genetic landscapes among different ethnic groups. Methods: To investigate the Han Chinese-specific genetic variants for AMD development and progression, we have presented a genome-wide association study (GWAS) on 339 AMD cases and 3,390 controls of a Han Chinese population recruited from the Taiwan Precision Medicine Initiative (TPMI). Results: In this study, we have identified several single nucleotide polymorphisms (SNPs) significantly associated with AMD, including rs10490924, rs3750848, and rs3750846 in the ARMS2 gene, and rs3793917, rs11200638, and rs2284665 in the HTRA1 gene, in which rs10490924 was highly linked to the other variants based upon linkage disequilibrium analysis. Moreover, certain systemic comorbidities, including chronic respiratory diseases and cerebrovascular diseases, were also confirmed to be independently associated with AMD. Stratified analysis revealed that both non-exudative and exudative AMD were significantly correlated with these risk factors. We also found that homozygous alternate alleles of rs10490924 could lead to an increased risk of AMD incidence compared to homozygous references or heterozygous alleles in the cohorts of chronic respiratory disease, cerebrovascular disease, hypertension, and hyperlipidemia. Ultimately, we established the SNP models for AMD risk prediction and found that rs10490924 combined with the other AMD-associated SNPs identified from GWAS improved the prediction model performance. Conclusion: These results suggest that genetic variants combined with the comorbidities could effectively identify any potential individuals at a high risk of AMD, thus allowing for both early prevention and treatment.

Risk of developing age-related macular degeneration in patients with osteoporosis: a population-based, longitudinal follow-up study.

To investigate the long-term risk of age-related macular degeneration (AMD) in patients with osteoporosis. This is a retrospective cohort study using the Longitudinal Health Insurance Database 2005, a subset of Taiwan's National Health Insurance research database. A total of 23,611 individuals aged 50 to 79 who were diagnosed with osteoporosis between January 1, 2002 and December 31, 2006, were enrolled in the osteoporosis group. An exactly equal number of propensity score-matched individuals without osteoporosis comprised the comparison group. The variables used in propensity score matching included age, sex, comorbidities, and socioeconomic status. Cox proportional hazard regression analysis was used to evaluate the association between osteoporosis and AMD. The main outcome measure is the occurrence of newly diagnosed AMD. The hazard ratio (HR) of AMD in the osteoporosis group was 1.34 times higher than in the comparison group (95% confidence interval [CI] 1.22-1.47, p < 0.05). The AMD-free survival rate of the osteoporosis group was significantly lower than that of the comparison group (p < 0.0001). Sex-stratified analysis revealed a significantly increased risk of AMD in both osteoporotic men (HR 1.45; 95% CI 1.20-1.76, p = 0.0002) and women (HR 1.31; 95% CI 1.17-1.46, p < 0.0001) compared with their non-osteoporotic counterparts. This longitudinal follow-up study revealed an increased risk of developing AMD in both men and women with osteoporosis.

Analysis of Wild Type and Variant B Cystatin C Interactome in Retinal Pigment Epithelium Cells Reveals Variant B Interacting Mitochondrial Proteins.

Cystatin C, a secreted cysteine protease inhibitor, is abundantly expressed in retinal pigment epithelium (RPE) cells. A mutation in the protein's leader sequence, corresponding to formation of an alternate variant B protein, has been linked with an increased risk for both age-related macular degeneration (AMD) and Alzheimer's disease (AD). Variant B cystatin C displays intracellular mistrafficking with partial mitochondrial association. We hypothesized that variant B cystatin C interacts with mitochondrial proteins and impacts mitochondrial function. We sought to determine how the interactome of the disease-related variant B cystatin C differs from that of the wild-type (WT) form. For this purpose, we expressed cystatin C Halo-tag fusion constructs in RPE cells to pull down proteins interacting with either the WT or variant B form, followed by identification and quantification by mass spectrometry. We identified a total of 28 interacting proteins, of which 8 were exclusively pulled down by variant B cystatin C. These included 18 kDa translocator protein (TSPO) and cytochrome B5 type B, both of which are localized to the mitochondrial outer membrane. Variant B cystatin C expression also affected RPE mitochondrial function with increased membrane potential and susceptibility to damage-induced ROS production. The findings help us to understand how variant B cystatin C differs functionally from the WT form and provide leads to RPE processes adversely affected by the variant B genotype.

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

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. The search of relevant English articles was conducted in PubMed, Medline, and Google Scholar databases until December 2022. 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. 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.

The Risk of Age-Related Macular Degeneration Is Reduced in Type 2 Diabetes Patients Who Use Metformin.

Whether metformin may reduce the risk of age-related macular degeneration (AMD) requires confirmation. This study compared the risk of AMD between ever users and never users of metformin matched on propensity score (PS) in Taiwanese patients with type 2 diabetes mellitus. We enrolled study subjects from Taiwan's National Health Insurance. A total of 423,949 patients with new onset diabetes from 1999 to 2005 were identified. After excluding ineligible patients and enrolling only patients aged between 50 and 79 years, we created 13,303 pairs of ever users and never users of metformin matched on PS. The patients were followed from 1 January 2006 to 31 December 2011. We estimated hazard ratios by Cox regression. AMD was newly diagnosed in 506 ever users and 639 never users. The respective incidence rates (per 100,000 person-years) were 778.72 and 1016.62. The hazard ratio (HR) and 95% confidence interval (CI) for ever versus never users was 0.756 (0.673-0.850). While ever users were categorized by tertiles of cumulative duration (<31.8, 31.8-63.9 and >63.9 months) and cumulative dose (<947.1, 947.1-2193.5 and >2193.5 g) of metformin, a dose-response pattern was observed. For the respective tertiles of cumulative duration, the HRs (95% CIs) were 1.131 (0.961-1.330), 0.821 (0.697-0.967) and 0.464 (0.384-0.561), while compared to never users. For the respective tertiles of cumulative dose, the HRs (95% CIs) were 1.131 (0.962-1.329), 0.739 (0.624-0.876) and 0.525 (0.438-0.629). A risk reduction among ever users was observed for all tertiles of defined daily dose but was most remarkable for the third tertile with a defined daily dose of >0.64. Subgroup analyses suggested that the benefit of metformin could be similarly observed among men and women and for age subgroups of 50-64 and 65-79 years. However, patients with diabetic retinopathy would not be significantly benefited and metformin did not seem to be preventive for exudative AMD. In general, metformin significantly reduces the risk of AMD.

Automation of Macular Degeneration Classification in the AREDS Dataset, Using a Novel Neural Network Design.

To create an ensemble of Convolutional Neural Networks (CNNs), capable of detecting and stratifying the risk of progressive age-related macular degeneration (AMD) from retinal photographs. Retrospective cohort study. Three individual CNNs are trained to accurately detect 1) advanced AMD, 2) drusen size and 3) the presence or otherwise of pigmentary abnormalities, from macular centered retinal images were developed. The CNNs were then arranged in a "cascading" architecture to calculate the Age-related Eye Disease Study (AREDS) Simplified 5-level risk Severity score (Risk Score 0 - Risk Score 4), for test images. The process was repeated creating a simplified binary "low risk" (Scores 0-2) and "high risk" (Risk Score 3-4) classification. There were a total of 188,006 images, of which 118,254 images were deemed gradable, representing 4591 patients, from the AREDS1 dataset. The gradable images were split into 50%/25%/25% ratios for training, validation and test purposes. The ability of the ensemble of CNNs using retinal images to predict an individual's risk of experiencing progression of their AMD based on the AREDS 5-step Simplified Severity Scale. When assessed against the 5-step Simplified Severity Scale, the results generated by the ensemble of CNN's achieved an accuracy of 80.43% (quadratic kappa 0.870). When assessed against a simplified binary (Low Risk/High Risk) classification, an accuracy of 98.08%, sensitivity of ≥85% and specificity of ≥99% was achieved. We have created an ensemble of neural networks, trained on the AREDS 1 dataset, that is able to accurately calculate an individual's score on the AREDS 5-step Simplified Severity Scale for AMD. If the results presented were replicated, then this ensemble of CNNs could be used as a screening tool that has the potential to significantly improve health outcomes by identifying asymptomatic individuals who would benefit from AREDS2 macular supplements.

The Relationship between Dietary Calcium and Age-Related Macular Degeneration.

Mineral element supplements are widely used in the older adult population. However, little is known of their impact on the progression of age-related macular degeneration (ARMD). The aim of this study was to examine the association between dietary micronutrients and ARMD in older adults. We enrolled 5227 participants from the National Health and Nutrition Examination Survey (NHANES 2005-2008) in this cross-sectional study. ARMD was evaluated using an ophthalmic digital imaging system and digital camera. Mineral element consumption was collected using a 24-hour dietary recall. The association between mineral element use and the presence of ARMD was determined by multivariable logistic regression. After adjusting for relevant variables, dietary calcium was negatively associated with ARMD (OR: 680, 95%CI: 0.482-0.960). In contrast to dietary form, serum concentration of calcium was not associated with ARMD. Moreover, increased dietary calcium was associated with reduced ARMD (OR: 0.684, 95%CI: 0.468-1.000). A lower consumption of dietary calcium was significantly associated with a higher risk of ARMD. Further longitudinal studies are necessary to explore these findings.

The LHX2-OTX2 transcriptional regulatory module controls retinal pigmented epithelium differentiation and underlies genetic risk for age-related macular degeneration.

Tissue-specific transcription factors (TFs) control the transcriptome through an association with noncoding regulatory regions (cistromes). Identifying the combination of TFs that dictate specific cell fate, their specific cistromes and examining their involvement in complex human traits remain a major challenge. Here, we focus on the retinal pigmented epithelium (RPE), an essential lineage for retinal development and function and the primary tissue affected in age-related macular degeneration (AMD), a leading cause of blindness. By combining mechanistic findings in stem-cell-derived human RPE, in vivo functional studies in mice and global transcriptomic and proteomic analyses, we revealed that the key developmental TFs LHX2 and OTX2 function together in transcriptional module containing LDB1 and SWI/SNF (BAF) to regulate the RPE transcriptome. Importantly, the intersection between the identified LHX2-OTX2 cistrome with published expression quantitative trait loci, ATAC-seq data from human RPE, and AMD genome-wide association study (GWAS) data, followed by functional validation using a reporter assay, revealed a causal genetic variant that affects AMD risk by altering TRPM1 expression in the RPE through modulation of LHX2 transcriptional activity on its promoter. Taken together, the reported cistrome of LHX2 and OTX2, the identified downstream genes and interacting co-factors reveal the RPE transcription module and uncover a causal regulatory risk single-nucleotide polymorphism (SNP) in the multifactorial common blinding disease AMD.

Genetic variation reveals the influence of steroid hormones on the risk of retinal neurodegenerative diseases.

It is difficult to get evidence from randomized trials of a causal relationship between steroid hormones produced by the adrenal gland and gonad and retinal neurodegenerative disorders (RND). In this study, genetic variations of aldosterone (Aldo), androstenedione (A4), progesterone (P4), hydroxyprogesterone (17-OHP), and testosterone/17β-estradiol (T/E2) were obtained from genome-wide association studies as instrumental variables. Mendelian randomization (MR) analysis was used to assess the impact on the risk of RND, including glaucoma (8,591 cases and 210,201 controls), diabetic retinopathy (DR, 14,584 cases and 202,082 controls) and age-related macular degeneration (AMD, 14,034 cases and 91,214 controls). As the main method, inverse variance weighted results suggest that the increased glaucoma risk was affected by T/E2 (OR = 1.11, 95% CI, 1.01-1.22, P = 0.03), which was further validated by other methods (PWM = 0.03, PMLE = 0.03, PMR-RAPS = 0.03). In the replicated stage, the causal relationship between T/E2 and glaucoma was verified based on the MRC-IEU consortium (P = 0.04). No impact of Aldo, A4, P4, 17-OHP, and T/E2 was observed for the risk of DR (P > 0.05) and AMD (P > 0.05). The heterogeneity test (P > 0.05) and pleiotropy test (P > 0.05) verified the robustness of the results. Our results suggest that T/E2 has a suggestive effect on the glaucoma risk. However, the genetic evidence based on a large sample does not support the effect of steroid hormones on DR and AMD risk. Further studies are vital to assess the possibility of steroid hormones as targets for prevention and treatment.

Increased end-stage renal disease risk in age-related macular degeneration: a nationwide cohort study with 10-year follow-up

Common etiologies between age-related macular degeneration (AMD) and kidney disease advocate a close link between AMD and end-stage renal disease (ESRD). However, the risk of ESRD in people with AMD was not reported. Here, we investigated the association between AMD and the risk of ESRD by using a nationwide, population-based cohort data in Korea. 4,206,862 participants aged 50 years or older were categorized by presence of AMD and visual disability. Risk of ESRD was the primary outcome. Cox regression hazard model was used to examine the hazard ratios (HRs) with adjustment for potential confounders. Stratified analyses by age, sex, baseline kidney function, and cardiometabolic comorbidities were performed. During the mean 9.95 years of follow-up, there were 21,759 incident ESRD events (0.52%). AMD was associated with 33% increased risk of ESRD (adjusted HR [aHR] 1.33, 95% confidence interval [CI] 1.24–1.44), and the risk was even higher when accompanied by visual disability (aHR 2.05, 95% CI 1.68–2.50) than when not (aHR 1.26, 95% CI 1.17–1.37). Age, baseline kidney function, and cardiometabolic comorbidities significantly interact between AMD and the risk of ESRD. Our findings have clinical implications on disease prevention and risk factor management of ESRD in patients with AMD.

Sleep duration and age-related macular degeneration: a cross-sectional and Mendelian randomization study.

To investigate the association between sleep duration and age-related macular degeneration (AMD). Cross-sectional study, bidirectional two-sample Mendelian randomization (MR). For cross-sectional analysis, we used survey data of 5,481 participants aged ≥40 years from the 2005 to 2008 National Health and Nutrition Examination Survey (NHANES). For MR analysis, we used sleep- and AMD-associated genome-wide association studies (GWAS) data involving large populations. The association between sleep duration and AMD was assessed using logistic regression models. For MR analysis, the primary approach for MR analysis was the inverse-variance weighted (IVW) method. In cross-sectional analysis, after adjusting for multiple covariates, short sleep duration (SSD) was found to be associated with increased risk of early AMD [odds ratio (OR) = 1.364, P = 0.036). MR analysis supported the results of cross-sectional analysis: SSD increases the risk of early AMD (β = 0.102, IVW-P = 0.003). Our findings provide the evidence supporting the association between sleep deficiency and higher risk of AMD. Further studies are required to confirm our findings and elucidate the mechanisms underlying this association.