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Single-Nucleotide Polymorphisms Associated With Age-Related Macular Degeneration and Lesion Phenotypes in the Comparison of Age-Related Macular Degeneration Treatments Trials.

ABSTRACT: Single-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.To evaluate the influence of genotype of SNPs previously associated with AMD on the phenotype of neovascular lesions.Participants 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.Pretreatment 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.A 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).CFH, 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.clinicaltrials.gov Identifier: NCT00593450.

SUBMITTER: Maguire MG

PROVIDER: S-EPMC6005698 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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Single-Nucleotide Polymorphisms Associated With Age-Related Macular Degeneration and Lesion Phenotypes in the Comparison of Age-Related Macular Degeneration Treatments Trials.

Maguire Maureen G MG Ying Gui-Shuang GS Jaffe Glenn J GJ Toth Cynthia A CA Daniel Ebenezer E Grunwald Juan J Martin Daniel F DF Hagstrom Stephanie A SA

JAMA ophthalmology 20160601 6

<h4>Importance</h4>Single-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.<h4>Objective</h4>To evaluate the influence of genotype of SNPs previously associated with ...[more]

PMID: 27099955

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Project description:ImportancePrevious 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.ObjectiveTo 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 participantsIn 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 measuresPresence and subtype of baseline pseudodrusen in either eye determined using color fundus photography, red-free images, and fluorescein angiograms.ResultsAmong 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 relevanceAmong 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.

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: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.

Project description:PurposeTo evaluate the association of subretinal hyperreflective material (SHRM) with visual acuity (VA), geographic atrophy (GA), and scar in the Comparison of Age-Related Macular Degeneration Treatments Trials (CATT).DesignProspective cohort study within a randomized clinical trial.ParticipantsThe 1185 CATT participants.MethodsMasked readers graded scar and GA on fundus photography and fluorescein angiography and graded SHRM on time-domain and spectral-domain (SD) optical coherence tomography (OCT) throughout 104 weeks. Measurements of SHRM height and width in the fovea, within the center 1 mm(2), or outside the center 1mm(2) were obtained on SD OCT images at 56 (n = 76) and 104 (n = 66) weeks.Main outcome measuresPresence of SHRM, as well as location and size, and associations with VA, scar, and GA.ResultsAmong CATT participants, the percentage with SHRM at enrollment was 77%, decreasing to 68% at 4 weeks after treatment and to 54% at 104 weeks. At 104 weeks, scar was present more often in eyes with persistent SHRM than in eyes with SHRM that resolved (64% vs. 31%; P < 0.0001). Among eyes with detailed evaluation of SHRM at weeks 56 (n = 76) and 104 (n = 66), mean VA letter score was 73.5 (standard error [SE], 2.8), 73.1 (SE, 3.4), 65.3 (SE, 3.5), and 63.9 (SE, 3.7) when SHRM was absent, present outside the central 1 mm(2), present within the central 1 mm(2) but not the foveal center, or present at the foveal center (P = 0.02), respectively. When SHRM was present, the median maximum height under the fovea, within the central 1 mm(2) including the fovea and anywhere within the scan, was 86 μm, 120 μm, and 122 μm, respectively. Visual acuity was decreased with greater SHRM height and width (P < 0.05).ConclusionsIn eyes with neovascular age-related macular degeneration (AMD), SHRM is common and often persists after anti-vascular endothelial growth factor treatment. At 2 years, eyes with scar were more likely to have SHRM than other eyes. Greater SHRM dimensions were associated with worse VA. In eyes with neovascular AMD, SHRM is an important morphologic biomarker.

Project description:ObjectiveTo describe risk factors for scar in eyes treated with ranibizumab or bevacizumab for neovascular age-related macular degeneration (AMD).DesignProspective cohort study within a randomized clinical trial.ParticipantsPatients with no scar on color fundus photography (CFP) or fluorescein angiography (FA) at enrollment in the Comparison of Age-related Macular Degeneration Treatments Trials (CATT).MethodsEyes were assigned to ranibizumab or bevacizumab treatment and to 1 of 3 dosing regimens for 2 years. Masked readers assessed CFP and FA. Baseline demographic characteristics, visual acuity, morphologic features on photography and optical coherence tomography (OCT), and genotypes associated with AMD risk were evaluated as risk factors using adjusted hazard ratios (aHRs) and associated 95% confidence intervals (CIs). Scars were classified as fibrotic with well-demarcated elevated mounds of yellowish white tissue or nonfibrotic with discrete flat areas of hyperpigmentation with varying amounts of central depigmentation.Main outcome measuresScar formation.ResultsScar developed in 480 of 1059 eyes (45.3%) by 2 years. Baseline characteristics associated with greater risk of scarring were predominantly classic choroidal neovascularization (CNV) (aHR, 3.1; CI, 2.4-3.9) versus occult CNV, blocked fluorescence (aHR, 1.4; CI, 1.1-1.8), foveal retinal thickness >212 μm (aHR, 2.4; CI, 1.7-3.6) versus <120 μm, foveal subretinal tissue complex thickness >275 μm (aHR, 2.4; CI, 1.7-3.6) versus ≤75 μm, foveal subretinal fluid (aHR, 1.5; CI, 1.1-2.0) versus no subretinal fluid, and subretinal hyperreflective material (SHRM) (aHR, 1.7; CI, 1.3-2.3) versus no SHRM. Eyes with elevation of the retinal pigment epithelium had lower risk (aHR, 0.6; CI, 0.5-0.8) versus no elevation. Drug, dosing regimen, and genotype had no statistically significant association with scarring. Fibrotic scars developed in 24.7% of eyes, and nonfibrotic scars developed in 20.6% of eyes. Baseline risk factors for the scar types were similar except that eyes with larger lesion size or visual acuity <20/40 were more likely to develop fibrotic scars.ConclusionsApproximately half of eyes enrolled in CATT developed scar by 2 years. Eyes with classic neovascularization, a thicker retina, and more fluid or material under the foveal center of the retina are more likely to develop scar.

Project description:To describe morphologic and visual outcomes in eyes with angiographic cystoid macular edema (CME) treated with ranibizumab or bevacizumab for neovascular age-related macular degeneration (nAMD).Prospective cohort study within a randomized clinical trial.A total of 1185 CATT study subjects.Baseline fluorescein angiography (FA) images of all CATT study eyes were evaluated for CME. Grading of other characteristics on optical coherence tomography (OCT) and photographic images at baseline and during 2-year follow-up was completed by readers at the CATT Reading Centers. Three groups were created on the basis of baseline CME and intraretinal fluid (IRF) status: (1) CME, (2) IRF without CME, (3) neither CME nor IRF.Visual acuity (VA) and total central retinal thickness (CRT) on OCT at baseline, year 1, and year 2.Among 1131 participants with images of sufficient quality for determining CME and IRF at baseline, 92 (8.1%) had CME, 766 (67.7%) had IRF without CME, and 273 (24.1%) had neither. At baseline, eyes with CME had worse mean VA (letters) than eyes with IRF without CME and eyes with neither CME nor IRF (52 vs. 60 vs. 66 letters, P < 0.001); higher mean total CRT (?m) on OCT (514 vs. 472 vs. 404, P < 0.001); and greater hemorrhage, retinal angiomatous proliferation (RAP) lesions, and classic choroidal neovascularization (CNV). All groups showed improvement in VA at follow-up; however, the CME group started and ended with the worst VA among the 3 groups. Central retinal thickness, although higher at baseline for the CME group, was similar at 1 and 2 years follow-up for all groups. More eyes with CME (65.3%) developed scarring during 2 years of follow-up compared with eyes with IRF without CME (43.8%) and eyes with neither CME nor IRF (32.5%; P < 0.001).In CATT, eyes with CME had worse baseline and follow-up VA, although all groups showed similar rates of improvement in VA during 2 years of follow-up. Cystoid macular edema seems to be a marker for poorer visual outcomes in nAMD because of underlying baseline retinal dysfunction and subsequent scarring.

Project description:PurposeTenomodulin (TNMD) is located in the X-chromosome encoding a putative angiogenesis inhibitor which is expressed in retina. Associations of single nucleotide polymorphisms of TNMD with the prevalence of age-related macular degeneration (AMD) were examined.MethodsSix markers covering 75% of the common sequence variation in the coding region of TNMD and 10 kb up- and downstream were genotyped in a sample consisting of 89 men and 175 women with exudative AMD, 18 men and 25 women with atrophic AMD, and 55 men and 113 women without AMD. All participants were over 65 years old and did not have diabetes mellitus. Due to the chromosomal locus, the association of genotypes with AMD was assessed genderwise.ResultsThree markers, rs1155974, rs2073163, and rs7890586, were associated with a risk of AMD in women. In comparison to women with other genotypes, the women who were homozygous for the minor allele (genotypes rs1155974-TT or rs2073163-CC) had 2.6 fold (p=0.021) or 1.9 fold (p=0.067) risk for having AMD, respectively. These differences were due to the unequal prevalence of exudative AMD. In comparison to women who were homozygous for the major alleles, the women with rs1155974-TT genotype had a 2.8 fold risk (p=0.021 in additive model; p=0.022 in recessive model) for exudative AMD, and the women with rs2073163-CC genotype had a 1.8 fold risk (p=0.09 in additive model; p=0.038 in recessive model). Furthermore, women carrying the rare rs7890586-AA genotype had a significantly smaller risk for having AMD than women with the other genotypes (odds ratio 0.083; p=0.001 in recessive model), but due to the low frequency of this genotype, this finding must be interpreted cautiously. The false discovery rate was <10% for all of the aforementioned results.ConclusionsOn the basis of the putative antiangiogenic role of TNMD and the present genetic associations of TNMD with AMD in women, we suggest that TNMD could be a novel candidate gene for AMD. These results should be confirmed in further studies.

Project description:To evaluate the growth of geographic atrophy (GA) during anti-vascular endothelial growth factor (VEGF) therapy.Cohort within a clinical trial.Patients included in the Comparison of Age-related Macular Degeneration Treatments Trials (CATT).Participants were randomly assigned to injections of ranibizumab or bevacizumab and to a 2-year dosing regimen of monthly or pro re nata (PRN) or to monthly for 1 year and PRN the following year. Digital color photographs and fluorescein angiograms at baseline and 1 and 2 years were evaluated for GA, and the total area of GA was measured by 2 graders masked to treatment; differences were adjudicated. Multivariate linear mixed models of the annual change in the square root of the area included baseline demographic, treatment, and ocular characteristics on imaging as candidate risk factors.Geographic atrophy growth rate.Among 1185 participants, 86 (7.3%) had GA at baseline, 120 (10.1%) developed GA during year 1, and 36 (3.0%) developed GA during year 2. Among 194 eyes evaluable for growth, the rate was 0.43 mm/yr (standard error [SE], ±0.03 mm/year). In multivariate analysis, the growth rate was 0.37 mm/year in eyes receiving bevacizumab and 0.49 mm/year in eyes receiving ranibizumab (difference, 0.11 mm/yr; 95% confidence interval [CI], 0.01-0.22; P = 0.03). Growth rate did not differ between eyes treated monthly and PRN (P = 0.85). Eyes with subfoveal choroidal neovascularization (CNV) lesions had a lower growth rate than eyes with nonsubfoveal CNV lesions (difference, 0.12; 95% CI, 0.01-0.22; P = 0.03). Eyes with GA farther from the fovea had higher growth rates by 0.14 (95% CI, 0.01-27) mm/year for every millimeter farther from the fovea. The growth rate was 0.58 mm/year for eyes with predominantly classic lesions, 0.41 mm/year for eyes with minimally classic lesions, and 0.30 mm/year for eyes with occult only lesions (P < 0.01). The growth rate in eyes having a fellow eye with GA was higher by 0.13 mm/year (95% CI, 0.01-0.24; P = 0.03) than in eyes without GA in the fellow eye. Eyes with epiretinal membrane had a higher growth rate than eyes without epiretinal membrane (difference, 0.16; 95% CI, 0.03-0.30; P = 0.02).Geographic atrophy growth depends on several ocular factors. Ranibizumab may accelerate GA growth.

Project description:PurposeTo determine the prevalence of, risk factors for, and visual acuity (VA) correlations with outer retinal tubulation (ORT) seen on spectral-domain optical coherence tomography (SD OCT) in eyes with neovascular age-related macular degeneration (AMD) after anti-vascular endothelial growth factor (VEGF) therapy.DesignProspective cohort study within a randomized clinical trial.ParticipantsPatients with SD OCT images at weeks 56 and 104 in the Comparison of AMD Treatments Trials (CATT).MethodsParticipants in the CATT were assigned randomly to ranibizumab (0.5 mg) or bevacizumab (1.25 mg) treatment and to a monthly or pro re nata (PRN) injection-dosing regimen. A subset of eyes was imaged with SD OCT beginning at week 56. Cirrus 512×128 or Spectralis 20°×20° volume cube scan protocols were used to acquire SD OCT images. Two independent readers at the CATT OCT reading center graded scans, and a senior reader arbitrated discrepant grades. The prevalence of ORT, identified as tubular structures seen on at least 3 consecutive Cirrus B scans or 2 consecutive Spectralis B scans, was determined. The associations of patient-specific and ocular features at baseline and follow-up with ORT were evaluated by univariate and multivariate analyses.Main outcome measuresOuter retinal tubulations.ResultsSeven of 69 eyes (10.1%) at 56 weeks and 64 of 368 eyes (17.4%) at week 104 had ORTs. Absence of diabetes, poor VA, blocked fluorescence, geographic atrophy, greater lesion size, and presence of subretinal hyperreflective material at baseline were associated independently with greater risk of ORT at 104 weeks (P < 0.05). Neither drug nor dosing regimen were associated significantly with ORT. The mean VA of eyes with ORT at week 104 (58.5 Early Treatment Diabetic Retinopathy Study letters) was worse than the mean VA of eyes without ORT (68.8 letters; P < 0.0001).ConclusionAt 2 years after initiation of anti-VEGF therapy for neovascular AMD, ORTs are present in a substantial proportion of eyes. We identified baseline features that independently predict ORTs. It is important to identify ORTs because eyes with ORTs have worse VA outcomes than those without this finding.

Dataset Information

Single-Nucleotide Polymorphisms Associated With Age-Related Macular Degeneration and Lesion Phenotypes in the Comparison of Age-Related Macular Degeneration Treatments Trials.

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Single-Nucleotide Polymorphisms Associated With Age-Related Macular Degeneration and Lesion Phenotypes in the Comparison of Age-Related Macular Degeneration Treatments Trials.

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