Occurrence Of Age-related Macular Degeneration Research Articles

Association of ARMS2, HTRA1 and CFH genes polymorphisms in patients with age-related macular degeneration in the Malaysian population

BackgroundDespite extensive research efforts, understanding the precise causes and molecular underpinnings of age-related macular degeneration (AMD) remains elusive. Exploring different populations becomes crucial to establish conclusive insights into the role of genetic factors in AMD.MethodologyThis study aimed to investigate the association between the well-documented major risk alleles in the HTRA1, ARMS2 and CFH genes with AMD in the Malaysian multi-ethnic population. A total of 205 subjects were enrolled in this study, 103 were diagnosed with AMD while 102 represented the control subjects. Genomic DNA was extracted from peripheral blood mononuclear cells and gene amplification was performed by polymerase chain reaction. Subsequently, genotyping for the HTRA1, ARMS2 and CFH genes was performed using direct DNA sequencing analysis.ResultsSignificant associations (p < 0.05) were detected with AMD for both SNP rs11200638: G > A in the promoter of HTRA1 and rs10490924: G > T in ARMS2 but not for variant Y402H in CFH gene (p > 0.05) in our study population. The A allele frequency of rs11200638 in the HTRA1 promoter was 51.9% in cases versus 39.2% in controls (p = 0.010). The frequency of AA genotype was 28.2% for AMD cases, compared to 17.6% in controls (OR 2.58, 95% CI 1.19–5.58; p = 0.043). The frequency of the TT genotype of rs10490924 in ARMS2 was 25.2% in cases versus 8.8% in controls (OR 2.23, 95% CI 0.83–5.99; p = 0.002).ConclusionThe study reveals an association between specific genetic variants in the HTRA1 and ARMS2 genes and the occurrence of AMD in the Malaysian population. However, contrary to expectations, the study did not identify a substantial correlation between AMD and the Y402H variant of the CFH gene in this specific population.

Association of TAS2R16 gene (rs860170, rs978739, rs1357949) polymorphisms and TAS2R16 serum levels in patients with age-related macular degeneration

ABSTRACT Background The aim of this study is to determine the association of TAS2R16 (rs860170, rs978739, rs1357949) gene polymorphisms and TAS2R16 serum levels in patients with the occurrence of age-related macular degeneration (AMD). Methods Subjects with early AMD, subjects with exudative AMD, and healthy controls participated in the study. DNA was isolated by salting out leukocytes from peripheral venous blood. Single nucleotide polymorphisms (SNPs) were analysed by RT-PCR. TAS2R16 levels were determined by enzyme-linked immunosorbent assay (ELISA) using the Abbexa Human Taste Receptor Type 2 Member 16 (TAS2R16) ELISA kit. Statistical data analysis was performed using “IBM SPSS Statistics 27.0” and SNPstats statistical data analysis programmes. Results The TAS2R16 rs860170 TT genotype is statistically significantly less frequent in the exudative AMD group than in the control group, whereas the TAS2R16 rs860170 C allele gene is statistically significantly more frequent in the exudative AMD group. Each C allele of TAS2R16 rs860170 is associated with a 2.8-fold increased probability of occurrence of exudative AMD. The C allele of TAS2R16 rs860170 is statistically significantly more frequent in men and women with exudative AMD than in the control group. The C allele of TAS2R16 rs860170 is associated with a 2.8-fold increased odds of occurrence of exudative AMD in women and a 2.9-fold increased odds of occurrence of exudative AMD in men. In TAS2R16 (rs860170, rs978739, and rs1357949), the T-T-A haplotype is associated with a 2.6-fold decreased likelihood of developing early AMD and the T-T-A haplotype is associated with a 3.2-fold decreased likelihood of developing early AMD in women. For TAS2R16 (rs860170, rs978739, and rs1357949), carriers of the T-T-G and T-T-A haplotypes are associated with a 2.2- and 3.2-fold decreased probability of exudative AMD, respectively. Individuals with the C-C-A haplotype are 9.2-fold more likely to develop exudative AMD. Specifically, the C-C-A haplotype is associated with a 9.3-fold increased likelihood of exudative AMD in men. In contrast, women with the T-T-A haplotype are 5.6-fold less likely to develop exudative AMD. Conclusion TAS2R16 plays an important role in the development of AMD.

The occurrence of age-related macular degeneration in the presence of a transferred, confirmed COVID-19

BACKGROUND: COVID-19 can affect the eyes and both the anterior and posterior segments of the eye. Retinal complications associated with COVID-19 have been reported.&#x0D; CLINICAL CASE DESCRIPTION: We present a clinical case of age-related macular degeneration that developed during the acute period of coronavirus infection. A patient with COVID-19 and pneumonia (CT-1) experienced sudden decrease in visual acuity within 1 month. A dark spot appeared in front of the left eye, which did not disappear despite eye movements, and distortion of objects was observed. The disease was manifested acutely. A complete ophthalmological examination revealed a sharp decrease in visual acuity and a positive Amsler test (distortion of lines at a distance of 30 cm). In the field of view, scotomas were noted in the center. Ophthalmoscopy revealed light and dark foci in the central macular zone of the retina. Cptical coherence tomography with an angiographic mode detected severe changes at the level of the neuroepithelium and retinal pigment epithelium with the formation of gray tissue. Aflibercept (approved for use in the Russian Federation, No. LP-003544) was intravitreally prescribed according to the clinical guidelines for treating age-related macular degeneration. After treatment with positive dynamics, visual acuity increased to 1.0, and the thickness of the retina decreased by 102 microns.&#x0D; CONCLUSION: The key objective in making a correct diagnosis was the use of optical coherence tomography with an angiographic mode. This method allows the visualization of the retinal layers without invasion The angiography mode allows the assessment of the state of the foveolar avascular zone and the density and perfusion of blood vessels, which enable the diagnosis of age-related macular degeneration and choroidal neovascularization. Timely antiangiogenic treatment, that is, a single intraocular injection, completely restored the visual acuity and visual field and normalized the state of the retina according to objective data of optical coherence tomography with angiography mode.

Pharmacogenetic Association between Allelic Variants of the Autophagy-Related Genes and Anti-Vascular Endothelial Growth Factor Treatment Response in Neovascular Age-Related Macular Degeneration.

Age-related macular degeneration (AMD) is the leading cause of late-onset blindness in elderly. The occurrence and development of AMD is a multifactorial complex process where autophagy plays an important role. The first-line drugs for neovascular AMD (nAMD) are inhibitors of VEGF, with up to 30% of patients having an incomplete response to treatment. Genetic factors may influence the response to anti-VEGF therapy and explain treatment outcome variability. We aimed to estimate the role of polymorphic markers of the MTOR (rs1064261, rs1057079, rs11121704, rs2295080), SQSTM1 (rs10277), ULK1 (rs11246867, rs3088051), MAP1LC3A (rs73105013) and ATG5 (rs573775) genes in the development of nAMD and the efficacy of anti-VEGF therapy response. Genotyping by allele-specific PCR was performed in 317 controls and 315 nAMD patients in the Russian population. Of them, 196 treatment-naive nAMD patients underwent three monthly intravitreal injections (IVIs) of aflibercept. Genotypic frequencies were compared with OCT markers of therapy effectiveness and best-corrected visual acuity (BCVA) measures. The main outcomes were the BCVA gain and decrease in central retinal thickness (CRT). MTOR-rs1057079-C, MTOR-rs11121704-C and MTOR-rs2295080-G alleles were associated with an increased risk of nAMD. The BCVA was increased in 117 (59.7%) patients by 10 [5-20] letters, did not changed in 59 (30.1%), and was decreased in 20 (10.2%) patients. ULK1-rs3088051 was associated with BCVA change. Among patients with the TT and CT genotypes for ULK1-rs3088051, an improvement in visual acuity was noted in 67.6% and 53.8% of cases, while in patients with the CC genotype, an increase in BCVA was recorded in 37.5% of cases (p = 0.01). The decrease in CRT was associated with SQSTM1-rs10277 (p = 0.001): it was significantly higher in TT (93 [58-122] mkm) and CT (66 [30-105] mkm) carriers compared to the CC genotype (47 [24-68] mkm). Other SNPs did not show significant associations with the outcome of anti-VEGF treatment. MTOR gene polymorphisms are moderately associated with the risk of nAMD. SQSTM1-rs10277 and ULK1-rs3088051 may influence short-term response to intravitreal anti-VEGF treatment. The results suggest that autophagy could be a target for future drugs to overcome resistance to anti-VEGF therapy.

Causal Effects of Gut Microbiota on Age-Related Macular Degeneration: A Mendelian Randomization Study.

Recently, the association between gut microbiota and age-related macular degeneration (AMD) through the gut-retina axis has attracted great interest. However, the causal relationship between them has not been elucidated. Using publicly available genome-wide association study summary statistics, we conducted a two-sample Mendelian randomization (MR) analysis to examine the causal relationship between the gut microbiota and the occurrence of AMD. The study used a variety of quality control techniques to select instrumental single nucleotide polymorphisms (SNPs) with strong exposure associations. We used a set of SNPs as instrumental variable that were below the genome-wide statistical significance threshold (5 × 10-8). Additionally, a separate group of SNPs below the locus-wide significance level (1 × 10-5) were selected as instrumental variables to ensure a comprehensive conclusion. Inverse variance-weighted (IVW) analysis was the primary technique we used to examine causality in order to confirm the validity of our findings. The MR-Egger intercept test, Cochran's Q test, and leave-one-out sensitivity analysis were used to evaluate the horizontal pleiotropy, heterogeneities, and stability of the genetic variants. IVW results showed that genus Anaerotruncus (P=5.00 × 10-3), genus Candidatus Soleaferrea (P=1.83 × 10-2), and genus unknown id.2071 (P=3.12 × 10-2) were protective factors for AMD. The Eubacterium oxidoreducens group (P=3.17 × 10-2), genus Faecalibacterium (P=2.67 × 10-2), and genus Ruminococcaceae UCG-011 (P=4.04 × 10-2) were risk factors of AMD. No gut microbiota (GM) taxa were found to be causally related to AMD at the phylum, class, order, and family levels (P>0.05). The robustness of MR results were confirmed by heterogeneity and pleiotropy analysis. (P>0.05). We also performed a bidirectional analysis, which showed that genus Anaerotruncus, genus Candidatus Soleaferrea, genus unknown id.2071 and the Eubacterium oxidoreducens group had an interaction with AMD, whereas genus Faecalibacterium showed only a unilateral unfavorable effect on AMD. We confirmed a causal relationship between AMD and GM taxa, including the Eubacterium oxidoreducens group, Faecalibacterium, Ruminococcaceae UCG-011, Anaerotruncus, and Candidatus Soleaferrea. These strains have the potential to serve as new biomarkers, offering valuable insights into the treatment and prevention of AMD.

Exploring the Effect of the Gut Microbiome on the Risk of Age-Related Macular Degeneration From the Perspective of Causality.

To explore the mechanisms relating the gut microbiome (GM) to age-related macular degeneration (AMD), as they remain unclear. GM taxa that appear to act within the gut-retina axis may affect the risk of AMD. Single-nucleotide polymorphisms (SNPs) of 196 GM taxa were obtained from the MiBioGen consortium, and a Mendelian randomization (MR) study was carried out to estimate the causality between GM taxa and AMD (defined as an endpoint based on ICD-9 and ICD-10). Using the data from the FinnGen consortium (6157 patients and 288,237 controls), we explored the GM taxa for causality and verified the results at the replication stage based on the MRC-IEU consortium (3553 cases and 147,089 controls). Inverse variance weighting (IVW) was the main method used to analyze causality, and the MR results were verified using heterogeneity tests and pleiotropy tests. According to the MR results, order Rhodospirillales (P = 3.38 × 10-2), family Victivallaceae (P = 3.14 × 10-2), family Rikenellaceae (P = 3.58 × 10-2), genus Slackia (P = 3.15 × 10-2), genus Faecalibacterium (P = 3.01 × 10-2), genus Bilophila (P = 1.11 × 10-2), and genus Candidatus Soleaferrea (P = 2.45 × 10-2) were suggestively associated with AMD. In the replication stage, only order Rhodospirillales (P = 0.03) passed validation. The heterogeneity (P > 0.05) and pleiotropy (P > 0.05) tests in two stages confirmed the robustness of the MR results. We confirmed that order Rhodospirillales influenced the risk of AMD based on the gut-retina axis, providing new impetus for the development of the GM as an intervention to prevent the occurrence and development of AMD.

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.

Application and mechanism of anti-VEGF drugs in age-related macular degeneration.

Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly. The incidence rate increases with age in people over 50 years of age. With the advent of China’s aging society, the number of patients is increasing year by year. Although researchers have done a lot of basic research and clinical research on the pathogenesis and treatment of AMD in recent years, the pathogenesis of AMD is still controversialdue to the complexity of the disease itself. AMD is the primary cause of blindness in the elderly over 50 years old. It is characterized by the formation of choroidal neovascularization (CNV) and the over secretion of vascular endothelial growth factor (VEGF) as its main mechanism, which can eventually lead to vision loss or blindness. The occurrence and development of AMD is an extremely complex process, in which a large number of regulatory factors and cytokines are involved. Most of the existing treatments are for its concomitant CNV. Targeted VEGF drugs for neovascularization, such as Lucentis and Aflibercept, are the first-line drugs for AMD. Their application has greatly reduced the blinding rate of patients. However, there are still some patients who have no response to treatment or cannot maintain their vision after long-term treatment. Frequent injection also increases the risk of complications and economic burden. In order to further improve the quality of life and long-term prognosis of AMD patients, a variety of new treatmentshave been or will be applied in clinic, including combined treatment with the same or different targets to improve the curative effect, change or simplify the mode of medication, inhibit VEGF receptor tyrosine protein kinase and so on. This article provides a brief review of the research progress of anti-VEGF drugs and their mechanisms for the treatment of AMD, it is expected to provide a better treatment plan for AMD treatment.

Increased probability of mood disorders after age-related macular degeneration: a population-based cohort study

We aim to investigate the association of mood disorders with age-related macular degeneration (AMD). This retrospective cohort study used data from 2000 and 2016 from National Health Insurance Research Database (NHIRD) in Taiwan. Patients with AMD diagnosis formed the exposed group, and an age- and sex-matched group without AMD served as the nonexposed group. Main outcomes were the incidence of mood disorders including psychological counseling, behavior therapy, sleep or anxiety-related disorders, and major depressive disorders (MDDs) in the exposed and non-exposed groups. The Cox proportional hazard regression analysis was used to evaluate the incidence and adjusted hazard ratio (aHR) of mood disorders. A total of 5916 and 11,832 individuals with and without AMD were enrolled into the exposed and nonexposed groups. There were 1017 (17.19%) and 1366 (11.54%) episodes of mood disorders occurred in the exposed and nonexposed groups, respectively. The aHRs of any psychological counseling, behavioral therapy, sleep or anxiety-related disorders, and MDD were significantly higher in patients with AMD than in those without AMD (all P < 0.05). Besides, patients with dry-AMD, participants aged 50–70 years, and women with AMD had a higher incidence of mood disorders (all P < 0.05) than did non-AMD individuals, patients > 70 years, and women without AMD. In conclusion, AMD occurrence leads to an increased rate of mood disorders, particularly among those with dry-AMD, middle aged participants (aged 50–70), and women.

Distinctive features of eye pathology in elderly and senile people in Arkhangelsk region

Purpose: to identify the features of the pathology of the eye in elderly and senile people in the Arkhangelsk region. Material and methods. Annual reports of medical eye care facilities for the 2009 to 2019 who offered ophthalmological assistance to individuals aged 60 or older were analyzed. To estimate the differences infrequency of occurrence Pearson's Chi-square was used. Results. The incidence of eye pathologies in elderly and senile people amounts to 20.74% (17.83 % male and 22.29 % female). The most common conditions included the pathology of the lens that occurred in almost 50 % of the old people, glaucoma was diagnosed in about 20 % and retinal conditions in one out of seven people. In the age group of 60 to 74 years, the most common pathologies included glaucoma, diabetic angioretinopathy, retinal conditions and refractive errors; in the people of advanced age (75—89 years), lens pathologies and age-related macular degeneration occurred more frequently than in the younger age group while glaucoma, diabetic angioretinopathy, retinal conditions and refractive errors occurred less frequently. The oldest age group (90 years and older) showed a different pathology distribution than people of the younger age groups: they have higher occurrence of lens pathologies, age-related macular degeneration, optic disc pathology. In contrast, they have a rarer occurrence of retinal diseases, whilst diabetic angioretinopathy or refractive errors were not diagnosed at all. Gender differences of eye pathology distribution are revealed in the fact that, among people aged 60 to 89, women have a higher occurrence of age-related macular degeneration, retinal diseases and refractive errors, while men are more often diagnosed with glaucoma. Conclusion. The identified features of eye pathology in elderly and senile people living in the Arkhangelsk region should be taken into account when medical care for advanced age groups is developed and improved.

Associations of Tumor Necrosis Factor-Alpha Gene Polymorphisms (TNF)-α TNF-863A/C (rs1800630), TNF-308A/G (rs1800629), TNF-238A/G (rs361525), and TNF-Alpha Serum Concentration with Age-Related Macular Degeneration.

Age-related macular degeneration (AMD) is a neurodegenerative disease leading to irreversible central vision loss among the elderly in developed countries. While the disease accounts for 9% of all cases of vision loss, the prevalence of AMD is likely to increase due to the exponential aging of the population. Due to this reason, our study aimed to determine the associations of tumor necrosis factor-alpha (TNF-α) gene single-nucleotide polymorphisms (SNPs) TNF-863A/C (rs1800630), TNF-308A/G (rs1800629), TNF-238A/G (rs361525), and TNF-α serum concentration with age-related macular degeneration. Analysis of TNF-α rs1800630, rs1800629, and rs361525 polymorphisms showed that the TNF-α rs1800630 A allele was statistically significantly more frequent in the exudative AMD group compared to the control group (p = 0.029). Additionally, the TNF-α rs1800630 A allele was more frequent in females with exudative AMD than in the control group of healthy females (p = 0.027). The TNF-α rs1800630 A allele was more frequent in females with exudative AMD than in females with early AMD (p = 0.014). TNF-α rs1800630, rs1800629, and rs361525 haplotype A-A-G were associated with decreased odds of exudative AMD (p < 0.0001), and haplotype A-G-G was associated with 24-fold increased exudative AMD occurrence (p < 0.0001). TNF-α protein levels were lower in subjects with exudative AMD compared to the control group (p < 0.001). The study showed significant associations between inflammatory cytokine TNF-α single-nucleotide polymorphisms and serum level with AMD pathogenesis. Analysis of TNF-α genotypes and serum concentration may be helpful for the AMD diagnosis.

Osteoarthritis Is Associated With an Increased Risk of Age-Related Macular Degeneration: A Population-Based Longitudinal Follow-Up Study.

AimsTo investigate the long-term risk of age-related macular degeneration (AMD) in persons with osteoarthritis (OA).MethodsThis retrospective cohort study first enrolled 71,609 subjects diagnosed with OA, and 236,169 without such a diagnosis between January 1, 2002 and December 31, 2005, from the Longitudinal Health Insurance Database 2005. All were aged 40–69. After excluding subjects who had pre-existing AMD and/or who had missing socioeconomic data, frequency matching by sex and age was performed. This resulted in there being 60,274 subjects in each of the final matched OA and non-OA groups. The study participants were followed up to the occurrence of AMD, death, or the end of 2011. We used Cox proportional-hazards regression to estimate the impact of OA on the risk of developing AMD, and performed subgroup analyses stratified by sex and age.ResultsThe median follow-up time was 8.9 years, with an interquartile range of 1.4 years. The incidence rate of AMD in the OA group was 2.77 per 1,000 person-years [95% confidence interval (CI), 2.62–2.92], and in the non-OA group, 2.06 per 1,000 person-years (95% CI, 1.94–2.19). The adjusted hazard ratio (HR) of AMD for the OA group was therefore 1.30 (95% CI, 1.20–1.41). In the subgroup analysis stratified by sex for the OA group, the adjusted HRs of AMD were 1.29 in the women's stratum and 1.31 in the men's. When stratified by age, the adjusted HRs of AMD for the younger (40–54 years) and older (55–69 years) strata were 1.28 and 1.31, respectively.ConclusionsPersons with OA have an increased risk of developing AMD, regardless of age and sex.

The Relationship between Statin and Risk of Age-Related Macular Degeneration: A Systematic Review and Meta-Analysis.

Methods Web of Science, PubMed, and Scopus databases were searched for articles that addressed the relationship between statin consumption and risk of AMD. The pooled odds ratio (OR) and 95% confidence interval (CI) were calculated using a random-effects model. Subgroup analyses and sensitivity analyses were also conducted. Cochran's Q test and the I2 statistic were used to evaluate the heterogeneity. To assess potential publication bias, Begg's test was used. Results In total, 22 studies were reviewed in the meta-analysis that included 2063195 participants and 313702 (15.20%) AMD patients compared to individuals not receiving statins. The OR of AMD in statin-receiving participants was 0.93 (95% CI; 0.83–1.05, P=0.225). The OR of AMD in those that received statins was 0.92 (95% CI; 0.75–1.13, P=0.440) in case-control studies, 0.95 (95% CI; 0.82–1.09, P=0.458) in cohort studies, 0.951 (95% CI; 0.59–1.53, P=0.831) in cross-sectional studies, 0.94 (95% CI; 0.80–1.10, P=0.468) in North America, 0.81 (95% CI; 0.54–1.21, P=0.308) in Europe, 1.05 (95% CI; 0.94–1.18, P=0.362) in Asia, and 0.52 (95% CI; 0.26–1.04, P=0.125) in Australia. No publication bias was observed in this study (P=0.114). Conclusion According to the results of this study, taking statins does not increase or decrease the risk of AMD development. Therefore, this drug group cannot be considered a protective or risk factor for the occurrence of AMD.

Recombinant human klotho protects against hydrogen peroxide-mediated injury in human retinal pigment epithelial cells via the PI3K/Akt-Nrf2/HO-1 signaling pathway

ABSTRACT Globally, age-related macular degeneration (AMD) is a common irreversible ophthalmopathy. Oxidative stress of retinal pigment epithelial cells is involved in AMD occurrence and development. Klotho is an anti-aging protein with antioxidant properties. We investigated the protective properties of Klotho on hydrogen peroxide (H2O2)-induced injury of retinal pigment epithelial cells (ARPE-19 cells) and its associated pathomechanisms. We found that Klotho pretreatment for 24 h could up-regulate Bcl-2 levels, decrease the cleaved-caspase-3 and Bax levels, inhibit H2O2-induced ARPE-19 cell apoptosis, and promote cell proliferation. Klotho pretreatment inhibited the H2O2-mediated elevations of reactive oxygen species (ROS) in ARPE-19 cells. It enhanced antioxidant activities of the cells and restored the glutathione peroxidase (GPX), superoxide dismutase (SOD2), catalase (CAT), as well as malondialdehyde (MDA) levels to close to the normal level. N-acetylcysteine (NAC), a reactive oxygen scavenger, could reverse the harmful effects of H2O2 on proliferation, apoptosis, and oxidative stress of ARPE-19 cells. Further, Klotho pretreatment enhanced Akt phosphorylation and expression as well as nuclear translocation of Nrf2 in H2O2-treated ARPE-19 cells. This indicates that Klotho protects cells from oxidative stress by activating phosphatidylinositol 3 kinase (PI3K)/protein kinase B (Akt)-nuclear factor E2-related factor 2 (Nrf2)/heme oxygenase 1 (HO-1) signaling pathway. Klotho is, therefore, a potential preventive or treatment option for AMD.

Association of CFI, IL-8, TF and TFR2 Genetic Polymorphisms with Age-Related Macular Degeneration in a Northeastern Chinese Population

Purpose: To explore the relationship between single-nucleotide polymorphisms (SNPs) in complement factor I (CFI), interleukin-8 (IL-8), transferrin (TF), and transferrin receptor 2 (TFR2) and age-related macular degeneration (AMD) in a northeastern Chinese population. Methods: A total of 400 AMD patients (200 wet AMD and 200 dry AMD) and 200 controls were enrolled in this study, and genetic polymorphisms in the above genes were detected by polymerase chain reaction–restriction fragment length polymorphism (PCR–RFLP). The χ2 test was used to compare differences in allele frequencies in each group, and the associations of genotype frequencies with AMD were determined by multivariate logistic regression analysis. Results: Our research shows that CFI rs141853578, IL-8 rs2227543, TF rs8177178 and TFR2 rs2075674 are associated with the incidence of AMD. In wet AMD, allele T of CFI rs141853578, IL-8 rs2227543 and TFR2 rs2075674 may be a risk factor. Allele A of TF rs8177178 may increase the risk of dry AMD. Conclusions: CFI rs141853578, IL-8 rs2227543, TF rs8177178 and TFR2 rs2075674 genetic polymorphisms are associated with the occurrence of AMD in a northeastern Chinese population, especially wet AMD.

Fibroblast growth factor-21 alleviates phenotypic characteristics of dry age-related macular degeneration in mice

Age-related macular degeneration (AMD) is the main cause of blindness in elderly individuals. As a metabolic regulator, fibroblast growth factor 21 (FGF-21) has been proven indicated to have an effect on wet AMD, but whether this cytokine has a therapeutic effect on dry AMD is unclear. The current study aimed to evaluate the preventive effects of FGF-21 against retinal degeneration in mice and provide mechanistic insights. FGF-21−/− mice were raised to 10 months of age. Then, the morphological changes in the retinal pigment epithelium (RPE)/choroid of the mice were observed by transmission electron microscopy (TEM), and iTRAQ was used to detect the variations in the protein profile. Next, FGF-21−/− and wild-type mice of the same age were fed hydroquinone to generate a dry AMD mouse model to examine whether exogenous FGF-21 can interfere with the occurrence and development of dry AMD. In vivo studies revealed that following FGF-21 knockout, there was an increase in the expression of complement in the RPE/choroid concomitant with the occurrence of dry AMD-like pathological changes. Furthermore, exogenous FGF-21 administration effectively reversed this phenomenon. FGF-21 also demonstrated strong anti-inflammatory effects in the RPE/choroid by inhibiting the NF-κB pathway. In conclusion, the present study demonstrates that FGF-21 treatment presents a novel therapeutic approach for the prevention and development of dry AMD by reducing complement.

Investigation of the effect of TNF-α on damage to retinal pigment epithelial cells in age-related macular degeneration

Oxidative stress alters cellular homeostasis and elicits a cellular response that depends on the severity and type of damage: some cells activate defense mechanisms designed to ensure survival; the other, provided that the defense mechanisms are inhibited, triggers alternative signaling pathways that lead to apoptosis, necrosis, pyroptosis, autophagy, and so on. However, the exact cause of such damage and induction of oxidative stress, including the associated oxidative effects around pigment epithelial cells in the context of the onset and progression of age-related macular degeneration – one of the world’s most common eye diseases with blindness, remains unclear. Therefore, in the course of the study we turned to key biogenetic points of regulation of inflammation and apoptosis, in particular TNF. The aim of the work is to shed light on the role of TNF as a genetic determinant that can initiate and influence the course of age-related macular degeneration. For this purpose, the main pathognomonic markers of the morphological structure of the macula were determined in 291 persons with age-related macular degeneration and in 105 persons without ophthalmic pathology, using optical coherence tomography to confirm or exclude the diagnosis of the disease. To detect polymorphism of the TNF gene, we used the method of real-time PCR diagnostics on the BioRad CFX 96 amplifier using LiTech reagents. Statistical processing of the results was performed using Hardy-Weinberg equilibrium, Kruskal-Wallis method, logistic regression analysis and construction of the ROC curve to determine the AUC range and sensitivity and specificity values. The study revealed a significant difference in the distribution of mutant genotypes between patients with both forms of AMD and the control group. There was also a statistically significant effect of mutant allele A on the development of both "dry" (OR = 3.40; 95.0 %; CI = 1.90-6.07, p&lt;0.001) and "wet" form of AMD (OR = 4.78; 95.0 % CI 2.65-8.64, p&lt;0.001), and in the analysis of mutant genotypes it was found that the GA genotype increases the chances of "dry" and "wet" forms of the disease by 3.13 and 4.74 times, respectively, while AA – 5 times, regardless of the form of the disease. confirms the influence of TNF gene polymorphism on the occurrence and progression of age-related macular degeneration. In the analysis of ROC-curves and AUC regions, it was found that all mutant genotypes have a significant effect on the occurrence of age-related macular degeneration (p&lt;0.05). However, the obtained values of sensitivity and specificity, especially in the AA genotype in both "dry" (17.9 % and 95.8 %, respectively) and "wet" (18.2 % and 95.8 %, respectively) forms of age-related macular degeneration indicate a low chance of error-free confirmation of the diagnosis. a disease that may be associated with multifactorial disease and requires further research.

A Pilot Application of an iTRAQ-Based Proteomics Screen Estimates the Effects of Cigarette Smokers' Serum on RPE Cells With AMD High-Risk Alleles.

PurposeThe aim of this study was to explore whether there are interactions between genetic (ARMS2/HTRA1) and environmental factors (cigarette smoking) in the pathogenesis of age-related macular degeneration (AMD).MethodsPrimary human retinal pigment epithelial (hRPE) cells were obtained from four donors’ eyes with AMD high-risk ARMS2/HTRA1 alleles, and two donors’ eyes with wild-type alleles were used as controls. The pooled serum from 32 smokers and 35 nonsmokers were collected and used separately to treat hRPE cells. The isobaric tag for relative and absolute quantitation (iTRAQ)-based proteomics was used to identify associated proteins and comparing the differences between AMD high-risk and low-risk HTRA1/ARMS2 alleles after exposure to smokers’ serum.ResultsAfter stimulation with the smokers’ serum, 400 differentially expressed proteins (DEPs) were detected in the high-risk allele cells. Several DEPs are involved in neuronal protein degeneration and oxidative stress pathways. The smokers’ serum stimulation or HTRA1 overexpression can both upregulate caveolin-1, which was one of the DEPs. Besides, the smokers’ serum enhanced the phagocytosis of cultured human RPE cells.ConclusionsThe study confirmed the AMD high-risk alleles, HTRA1, and cigarette smoking can promote AMD development by regulating caveolin-1 expression.Translational RelevanceAMD high-risk alleles and environmental risk factors can promote the occurrence and development of AMD by regulating caveolin-1 expression, upregulation of which will induce apoptotic cell death in response to cellular stress in early AMD conditions.

Age-related macular degeneration and premorbid allergic diseases: a population-based case\u2013control study

Evidence indicates that age-related macular degeneration (AMD) is associated with the prior presence of allergic diseases; however, large-scale studies in the literature are limited. A case–control study was conducted to describe the relationship between premorbid allergic diseases and AMD using Taiwan’s National Health Insurance database. Eligibility criteria for inclusion of new adult AMD cases from 2000 to 2013 were set up. We defined the year of diagnosis as the index year. Age-, gender-, index year- matched controls who were drawn from the same database. The case control ratio was 1:4. For all participants, all premorbid conditions staring 1996 to index year were documented. Binary logistic regression was used to describe factors related to AMD occurrence. The AMD group consisted of 10,911 patients, and the comparison group consisted of 43,644 individuals. Patients with AMD showed significant associations with premorbid allergic diseases (aOR 1.54, 95% CI 1.47–1.61), specifically with allergic conjunctivitis (aOR 2.07, 95% CI 1.94–2.20), allergic rhinitis (aOR 1.32, 95% CI 1.25–1.39), asthma (aOR 0.99, 95% CI 0.93–1.06), and atopic dermatitis (aOR 1.04, 95% CI 0.94–1.17). Further analyses indicated that patients with more concurrent allergic diseases have higher associations with AMD than those with fewer concurrent diseases. Patients with more annual medical visits for their allergic diseases also showed higher associations with AMD than those with fewer visits. AMD is significantly associated with premorbid allergic diseases. The underlying mechanisms must be further investigated.

Complement System and Potential Therapeutics in Age-Related Macular Degeneration

Age-related macular degeneration (AMD) is a complex multifactorial disease characterized in its late form by neovascularization (wet type) or geographic atrophy of the retinal pigment epithelium cell layer (dry type). The complement system is an intrinsic component of innate immunity. There has been growing evidence that the complement system plays an integral role in maintaining immune surveillance and homeostasis in AMD. Based on the association between the genotypes of complement variants and AMD occurrence and the presence of complement in drusen from AMD patients, the complement system has become a therapeutic target for AMD. However, the mechanism of complement disease propagation in AMD has not been fully understood. This concise review focuses on an overall understanding of the role of the complement system in AMD and its ongoing clinical trials. It provides further insights into a strategy for the treatment of AMD targeting the complement system.