Advanced Age-related Macular Degeneration Research Articles

Evaluating a Causal Relationship between Complement Factor I Protein Level and Advanced Age-Related Macular Degeneration Using Mendelian Randomization.

PurposeRisk of advanced age-related macular degeneration (AAMD) is associated with rare genetic variants in the gene encoding complement factor I (CFI), which is associated with lower circulating CFI protein levels, but the nature of the relationship is unclear. Can genetic factors be used to infer whether low circulating CFI is associated with AAMD risk?DesignTwo-sample inverse variance-weighted Mendelian randomization (MR) was used to evaluate evidence for a relationship between CFI levels and AAMD risk, comparing CFI levels from genetically predefined subsets in AAMD and control cohorts.ParticipantsWe derived genetic instruments for systemic CFI level in 3301 healthy INTERVAL study participants. To evaluate a genetic causal odds ratio (OR) for the effect of CFI levels on AAMD risk, results from an AAMD genome-wide association study from the International AMD Genomics Consortium, were combined with CFI levels from SCOPE and SIGHT AAMD patients.MethodsPublished genetic and proteomic data was combined with data from cohorts of patients with geographic atrophy (GA) in a series of MR analyses.Main Outcome MeasuresEstablishing a causal relationship for CFI on AAMD.ResultsOne common CFI variant, rs7439493, was associated strongly with low CFI level, explaining 4.8% of phenotypic variance. Using rs7439493, MR estimates for AAMD odds increased per standard deviation (SD) CFI decrease in were 1.47 (95% confidence interval [CI], 1.30–1.65; P = 2.1 × 10–10). MR using rare variant (rs141853578 encoding p.Gly119Arg) indicated 1-SD decrease in CFI led to increased AAMD OR of 1.79 (95% CI, 1.46–2.19; P = 1.9 × 10–8). The rare variant rs141853578 explained a further 1.7% of phenotypic variance. To benchmark the effect of low CFI levels on AAMD ORs using a CFI-specific proteomic assay, we estimated the effect using CFI levels from 24 rs141853578 positive GA patients; each 1-SD reduction (3.5 μg/mL) in CFI associated with a 1.67-fold increased odds of AAMD (95% CI, 1.40–2.00; P = 1.85 × 10–8).ConclusionsConcordance in MR calculations provide good genetic evidence for a potentially causal role of lower CFI level increasing AAMD risk.

Incidence and risk of advanced age-related macular degeneration in eyes with drusenoid pigment epithelial detachment

To investigate the incidence and risk of advanced age-related macular degeneration (AMD), including geographic atrophy (GA) and macular neovascularization (MNV), in eyes with drusenoid pigment epithelial detachment (PED). Eighty-five eyes with drusenoid PED from 85 patients (77.2 ± 7.0 years, male/female: 44/41) were included in this study. Patients were followed up every 1–3 months via spectral-domain optical coherence tomography (SD-OCT) and color fundus photography. If exudation was observed on SD-OCT, fluorescein and indocyanine green angiography were performed to confirm the MNV subtype accordingly. The maximum follow-up period was 60 months. During the study period, GA developed in 8 eyes while MNV also developed in 8 eyes. The Kaplan–Meier estimator revealed that the cumulative incidence for 60 months was 17.9% and 12.2% for GA and MNV, respectively. In eyes developing MNV, retinal angiomatous proliferation was the most common. Cox regression analysis revealed that baseline PED width was the only factor associated with advanced AMD. (p = 0.0026, Cox regression analysis). The 5-year cumulative incidence of advanced AMD, including GA and MNV, was approximately 30% in eyes with drusenoid PED among the Japanese elderly. A larger baseline PED width was the only risk factor for advanced AMD.

Long-term outcomes of drusenoid pigment epithelium detachment in intermediate AMD treated with 577 nm subthreshold micropulse laser: a preliminary clinical study.

To evaluate the long-term anatomical and visual outcomes of drusenoid pigment epithelial detachment (D-PED) in intermediate age-related macular degeneration (AMD) eyes treated with 577 nm yellow subthreshold micropulse laser (SML). In this retrospective study, 21 eyes of 16 patients with D-PED in intermediate AMD were consecutively included and assessed. All the eyes were treated with 577 nm SML in several sessions according to D-PED growth status. The logarithm of the minimum angle of resolution (logMAR) best-corrected visual acuity (BCVA) were assessed at the initial visit and after treatment. Spectral-domain optical coherence tomography (SD-OCT) was performed to evaluate the D-PED lifecycle by volumetric calculations. Regression analysis was used to determine the breakpoint, growth, and collapse rate of the D-PED lesions. The progression to advanced AMD was also documented. All the eyes were treated with SML for 2.9±1.0 sessions. The mean follow-up period was 25.3±12.6mo. The BCVA was stable from the baseline to final visit. All the eyes were categorized into two groups according to the anatomical changes of the D-PED lesion: the collapse group (n=6, 28.6%) and non-collapse group (n=15, 71.4%). The change in logMAR BCVA did not differ significantly between the collapse group 0.00 (-0.31, 0.85) and non-collapse group 0.00 (0.00, 0.00; P=1). Regression analysis showed that the growth rate was significantly higher in the collapse group (0.090±0.095 mm3/mo) than in the non-collapse group (0.025±0.035 mm3/mo; P<0.001). One eye (4.8%) developed macular neovascularization at 11mo after SML treatment in the non-collapse group. Three eyes (14.3%) developed geographic atrophy (GA) in the collapse group. Compared to the natural course of D-PED reported by previous studies, our results preliminarily show that SML can alleviate visual loss and possibility of progression to advanced AMD in eyes with D-PED in intermediate AMD. A controlled clinical trial needs to further verify the benefit of the intervention.

AMD Genomics: Non-Coding RNAs as Biomarkers and Therapeutic Targets.

Age-related macular degeneration (AMD) is a progressive neurodegenerative disease that is the world’s leading cause of blindness in the aging population. Although the clinical stages and forms of AMD have been elucidated, more specific prognostic tools are required to determine when patients with early and intermediate AMD will progress into the advanced stages of AMD. Another challenge in the field has been the appropriate development of therapies for intermediate AMD and advanced atrophic AMD. After numerous negative clinical trials, an anti-C5 agent and anti-C3 agent have recently shown promising results in phase 3 clinical trials, in terms of slowing the growth of geographic atrophy, an advanced form of AMD. Interestingly, both drugs appear to be associated with an increased incidence of wet AMD, another advanced form of the disease, and will require frequent intravitreal injections. Certainly, there remains a need for other therapeutic agents with the potential to prevent progression to advanced stages of the disease. Investigation of the role and clinical utility of non-coding RNAs (ncRNAs) is a major advancement in biology that has only been minimally applied to AMD. In the following review, we discuss the clinical relevance of ncRNAs in AMD as both biomarkers and therapeutic targets.

Serum 25-hydroxy vitamin D levels in age-related macular degeneration

BackgroundThe aim of this study was to determine the 25-hydroxy vitamin D (25(OH)D) levels in age-related macular degeneration (AMD) patients.MethodsAge-related macular degeneration (AMD) patients were classified into four groups: early AMD (N = 10), intermediate AMD (N = 12), advanced atrophic AMD (N = 19) and advanced neovascular AMD (N = 52) after undergoing fundus photography. Serum 25(OH)D levels of all subjects were evaluated. From a random control group of 326 patients whose 25(OH)D levels had been measured, a group of 93 were selected to match the age range of the AMD group. We measured 25(OH)D levels during the same period to rule out seasonal variation.ResultsA total of 93 AMD patients (36 males and 57 females) and 93 healthy individuals (39 males and 54 females) were enrolled in this study with the mean age of 78.96 ± 8.46 vs. 78.80 ± 8.35, respectively. The patients affected by AMD had statistically significant lower 25(OH)D levels (15 ± 10 ng/mL) than the healthy subjects control group (21 ± 14 ng/mL) (p = 0.004). However, the median 25(OH)D levels in early AMD, intermediate AMD, advanced atrophic AMD and advanced neovascular AMD (12.5 ± 7.3; 15 ± 11; 15 ± 8 and 17 ± 11.5, respectively) were not statistically significant (p = 0.442).ConclusionThis study shows that patients affected by AMD had lower vitamin D levels compared to healthy subjects. Further research is necessary to investigate the possible association between 25(OH)D levels and AMD.

Comparison between sodium iodate and lipid peroxide murine models of age-related macular degeneration for drug evaluation-a narrative review.

In this review, non-transgenic models of age-related macular degeneration (AMD) are discussed, with focuses on murine retinal degeneration induced by sodium iodate and lipid peroxide (HpODE) as preclinical study platforms. AMD is the most common cause of vision loss in a world with an increasingly aging population. The major phenotypes of early and intermediate AMD are increased drusen and autofluorescence, Müller glia activation, infiltrated subretinal microglia and inward moving retinal pigment epithelium cells. Intermediate AMD may progress to advanced AMD, characterized by geography atrophy and/or choroidal neovascularization. Various transgenic and non-transgenic animal models related to retinal degeneration have been generated to investigate AMD pathogenesis and pathobiology, and have been widely used as potential therapeutic evaluation platforms. Two retinal degeneration murine models induced by sodium iodate and HpODE are described. Distinct pathological features and procedures of these two models are compared. In addition, practical protocol and material preparation and assessment methods are elaborated. Retina degeneration induced by sodium iodate and HpODE in mouse eye resembles many clinical aspects of human AMD and complimentary to the existent other animal models. However, standardization of procedure and assessment protocols is needed for preclinical studies. Further studies of HpODE on different routes, doses and species will be valuable for the future extensive use. Despite many merits of murine studies, differences between murine and human should be always considered.

Histology and Clinical Lifecycle of Acquired Vitelliform Lesion, a Pathway to Advanced Age-Related Macular Degeneration

To evaluate hypotheses about the role of acquired vitelliform lesion (AVL) in age-related macular degeneration pathophysiology. Laboratory histology study; retrospective, observational case series. Two donor eyes in a research archive with AVL and age-related macular degeneration were analyzed with light and electron microscopy for AVL content at locations matched to ex vivo B-scans. A retrospective, observational clinical cohort study of 42 eyes of 30 patients at 2 referral clinics determined the frequency of optical coherence tomography features stratified by AVL fate. Histologic and clinical cases showed subretinal drusenoid deposit and drusen. Ultrastructural AVL components in 2 donor eyes included retinal pigment epithelium (RPE) organelles (3%-22% of volume), outer segments (2%-10%), lipid droplets (0.2%-12%), and a flocculent material (57%-59%). Of 48 AVLs (mean follow-up 46 ± 39 months), 50% collapsed to complete RPE and outer retinal atrophy, 38% were stable, 10% resorbed, and 2% developed neovascularization. The Early Treatment Diabetic Retinopathy Study grid central subfield contained 77% of AVLs. Hyperreflective foci, ellipsoid zone disruption, and hyperreflective thickening of the RPE-basal lamina-Bruch membrane band were common at maximum AVL expansion. Collapsing and noncollapsing AVLs had different growth rates (rapid vs slow, respectively). AVL deposits contain unexpectedly low levels of RPE organelles and outer segments. Subfoveal predilection, reflectivity on optical coherence tomography, hyperautofluorescence, yellow color, and growth-regression phases suggest dysregulation of lipid transfer pathways specific to cone photoreceptors and supporting cells in formation of AVL deposit, analogous to drusen and subretinal drusenoid deposit. Prediction of AVL outcomes via growth rates should be confirmed in larger clinical studies.

A Surgical Kit for Stem Cell-Derived Retinal Pigment Epithelium Transplants: Collection, Transportation, and Subretinal Delivery.

Transplantation of stem cell-derived retinal pigment epithelium (RPE) cells is a promising potential therapy for currently incurable retinal degenerative diseases like advanced dry age-related macular degeneration. In this study, we designed a set of clinically applicable devices for subretinal implantation of RPE grafts, towards the overarching goal of establishing enabling technologies for cell-based therapeutic approaches to regenerate RPE cells. This RPE transplant kit includes a custom-designed trephine for the production of RPE transplants, a carrier for storage and transportation, and a surgical device for subretinal delivery of RPE transplants. Cell viability assay confirmed biocompatibility of the transplant carrier and high preservation of RPE transplants upon storage and transportation. The transplant surgical device combines foldable technology that minimizes incision size, controlled delivery speed, no fluid reflux, curved translucent tip, usability of loading and in vivo reloading, and ergonomic handle. Furthermore, the complementary design of the transplant carrier and the delivery device resulted in proper grasping, loading, and orientation of the RPE transplants into the delivery device. Proof-of-concept transplantation studies in a porcine model demonstrated no damage or structural change in RPE transplants during surgical manipulation and subretinal deployment. Post-operative assessment confirmed that RPE transplants were delivered precisely, with no damage to the host retina or choroid, and no significant structural change to the RPE transplants. Our novel surgical kit provides a comprehensive set of tools encompassing RPE graft manufacturing to surgical implantation rendering key enabling technologies for pre-clinical and clinical phases of stem cell-derived RPE regenerative therapies.

Telemedicine for the Diagnosis and Management of Age-Related Macular Degeneration: A Review.

Use of ophthalmic telemedicine for patients with age-related macular degeneration (AMD) has shown remarkable advances over recent years. The recent COVID pandemic accelerated this transition since in-person evaluation of elderly patients at high risk for advanced AMD and severe vision loss were also at higher risk for complications from COVID infection. To date, ophthalmic telemedicine has been successfully used in remote retinal consultation by general ophthalmologists for AMD management, hybrid testing visits with both in-office testing and remote evaluation, as well as early successes in home-based remote monitoring of patients with high-risk AMD. We therefore review the current literature and evidence base related to ophthalmic telemedicine for AMD.

Fixation Stability and Preferred Retinal Locus in Advanced Age-Related Macular Degeneration

Objectives:To evaluate fixation stability and characteristics of the preferred retinal locus (PRL) in patients with advanced age-related macular degeneration (AMD).Materials and Methods:Sixty-three eyes of 63 patients with AMD who presented to the low vision unit were included in this prospective study. Sociodemographic characteristics, eye examination findings, and reading performance results with the Minnesota Low Vision Reading test were evaluated. Microperimetry was used to evaluate fixation stability and PRL characteristics.Results:There was unstable fixation in 68% of the eyes, relative stable fixation in 27%, and stable fixation in 5%. The mean PRL-foveal distance was 5.15°±3.31° (range 0.75°-14.2°). PRL-foveal distance was greater in cases with unstable fixation than cases with stable fixation (p=0.023). Distance of the PRL from the lesion margin was not associated with absolute scotoma size or fixation stability (p=0.315, p=0.095, respectively). PRLs were most frequently located in the nasal quadrant (31%), followed by the superior quadrant (26%) of the retina. There was no significant relationship between PRL location and fixation stability (p=0.088). Fixation stability was significantly associated with reading speed (p=0.003).Conclusion:In advanced AMD, PRL-foveal distance is an important factor in fixation stability. Knowing the factors that affect fixation stability may be important in determining low vision rehabilitation strategies for these patients because of the strong association between fixation stability and reading speed.

Systemic Complement Activation Profiles in Nonexudative Age-Related Macular Degeneration: A Systematic Review.

Topic:To evaluate whether differences exist in systemic complement activation profiles in patients with early to intermediate nonexudative age-related macular degeneration (AMD) or geographic atrophy (GA) compared with control participants without AMD.Clinical Relevance:Complement inhibition has emerged as a therapeutic strategy for GA, although clinical trials to date have yielded mixed results. Despite these efforts, no clear consensus exists regarding what portions of the complement pathway are dysregulated in AMD or when this dysregulation occurs relative to AMD stage. Although past studies have compared systemic complement activation profiles in patients with AMD versus in control participants without AMD, differences in AMD case definition and differing analytical approaches complicate their interpretation.Methods:We performed a systematic review by identifying articles from database inception through October 11, 2020, that reported systemic complement activation profiles in patients with early or intermediate nonexudative AMD or GA versus control participants without AMD by searching PubMed, Google Scholar, and Embase. Risk of bias was assessed using a modified Newcastle-Ottawa score.Results:The 8 reviewed studies included 2131 independent participants. Most studies report significantly higher systemic levels of products associated with complement activation and significantly lower systemic levels of products associated with complement inhibition in patients with early and advanced nonexudative AMD compared with control participants without AMD.Discussion:Evidence suggests that systemic complement overactivation is a feature of early or intermediate and advanced nonexudative AMD. However, given significant heterogeneity, these findings are not conclusive and warrant further investigation.

The Long Pentraxin PTX3 as a New Biomarker and Pharmacological Target in Age-Related Macular Degeneration and Diabetic Retinopathy.

Age related macular degeneration (AMD) and diabetic retinopathy (DR) are multifactorial, neurodegenerative and inflammatory diseases of the eye primarily involving cellular and molecular components of the outer and inner blood-retina barriers (BRB), respectively. Largely contributed by genetic factors, particularly polymorphisms in complement genes, AMD is a paradigm of retinal immune dysregulation. DR, a major complication of diabetes mellitus, typically presents with increased vascular permeability and occlusion of the retinal vasculature that leads, in the proliferative form of the disease, to neovascularization, a pathogenic trait shared with advanced AMD. In spite of distinct etiology and clinical manifestations, both pathologies share common drivers, such as chronic inflammation, either of immune (in AMD) or metabolic (in DR) origin, which initiates and propagates degeneration of the neural retina, yet the underlying mechanisms are still unclear. As a soluble pattern recognition molecule with complement regulatory functions and a marker of vascular damage, long pentraxin 3 (PTX3) is emerging as a novel player in ocular homeostasis and a potential pharmacological target in neurodegenerative disorders of the retina. Physiologically present in the human eye and induced in inflammatory conditions, this protein is strategically positioned at the BRB interface, where it acts as a “molecular trap” for complement, and modulates inflammation both in homeostatic and pathological conditions. Here, we discuss current viewpoints on PTX3 and retinal diseases, with a focus on AMD and DR, the roles therein proposed for this pentraxin, and their implications for the development of new therapeutic strategies.

Role of Optical Coherence Tomography Imaging in Predicting Progression of Age-Related Macular Disease: A Survey.

In developed countries, age-related macular degeneration (AMD), a retinal disease, is the main cause of vision loss in the elderly. Optical Coherence Tomography (OCT) is currently the gold standard for assessing individuals for initial AMD diagnosis. In this paper, we look at how OCT imaging can be used to diagnose AMD. Our main aim is to examine and compare automated computer-aided diagnostic (CAD) systems for diagnosing and grading of AMD. We provide a brief summary, outlining the main aspects of performance assessment and providing a basis for current research in AMD diagnosis. As a result, the only viable alternative is to prevent AMD and stop both this devastating eye condition and unwanted visual impairment. On the other hand, the grading of AMD is very important in order to detect early AMD and prevent patients from reaching advanced AMD disease. In light of this, we explore the remaining issues with automated systems for AMD detection based on OCT imaging, as well as potential directions for diagnosis and monitoring systems based on OCT imaging and telemedicine applications.

Narrative review-drug delivery in age-related macular degeneration

: This narrative review highlights routes of ocular drug delivery for age-related macular degeneration (AMD). AMD is the leading cause of irreversible blindness in industrialized countries and accounts for 8.7% of blindness worldwide. Advanced AMD can be classified into two subtypes: late-stage dry AMD [known as geographic atrophy (GA)] and neovascular AMD (nAMD). GA is often bilateral and results from progressive and irreversible loss of photoreceptors and areas of the retinal pigment epithelium. Wet AMD is characterized by angiogenesis from the choroid to the normally avascular regions underneath the retinal pigment epithelium (RPE) or retina, a process known as choroidal neovascularization (CNV). Various targeted therapeutic options are currently available to reduce the progression rate and maintain vision in patients with nAMD. Intravitreal delivery of anti-VEGF protein treatments to halt CNV is currently the gold-standard of care for nAMD. Subretinal and suprachoroidal delivery approaches are also being explored for gene and molecular therapies. Advancements in nanotechnology and biomaterials have also led to the development of microscopic drug delivery systems, including hydrogels, microparticles, nanoparticles, implants, and liposomes. Gene therapy and stem cell therapy has recently emerged as a potential candidate treatment modality for AMD and other retinal degenerations. New drug targets and modalities have stimulated exciting developments in ocular drug delivery with the promise of greater efficacy and durability of AMD treatment.

GEOGRAPHIC ATROPHY INCIDENCE AND PROGRESSION AFTER INTRAVITREAL INJECTIONS OF ANTI-VASCULAR ENDOTHELIAL GROWTH FACTOR AGENTS FOR AGE-RELATED MACULAR DEGENERATION: A Meta-Analysis.

Geographic atrophy (GA) is a complication of advanced neovascular age-related macular degeneration that can lead to permanent vision loss. We sought to estimate the incidence and progression of GA after intravitreal injections of antivascular endothelial growth factor agents in eyes with neovascular age-related macular degeneration. Ovid MEDLINE, EMBASE, and Cochrane CENTRAL were searched from inception to May 2020. Included studies reported on the progression or development of GA in eyes with neovascular age-related macular degeneration after antivascular endothelial growth factor therapy. Thirty-one articles and 4,609 study eyes (4,501 patients) were included. Eyes received a mean of 17.7 injections over 35.2 months. The prevalence of GA at baseline was 9.7%. The pooled incidence of GA was 30.5% at the end of follow-up. There was a positive, moderate linear correlation between the mean total number of injections and GA incidence at the final follow-up (R2 = 0.30; P = 0.01). Monthly treatment was associated with a significantly higher risk for GA development relative to pro re nata (relative risk = 1.40, 95% confidence interval = [1.21-1.61], P < 0.001). Risk factors for GA development included GA in the fellow eye, retinal angiomatous proliferation, drusen, and reticular pseudodrusen. We found an association between the frequency and number of treatments with antivascular endothelial growth factor agents and the development of GA in neovascular age-related macular degeneration. Future studies should clarify risk factors, population characteristics, and relative contributions of treatment and disease progression on GA development in this context.

Unilateral Cilioretinal Artery and Advanced Age-Related Macular Degeneration: A Retrospective Cross-Sectional Study

To investigate the association between the presence of a cilioretinal artery (CRA) and advanced age-related macular degeneration (AMD), including the prevalence of choroidal neovascularization (CNV) and geographic atrophy (GA). Retrospective cross-sectional study. This was a single-center study. A total of 738 patients with AMD who underwent optical coherence tomography angiography (OCTA) were included in the study. Fundus photographs were reviewed to determine the presence of the CRA. In patients with a unilateral CRA, paired tests were performed between eyes with and without the CRA to compare AMD severity and prevalence of CNV and GA. The main outcomes of interest were AMD stage and prevalence of CNV and GA. Macular vasculature, including vessel density, perfusion density, and foveal avascular zone, were examined using OCTA. A total of 174 eyes from 87 patients with a unilateral CRA were examined. A total of 27.8% and 8.1% of patients had a CRA in 1 eye and both eyes, respectively. Eyes with a CRA showed lower AMD stage (4-step AREDS category; P=.037) and a lower prevalence of CNV (23.0% vs 41.4%; P=.024) than those without a CRA. The prevalence of GA and macular vessel density, perfusion density, and foveal avascular zone measured by OCTA were similar in both groups. In the eyes with a CRA, AMD stage and prevalence of CNV were lower than those in the eyes without a CRA. However, the effect of the CRA on the macular vascular system remains unclear.

Substrate stiffening promotes VEGF-A functions via the PI3K/Akt/mTOR pathway

While it is now well-established that substrate stiffness regulates vascular endothelial growth factor-A (VEGF-A) mediated signaling and functions, causal mechanisms remain poorly understood. Here, we report an underlying role for the PI3K/Akt/mTOR signaling pathway. This pathway is activated on stiffer substrates, is amplified by VEGF-A stimulation, and correlates with enhanced endothelial cell (EC) proliferation, contraction, pro-angiogenic secretion, and capillary-like tube formation. In the settings of advanced age-related macular degeneration, characterized by EC and retinal pigment epithelial (RPE)-mediated angiogenesis, these data implicate substrate stiffness as a novel causative mechanism and Akt/mTOR inhibition as a novel therapeutic pathway.

Association of Smoking, Alcohol Consumption, Blood Pressure, Body Mass Index, and Glycemic Risk Factors With Age-Related Macular Degeneration

Advanced age-related macular degeneration (AMD) is a leading cause of blindness in Western countries. Causal, modifiable risk factors need to be identified to develop preventive measures for advanced AMD. To assess whether smoking, alcohol consumption, blood pressure, body mass index, and glycemic traits are associated with increased risk of advanced AMD. This study used 2-sample mendelian randomization. Genetic instruments composed of variants associated with risk factors at genome-wide significance (P < 5 × 10-8) were obtained from published genome-wide association studies. Summary-level statistics for these instruments were obtained for advanced AMD from the International AMD Genomics Consortium 2016 data set, which consisted of 16 144 individuals with AMD and 17 832 control individuals. Data were analyzed from July 2020 to September 2021. Smoking initiation, smoking cessation, lifetime smoking, age at smoking initiation, alcoholic drinks per week, body mass index, systolic and diastolic blood pressure, type 2 diabetes, glycated hemoglobin, fasting glucose, and fasting insulin. Advanced AMD and its subtypes, geographic atrophy (GA), and neovascular AMD. A 1-SD increase in logodds of genetically predicted smoking initiation was associated with higher risk of advanced AMD (odds ratio [OR], 1.26; 95% CI, 1.13-1.40; P < .001), while a 1-SD increase in logodds of genetically predicted smoking cessation (former vs current smoking) was associated with lower risk of advanced AMD (OR, 0.66; 95% CI, 0.50-0.87; P = .003). Genetically predicted increased lifetime smoking was associated with increased risk of advanced AMD (OR per 1-SD increase in lifetime smoking behavior, 1.32; 95% CI, 1.09-1.59; P = .004). Genetically predicted alcohol consumption was associated with higher risk of GA (OR per 1-SD increase of log-transformed alcoholic drinks per week, 2.70; 95% CI, 1.48-4.94; P = .001). There was insufficient evidence to suggest that genetically predicted blood pressure, body mass index, and glycemic traits were associated with advanced AMD. This study provides genetic evidence that increased alcohol intake may be a causal risk factor for GA. As there are currently no known treatments for GA, this finding has important public health implications. These results also support previous observational studies associating smoking behavior with risk of advanced AMD, thus reinforcing existing public health messages regarding the risk of blindness associated with smoking.

Revisiting the Alcohol Consumption Association With Age-Related Macular Degeneration

Age-related macular degeneration (AMD) is a leading cause of blindness globally, with substantial visual morbidity in patients with advanced AMD, primarily due to vision loss from neovascular AMD (nAMD) and/or geographic atrophy (GA).

Epithelial-mesenchymal transition-related serum markers ET-1, IL-8 and TGF-β2 are elevated in a Finnish wet age-related macular degeneration cohort.

It has been hypothesized that epithelial-mesenchymal transition (EMT) may occur in the retinal pigment epithelium of advanced stage age-related macular degeneration (AMD). Various serum and plasma growth factors and inflammatory mediators have been linked to AMD. We were interested in finding out whether systemic levels of EMT-associated markers were altered in the serum of wet AMD patients. Serum biomarkers associated with the various pathological processes of AMD may present an avenue towards identifying and characterizing the birth mechanisms of wet AMD, its progression and severity, paving the way towards the application of precision medicine. We chose to measure the serum levels of known biomarkers of EMT - EGF (epidermal growth factor), ET-1 (endothelin 1), IL-8 (interleukin 8), TGF-β1 and TGF-β2 (transforming growth factor-beta 1 and 2) and VEGF-A (vascular endothelial growth factor A) - using enzyme-linked immunosorbent assays. We measured them from 71 Finnish wet AMD patients who were receiving intravitreal anti-VEGF-A injection treatments, as well as 64 age-adjusted controls. We found significantly elevated levels of ET-1, IL-8 and TGF-β2 in the serums of wet AMD patients. ET-1, IL-8 and TGF-β2 appear to be useful serum biomarkers in understanding active wet AMD. However, we cannot conclude that local retinal EMT-processes could be observed from the corresponding systemic serum biomarkers in patients undergoing anti-VEGF-A treatments.