Dataset Information

Association of Single-Nucleotide Polymorphisms in Age-Related Macular Degeneration With Pseudodrusen: Secondary Analysis of Data From the Comparison of AMD Treatments Trials.

ABSTRACT: Importance:Previous studies investigating the association of single-nucleotide polymorphisms (SNPs) that confer increased risk of age-related macular degeneration (AMD) with pseudodrusen have yielded conflicting results and have not evaluated other AMD SNPs or pseudodrusen subtypes. Objective:To determine the association of SNPs in the complement factor H (CFH), age-related maculopathy susceptibility 2 (ARMS2), HtrA serine peptidase 1 (HTRA1), complement C2 (C2), complement C3 (C3), lipase C (LIPC), and complement factor B (CFB) genes with the presence of pseudodrusen and pseudodrusen subtypes (ie, dot, reticular, and confluent). Design, Setting, and Participants:In this post hoc analysis of cross-sectional data from US participants in the Comparison of AMD Treatments Trials, genotyping was performed in 835 participants with TaqMan assays for the SNPs rs1061170 (Y402H variant in CFH), rs800292 (I62V variant in CFH), rs10490924 (A69S variant in ARMS2), rs11200638 (HTRA1), rs547154 (C2), rs2230199 (R102G variant in C3), rs10468017 (LIPC), and rs4151667 (L9H variant in CFB). Main Outcomes and Measures:Presence and subtype of baseline pseudodrusen in either eye determined using color fundus photography, red-free images, and fluorescein angiograms. Results:Among 835 participants enrolled for genotyping, 755 (90.4%) were evaluated for pseudodrusen. Of these, 471 (62.4%) were female and 750 (99.3%) were white, and the mean (SD) age was 78.3 (7.5) years. A total of 213 of 755 participants (28.2%) had pseudodrusen (107 [14.2%] had dot pseudodrusen, 180 [23.8%] had reticular pseudodrusen, and 102 [13.5%] had confluent pseudodrusen). After adjusting for age, sex, and smoking status, the ARMS2 risk allele T was associated with higher risk of pseudodrusen (odds ratio [OR], 1.93; 95% CI, 1.19-3.12) for TT vs GG (P?=?.04). A similar association was found for HTRA1 (OR, 2.04; 95% CI, 1.26-3.31) for AA vs GG (P?=?.03). The CFH Y402H risk allele C was associated with lower risk of pseudodrusen (OR, 0.61; 95% CI, 0.38-0.97) for CC vs TT but was not statistically significant after correcting for multiple comparison (P?=?.20). CFH Y402H, ARMS2, HTRA1, and C3 were significantly associated with reticular pseudodrusen. Conclusions and Relevance:Among patients with neovascular AMD, the AMD risk alleles ARMS2 and HTRA1 were associated with an increased risk of pseudodrusen and the risk allele CFH Y402H was associated with lower risk of pseudodrusen, supporting findings from previous studies. Understanding the role of these SNPs in the development of pseudodrusen might improve our understanding of the pathogenesis of AMD and help develop future therapies.

SUBMITTER: Lin LY

PROVIDER: S-EPMC6145774 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Association of Single-Nucleotide Polymorphisms in Age-Related Macular Degeneration With Pseudodrusen: Secondary Analysis of Data From the Comparison of AMD Treatments Trials.

Lin Lisa Y LY Zhou Qiang Q Hagstrom Stephanie S Maguire Maureen G MG Daniel Ebenezer E Grunwald Juan E JE Martin Daniel F DF Ying Gui-Shuang GS

JAMA ophthalmology 20180601 6

<h4>Importance</h4>Previous studies investigating the association of single-nucleotide polymorphisms (SNPs) that confer increased risk of age-related macular degeneration (AMD) with pseudodrusen have yielded conflicting results and have not evaluated other AMD SNPs or pseudodrusen subtypes.<h4>Objective</h4>To determine the association of SNPs in the complement factor H (CFH), age-related maculopathy susceptibility 2 (ARMS2), HtrA serine peptidase 1 (HTRA1), complement C2 (C2), complement C3 (C3 ...[more]

PMID: 29801032

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Project description:To evaluate the association between pseudodrusen and incidence of late age-related macular degeneration (AMD) in fellow eyes of patients with unilateral neovascular AMD (nAMD).Cohort study within the Comparison of AMD Treatments Trials (CATT).Patients with neither nAMD nor geographic atrophy (GA) in the fellow eye at baseline.Presence and type (dot, reticular, or confluent) of baseline pseudodrusen were assessed using digital color fundus photography (CFP) viewed under full color, green channel, and blue channel; red-free images; and fluorescein angiography (FA). Incidence of nAMD was based on monthly clinical examination and reading center evaluation of images at years 1 and 2. Incidence of GA was based on reading center evaluation of CFP and FA images at years 1 and 2. Associations of baseline pseudodrusen with incident nAMD and GA were summarized with adjusted risk ratios (aRRs) and their 95% confidence intervals (CIs) from multivariate Cox models, with adjustment of covariates identified through backward stepwise selection.Incident nAMD and GA.Among 620 fellow eyes, 176 (28.4%) had baseline pseudodrusen (55% dot, 82% reticular, 35% confluent). Within 2 years, nAMD occurred in 54 eyes (30.7%) with pseudodrusen and in 72 eyes (16.2%) without pseudodrusen (aRR, 2.05; 95% CI, 1.43-2.93); GA occurred in 27 eyes (15.3%) with pseudodrusen and in 37 eyes (8.3%) without pseudodrusen (aRR, 1.89; 95% CI, 1.13-3.17); late AMD occurred in 73 eyes (41.5%) with pseudodrusen and in 101 eyes (22.8%) without pseudodrusen (aRR, 2.07; 95% CI, 1.51-2.83). Dot pseudodrusen were associated independently with nAMD (aRR, 2.53; 95% CI, 1.60-4.00), whereas confluent pseudodrusen were associated independently with GA (aRR, 4.35; 95% CI, 1.69-11.2). Eyes with pseudodrusen had increased incidence of late AMD regardless of whether the Age-Related Eye Diseases Study (AREDS) severity score was 2 (28.7% vs. 10.3%), 3 (34.9% vs. 13.7%), or 4 (50.5% vs. 32.0%).In fellow eyes of CATT participants, pseudodrusen were associated independently with a higher incidence of both nAMD and GA. Dot pseudodrusen were associated with nAMD, whereas confluent pseudodrusen were associated with GA. Pseudodrusen should be considered along with the AREDS severity score for predicting late AMD.

Project description:ImportanceSingle-nucleotide polymorphisms (SNPs) associated with the CFH, ARMS2, C3, LIPC, CFB, and C2 genes are associated with age-related macular degeneration (AMD); however, the association of these SNPs with angiographic features of neovascular AMD has been inconsistent in previous studies, and to date, no studies have addressed their association with features on optical coherence tomography.ObjectiveTo evaluate the influence of genotype of SNPs previously associated with AMD on the phenotype of neovascular lesions.Design, setting, and participantsParticipants for this cross-sectional study were recruited from the 1185 patients enrolled in the Comparison of Age-Related Macular Degeneration Treatments Trials (CATT), a randomized clinical trial. Eligibility criteria for CATT specified that eyes have choroidal neovascularization and visual acuity between 20/25 and 20/320. A subgroup of 835 patients provided blood samples from July 2010 through September 2011 and were genotyped for the SNPs rs1061170 (CFH), rs10490924 (ARMS2),rs2230199 (C3), rs10468017 (LIPC), rs4151667 (CFB), rs547154 (C2) using TaqMan SNP genotyping assays. Data analysis was initiated in November 2013 and completed in January 2016.Main outcomes and measuresPretreatment ocular characteristics on fluorescein angiography (lesion type, area of neovascularization and total lesion, retinal angiomatous proliferation) and on time-domain optical coherence tomography (presence of intraretinal, subretinal, and subretinal pigment epithelium fluid; thickness at the foveal center of the retina, subretinal fluid, and subretinal tissue complex), visual acuity, and age.ResultsA total of 835 (73%) of 1150 CATT patients were genotyped. Mean age decreased with the number of risk alleles for CFH (P < .001), ARMS2 (P < .001), and C3 (P = .005). The following results were found as the number of risk alleles increased from 0 to 1 to 2. For CFH, mean total thickness decreased from 476 to 476 to 434 µm (P = .01; adjusted for age, sex, and smoking status). For ARMS2, the mean area of the total lesion increased from 2.0 to 2.8 to 2.4 mm2 (P = .03), the proportion with retinal angiomatous proliferation lesions increased from 8% to 10% to 12% (P = .05), and the proportion with intraretinal fluid increased from 72% to 71% to 82% (P = .008). For C3, the proportion with intraretinal fluid decreased from 78% to 69% to 64% (P = .001), and the mean retinal thickness decreased from 225 to 207 to 197 µm (P = .02).Conclusions and relevanceCFH, ARMS2, and C3 were associated with specific features of neovascularization at the time patients were enrolled in CATT. Previously identified associations of ARMS2 and CFH with type of choroidal neovascularization on fluorescein angiography were not confirmed. New associations with OCT features identified in CATT need confirmation to establish whether a true association exists.Trial registrationclinicaltrials.gov Identifier: NCT00593450.

Project description:PurposeTo evaluate the pharmacogenetic relationship between genotypes of single nucleotide polymorphisms (SNPs) known to be associated with age-related macular degeneration (AMD) and response to treatment with ranibizumab (Lucentis; Genentech, South San Francisco, CA) or bevacizumab (Avastin; Genentech) for neovascular AMD.DesignClinical trial.ParticipantsEight hundred thirty-four (73%) of 1149 patients participating in the Comparison of AMD Treatments Trials (CATT) were recruited through 43 CATT clinical centers.MethodsEach patient was genotyped for SNPs rs1061170 (CFH), rs10490924 (ARMS2), rs11200638 (HTRA1), and rs2230199 (C3), using TaqMan SNP genotyping assays (Applied Biosystems, Foster City, CA).Main outcomes measuresGenotypic frequencies were compared with clinical measures of response to therapy at one year, including mean visual acuity (VA), mean change in VA, 15-letter or more increase in VA, retinal thickness, mean change in total foveal thickness, presence of fluid on OCT, presence of leakage on fluorescein angiography (FA), mean change in lesion size, and mean number of injections administered. Differences in response by genotype were evaluated with tests of linear trend calculated from logistic regression models for categorical outcomes and linear regression models for continuous outcomes. To adjust for multiple comparisons, P?0.01 was considered statistically significant.ResultsNo statistically significant differences in response by genotype were identified for any of the clinical measures studied. Specifically, there were no high-risk alleles that predicted final VA or change in VA, the degree of anatomic response (fluid on OCT or FA, retinal thickness, change in total foveal thickness, change in lesion size), or the number of injections. Furthermore, a stepwise analysis failed to show a significant epistatic interaction among the variants analyzed; that is, response did not vary by the number of risk alleles present. The lack of association was similar whether patients were treated with ranibizumab or bevacizumab or whether they received monthly or pro re nata dosing.ConclusionsAlthough specific alleles for CFH, ARMS2, HTRA1, and C3 may predict the development of AMD, they did not predict response to anti-vascular endothelial growth factor therapy.

Project description:ObjectiveTo describe the effects of treatment for 1 year with ranibizumab or bevacizumab on macular morphology and the association of macular morphology with visual acuity (VA) in eyes with neovascular age-related macular degeneration (AMD).DesignProspective cohort study within a randomized clinical trial.ParticipantsParticipants in the Comparison of Age-related Macular Degeneration Treatments Trials.MethodsParticipants were assigned randomly to treatment with ranibizumab or bevacizumab on a monthly or as-needed schedule. Optical coherence tomography (OCT), fluorescein angiography (FA), color fundus photography (FP), and VA testing were performed periodically throughout 52 weeks. Masked readers graded images. General linear models were applied to evaluate effects of time and treatment on outcomes.Main outcome measuresFluid type and location and thickness by OCT, size, and lesion composition on FP, FA, and VA.ResultsIntraretinal fluid (IRF), subretinal fluid (SRF), subretinal pigment epithelium fluid, and retinal, subretinal, and subretinal tissue complex thickness decreased in all treatment groups. A higher proportion of eyes treated monthly with ranibizumab had fluid resolution at 4 weeks, and the difference persisted through 52 weeks. At 52 weeks, there was little association between the presence of fluid of any type (without regard to fluid location) and the mean VA. However, at all time points, eyes with residual IRF, especially foveal IRF, had worse mean VA (9 letters) than those without IRF. Eyes with abnormally thin (<120 μm) or thick (>212 μm) retinas had worse VA than those with normal thickness (120-212 μm). At week 52, eyes with larger neovascular lesions or with foveal scar had worse VA than eyes without these features.ConclusionsAnti-vascular endothelial growth factor (VEGF) therapy reduced lesion activity and improved VA in all treatment groups. At all time points, eyes with residual IRF had worse VA than those without. Eyes with abnormally thin or thick retinas, residual large lesions, and scar also had worse VA. Monthly ranibizumab dosing yielded more eyes with no fluid and an abnormally thin retina, although the long-term significance is unknown. These results have important treatment implications in eyes undergoing anti-VEGF therapy for neovascular AMD.Financial disclosure(s)Proprietary or commercial disclosure may be found after the references.

Dataset Information

Association of Single-Nucleotide Polymorphisms in Age-Related Macular Degeneration With Pseudodrusen: Secondary Analysis of Data From the Comparison of AMD Treatments Trials.

Publications

Association of Single-Nucleotide Polymorphisms in Age-Related Macular Degeneration With Pseudodrusen: Secondary Analysis of Data From the Comparison of AMD Treatments Trials.

Similar Datasets

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