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The interplay of oxidative stress and ARMS2-HTRA1 genetic risk in neovascular AMD.

ABSTRACT: Age-related macular degeneration (AMD) is the leading cause of vision loss in adults over 60 years old globally. There are two forms of advanced AMD: "dry" and "wet". Dry AMD is characterized by geographic atrophy of the retinal pigment epithelium and overlying photoreceptors in the macular region; whereas wet AMD is characterized by vascular penetrance from the choroid into the retina, known as choroidal neovascularization (CNV). Both phenotypes eventually lead to loss of central vision. The pathogenesis of AMD involves the interplay of genetic polymorphisms and environmental risk factors, many of which elevate retinal oxidative stress. Excess reactive oxygen species react with cellular macromolecules, forming oxidation-modified byproducts that elicit chronic inflammation and promote CNV. Additionally, genome-wide association studies have identified several genetic variants in the age-related maculopathy susceptibility 2/high-temperature requirement A serine peptidase 1 (ARMS2-HTRA1) locus associated with the progression of late-stage AMD, especially the wet subtype. In this review, we will focus on the interplay of oxidative stress and HTRA1 in drusen deposition, chronic inflammation, and chronic angiogenesis. We aim to present a multifactorial model of wet AMD progression, supporting HTRA1 as a novel therapeutic target upstream of vascular endothelial growth factor (VEGF), the conventional target in AMD therapeutics. By inhibiting HTRA1's proteolytic activity, we can reduce pro-angiogenic signaling and prevent proteolytic breakdown of the blood-retina barrier. The anti-HTRA1 approach offers a promising alternative treatment option to wet AMD, complementary to anti-VEGF therapy.

SUBMITTER: Lu ZG

PROVIDER: S-EPMC8133762 | biostudies-literature |

REPOSITORIES: biostudies-literature

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CRISPR editing demonstrates rs10490924 raised oxidative stress in iPSC-derived retinal cells from patients with ARMS2/HTRA1-related AMD.

Project description:Genome-wide association studies (GWAS) have identified genetic risk loci for age-related macular degeneration (AMD) on the chromosome 10q26 (Chr10) locus and are tightly linked: the A69S (G>T) rs10490924 single-nucleotide variant (SNV) and the AATAA-rich insertion-deletion (indel, del443/ins54), which are found in the age-related maculopathy susceptibility 2 (ARMS2) gene, and the G512A (G>A) rs11200638 SNV, which is found in the high-temperature requirement A serine peptidase 1 (HTRA1) promoter. The fourth variant is Y402H complement factor H (CFH), which directs CFH signaling. CRISPR manipulation of retinal pigment epithelium (RPE) cells may allow one to isolate the effects of the individual SNV and thus identify SNV-specific effects on cell phenotype. Clustered regularly interspaced short palindromic repeats (CRISPR) editing demonstrates that rs10490924 raised oxidative stress in induced pluripotent stem cell (iPSC)-derived retinal cells from patients with AMD. Sodium phenylbutyrate preferentially reverses the cell death caused by ARMS2 rs10490924 but not HTRA1 rs11200638. This study serves as a proof of concept for the use of patient-specific iPSCs for functional annotation of tightly linked GWAS to study the etiology of a late-onset disease phenotype. More importantly, we demonstrate that antioxidant administration may be useful for reducing reactive oxidative stress in AMD, a prevalent late-onset neurodegenerative disorder.

| S-EPMC10175836 | biostudies-literature

Gene-gene interaction of CFH, ARMS2, and ARMS2/HTRA1 on the risk of neovascular age-related macular degeneration and polypoidal choroidal vasculopathy in Chinese population.

Project description:To evaluate the association and interaction of five single-nucleotide polymorphisms (SNPs) in three genes (CFH, ARMS2, and ARMS2/HTRA1) with neovascular age-related macular degeneration (nAMD) and polypoidal choroidal vasculopathy (PCV) in Chinese population.A total of 300 nAMD and 300 PCV patients and 301 normal subjects participated in the present study. The allelic variants of rs800292, rs2274700, rs3750847, rs3793917, and rs1065489 were determined by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS). Gene-gene interactions were evaluated by the data mining approach multifactor-dimensionality reduction (MDR) method.The risk alleles of CFH rs800292, rs2274700, ARMS2 rs3057847, and ARMS2/HTRA1 rs3793917 showed significant difference between nAMD or PCV patients and controls (all P<0.01). The homozygosity of risk alleles for rs800292, rs2274700, rs3750847, and rs3793917 were significantly different between nAMD patients and controls (all P<0.01), and predisposed to PCV patients (all P<0.01). After cross-validation consistency (CVC) and permutation tests, the two-locus model rs2274700_rs3750847 has a balanced accuracy of 64.37% in predicting nAMD disease risk. The one-marker model, rs3750847, and two-locus model rs2274700_rs3750847 has a balanced accuracy of 66.07% and 65.89% in predicting PCV disease risk, respectively. Furthermore, CFH rs1065489 did not show significant association with nAMD (P>0.01), but was strongly associated with PCV in Chinese patients (P<0.001).In this study, we found that the interaction of ARMS2 and ARMS2/HTRA1 is significantly associated with nAMD, and the interaction of CFH and ARMS2 is pronounced in PCV development in Chinese population.

| S-EPMC4429281 | biostudies-literature

The impact of oxidative stress and inflammation on RPE degeneration in non-neovascular AMD.

Project description:The retinal pigment epithelium (RPE) is a highly specialized, unique epithelial cell that interacts with photoreceptors on its apical side and with Bruch's membrane and the choriocapillaris on its basal side. Due to vital functions that keep photoreceptors healthy, the RPE is essential for maintaining vision. With aging and the accumulated effects of environmental stresses, the RPE can become dysfunctional and die. This degeneration plays a central role in age-related macular degeneration (AMD) pathobiology, the leading cause of blindness among the elderly in western societies. Oxidative stress and inflammation have both physiological and potentially pathological roles in RPE degeneration. Given the central role of the RPE, this review will focus on the impact of oxidative stress and inflammation on the RPE with AMD pathobiology. Physiological sources of oxidative stress as well as unique sources from photo-oxidative stress, the phagocytosis of photoreceptor outer segments, and modifiable factors such as cigarette smoking and high fat diet ingestion that can convert oxidative stress into a pathological role, and the negative impact of impairing the cytoprotective roles of mitochondrial dynamics and the Nrf2 signaling system on RPE health in AMD will be discussed. Likewise, the response by the innate immune system to an inciting trigger, and the potential role of local RPE production of inflammation, as well as a potential role for damage by inflammation with chronicity if the inciting trigger is not neutralized, will be debated.

| S-EPMC5600827 | biostudies-literature

Joint Effect of CFH and ARMS2/HTRA1 Polymorphisms on Neovascular Age-Related Macular Degeneration in Chinese Population.

Project description:Purpose. The etiology of neovascular age-related macular degeneration (nAMD) cannot be completely explained by identified environmental risk factors or single-locus gene variants. This study was to explore the potential interactions among gene variants on nAMD in Chinese population. Methods. 43 SNPs located in different genes were genotyped in 932 Chinese individuals (464 nAMD patients and 468 controls). We explored the potential interactions among gene variants using generalized multifactor dimensionality reduction (GMDR) algorithm and the method to measure the departure from the additivity model. Results. The joint effect that involved CFH rs1061170 and HTRA1 rs3793917 was shown statistically significant (P < 0.001) with the highest cross-validation consistency (10/10) and the best testing balanced accuracy (64.50%). In addition, based on the method to measure the departure from the additivity model, the synergy index (S) was 2.63 (1.09-6.38) and the attributable proportion due to interaction (AP) was 55.7% (21.4%-89.9%), which suggested that a common pathway may exist for these genes for nAMD. Those who carried CC for rs3793917 and TC/CC for rs1061170 were at the highest risk of nAMD (OR: 9.76, 95% CI: 4.65-20.51). Conclusions. Evidence that the joint effect that involved CFH and ARMS2/HTRA1 may contribute to the risk of neovascular AMD in Chinese population was obtained.

| S-EPMC4389821 | biostudies-literature

Joint effects of polymorphisms in the HTRA1, LOC387715/ARMS2, and CFH genes on AMD in a Caucasian population.

Project description:PurposeTo estimate the joint effects of single nucleotide polymorphisms (SNPs) in the genes complement factor H (CFH), HtrA serine peptidase 1 (HTRA1), and age-related maculopathy susceptibility 2 (LOC387715/ARMS2) in a Caucasian age related macular degeneration (AMD) case-control cohort.MethodsWe genotyped three SNPs, rs1061170 (exon 9, CFH), rs11200638 (HTRA1 promoter, -512 bp), and rs10490924 (6.6 kb upstream of HTRA1 in LOC387715/ARMS2) in 333 cases with advanced AMD (choroidal neovascularization [CNV] and geographic atrophy) and 171 age-matched examined controls. Association tests were performed for individual SNPs and jointly with the CFH SNP Y402H. Analyses for interaction were also performed.ResultsThe linkage disequilibrium measure for two SNPs on 10q26, rs10490924 and rs11200638, is D'=0.8 and all four possible haplotypes of the two SNPs were detected in the samples. The allelic association test for rs11200638 on the promoter of HTRA1 yielded p-values less than 10(-10) for geographic atrophy, less than 10(-16) for neovascularization, and less than 10(-19) for the pooled phenotypes (with an odds ration [OR] of 3.973; 95% confidence interval [CI] 2.928, 5.390). Disease risk is conferred in a dosage-dependent fashion. Similar figures were observed for the LOC387715/ARMS2 SNP. No interaction was detected between either between the 10q26 SNPs or the CFH SNP.ConclusionsThis is the first analysis to show that the two 10q26 SNPs are not in complete linkage disequilibrium. Our studies however show that both the HTRA1 and LOC387715/ARMS2 SNP appear to contribute equally to disease risk (both geographic atrophy and choroidal neovascularization) with no evidence of interaction with CFH.

| S-EPMC2493023 | biostudies-literature

Association of HTRA1 and ARMS2 gene polymorphisms with response to intravitreal ranibizumab among neovascular age-related macular degenerative subjects.

Project description:BackgroundThe association of HTRA1 rs11200638 and ARMS2 rs10490924 gene polymorphisms with response to intravitreal ranibizumab therapy among neovascular AMD (nAMD) subjects in Malaysia was determined in this study, followed by the expression of HTRA1 and ARMS2 genes.ResultsBoth single nucleotide polymorphisms (SNPs) recorded a significant association between nAMD and controls with HTRA1 rs11200638 at P = 0.018 (OR = 1.52, 95% CI = 1.07-215) and ARMS2 rs10490924 at P < 0.001 (OR = 2.44, 95% CI = 1.75-3.42). An association was also observed in response to ranibizumab for both SNPs in a logistic regression analysis (P < 0.001). The mRNA levels in the HTRA1 variant between responder and non-responder groups were significantly different for the homozygous non-risk GG genotype (P = 0.032).ConclusionsThe HTRA1 rs11200638 and ARMS2 rs10490924 gene polymorphisms are associated with nAMD among Malaysians. Both gene polymorphisms were also correlated with response to intravitreal ranibizumab therapy based on visual and anatomical outcomes especially the HTRA1 rs11200638 variant.

| S-EPMC6387522 | biostudies-literature

Binding of Gtf2i-β/δ transcription factors to the ARMS2 gene leads to increased circulating HTRA1 in AMD patients and in vitro.

Project description:The disease-initiating molecular events for age-related macular degeneration (AMD), a multifactorial retinal disease affecting many millions of elderly individuals worldwide, are still unknown. Of the over 30 risk and protective loci so far associated with AMD through whole genome-wide association studies (GWAS), the Age-Related Maculopathy Susceptibility 2 (ARMS2) gene locus represents one of the most highly associated risk regions for AMD. A unique insertion/deletion (in/del) sequence located immediately upstream of the High Temperature Requirement A1 (HTRA1) gene in this region confers high risk for AMD. Using electrophoretic mobility shift assay (EMSA), we identified that two Gtf2i-β/δ transcription factor isoforms bind to the cis-element 5'- ATTAATAACC-3' contained in this in/del sequence. The binding of these transcription factors leads to enhanced upregulation of transcription of the secretory serine protease HTRA1 in transfected cells and AMD patient-derived induced pluripotent stem cells (iPSCs). Overexpression of Htra1 in mice using a CAG-promoter demonstrated increased blood concentration of Htra1 protein, caused upregulation of vascular endothelial growth factor (VEGF), and produced a choroidal neovascularization (CNV)-like phenotype. Finally, a comparison of 478 AMD patients to 481 healthy, age-matched controls from Japan, India, Australia, and the USA showed a statistically increased level of secreted HTRA1 blood concentration in AMD patients compared with age-matched controls. Taken together, these results suggest a common mechanism across ethnicities whereby increased systemic blood circulation of secreted serine protease HTRA1 leads to subsequent degradation of Bruch's membrane and eventual CNV in AMD.

| S-EPMC8039566 | biostudies-literature

Complement factor H and LOC387715/ARMS2/HTRA1 variant's frequencies and phenotypic associations in neovascular age-related macular degeneration, a pilot study.

Project description:PurposeTo evaluate the frequency of 12 single nucleotide polymorphisms (SNPs) of complement factor H (CFH) and LOC387715/ARMS2/HRTA1 and their association with some of the presenting clinical features of neovascular age-related macular degeneration (AMD).MethodsIn this prospective non-comparative case series forty four naïve patients with neovascular AMD were genotyped using sequencing or Sequenom iPLEX technology. Descriptive tests were used for displaying the magnitude of each allele, gender distribution, and age at diagnosis. Fisher exact test was used to evaluate the correlation between visual acuity (VA) and different alleles. Also Kruskal-Wallis test was used for comparison between age at the time of diagnosis and different alleles.ResultsThe most frequent SNP among studied patients was rs1061147 with 100% frequency rate. The least common was rs2672598 with a frequency of 52.27%. Only the allele rs800292 of CFH locus on 1q32 was associated with VA better than 20/200 (p value = 0.034). The frequency of this allele was 77.27% (34 patients) in this study. There was no significant association between any of alleles, and VA worse than 20/200(p > 0.05). Fifteen patients had bilateral exudative AMD (34.09%). There was no significant difference between alleles in bilateral neovascular AMD and unilateral disease. Also bilateral and unilateral patients were not different in terms of age, gender or VA (p value: 0.330, 0.764 and 0.456 respectively). There was also no significant association between any of SNPs and bilaterality of disease.ConclusionWe designated the frequencies of SNPs of CFH and LOC387715/ARMS2/HRTA1 in neovascular AMD in a sample of Iranian patients. Only the allele rs800292 of CFH locus on chromosome 1q32 was associated with better VA.

| S-EPMC4881216 | biostudies-literature

CFH and ARMS2 genetic risk determines progression to neovascular age-related macular degeneration after antioxidant and zinc supplementation.

Project description:We evaluated the influence of an antioxidant and zinc nutritional supplement [the Age-Related Eye Disease Study (AREDS) formulation] on delaying or preventing progression to neovascular AMD (NV) in persons with age-related macular degeneration (AMD). AREDS subjects (n = 802) with category 3 or 4 AMD at baseline who had been treated with placebo or the AREDS formulation were evaluated for differences in the risk of progression to NV as a function of complement factor H (CFH) and age-related maculopathy susceptibility 2 (ARMS2) genotype groups. We used published genetic grouping: a two-SNP haplotype risk-calling algorithm to assess CFH, and either the single SNP rs10490924 or 372_815del443ins54 to mark ARMS2 risk. Progression risk was determined using the Cox proportional hazard model. Genetics-treatment interaction on NV risk was assessed using a multiiterative bootstrap validation analysis. We identified strong interaction of genetics with AREDS formulation treatment on the development of NV. Individuals with high CFH and no ARMS2 risk alleles and taking the AREDS formulation had increased progression to NV compared with placebo. Those with low CFH risk and high ARMS2 risk had decreased progression risk. Analysis of CFH and ARMS2 genotype groups from a validation dataset reinforces this conclusion. Bootstrapping analysis confirms the presence of a genetics-treatment interaction and suggests that individual treatment response to the AREDS formulation is largely determined by genetics. The AREDS formulation modifies the risk of progression to NV based on individual genetics. Its use should be based on patient-specific genotype.

| S-EPMC5789949 | biostudies-literature

Oxidative and carbonyl stress induced AMD and Codonopsis lanceolata ameliorates AMD via controlling oxidative and carbonyl stress.

Project description:Age-related macular degeneration (AMD) is one of the leading causes of blindness. AMD is currently incurable; the best solution is to prevent its occurrence. To develop drugs for AMD, it is crucial to have a model system that mimics the symptoms and mechanisms in patients. It is most important to develop safer and more effective anti-AMD drug. In this study, the dose of A2E and the intensity of blue light were evaluated to establish an appropriate atrophic in vitro model of AMD and anti-AMD effect and therapeutic mechanism of Codonopsis lanceolata. The experimental groups included a control group an AMD group treated with A2E and blue light, a lutein group treated with 25 μM lutein after AMD induction, and three groups treated with different doses of C. lanceolata (10, 20, and 50 μg/mL) after AMD induction. Intrinsic apoptotic pathway (Bcl-2 family), anti-oxidative system (Keap1/Nrf2/HO-1 antioxidant response element), and anti-carbonyl effect (4-hydroxynonenal [4-HNE]) were evaluated using immunofluorescence, MTT, TUNEL, FACS, and western blotting analyses. A2E accumulation in the cytoplasm of ARPE-19 cells depending on the dose of A2E. Cell viability of ARPE-19 cells according to the dose of A2E and/or blue light intensity. The population of apoptotic or necrotic cells increased based on the A2E dose and blue light intensity. Codonopsis lanceolata dose-dependently prevented cell death which was induced by A2E and blue light. The antiapoptotic effect of that was caused by activating Keap1/Nrf2/HO-1 pathway, suppressing 4-HNE, and modulating Bcl-2 family proteins like increase of antiapoptotic proteins such as Bcl-2 and Bcl-XL and decrease of proapoptotic protein such as Bim. Based on these findings, 30 μM A2E and 20 mW/cm2 blue light on adult retinal pigment epithelium-19 cells was an appropriate condition for AMD model and C. lanceolata shows promise as an anti-AMD agent.

| S-EPMC11251066 | biostudies-literature

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