Drusenoid Pigment Epithelial Detachment: Genetic and Clinical Characteristics.

Few studies report drusenoid pigment epithelial detachment (DPED) in Asians. In this multicenter study, we report the clinical and genetic characteristics of 76 patients with DPED, and, for comparison, 861 patients with exudative age-related macular degeneration (AMD) were included. On the initial presentation, the mean best-corrected visual acuity was 0.087 ± 0.17 (logMAR unit), and mean DPED height and width were 210 ± 132 and 1633 ± 1114 µm, respectively. Fifty-one (67%) patients showed macular neovascularization in the contralateral eye. The risk allele frequency of both ARMS2 A69S and CFH I62V was significantly higher in DPED than in typical AMD and polypoidal choroidal vasculopathy (PCV) (ARMS2 A69S risk allele frequency: DPED 77% vs. typical AMD 66% vs. PCV 57%, CFH I62V risk allele frequency: DPED 87% vs. typical AMD 73% vs. PCV 73%), although the risk allele frequency of both genes was similar between the DPED group and retinal angiomatous proliferation (RAP) group (ARMS2 A69S: p = 0.32, CFH I62V, p = 0.11). The prevalence of reticular pseudodrusen (RPD) was highest in RAP (60%), followed by DPED (22%), typical AMD (20%), and PCV (2%). Although the prevalence of RPD differs between DPED and RAP, these entities share a similar genetic background in terms of ARMS2 and CFH genes.

Genetic and environmental risk factors for reticular pseudodrusen in the EUGENDA study.

PURPOSE: The purpose of this study was to analyze genetic and nongenetic associations with reticular pseudodrusen (RPD) in patients with and without age-related macular degeneration (AMD). METHODS: This case-control study included 2,719 consecutive subjects from the prospective multicenter European Genetic Database (EUGENDA). Color fundus photographs and optical coherence tomography (OCT) scans were evaluated for the presence of AMD and RPD. Association of RPD with 39 known AMD polymorphisms and various nongenetic risk factors was evaluated. Stepwise backward variable selection via generalized linear models (GLMs) was performed based on models including the following: a) age, sex, and genetic factors and b) all predictors. Receiver operating characteristic (ROC) curves and the areas under the curve (AUCs) were determined. RESULTS: RPD were present in 262 cases (no AMD, n = 9 [0.7%; early/intermediate AMD, n = 75 [12.4%]; late AMD, n = 178 [23.8%]). ROC analysis of the genetic model including age, APOE rs2075650, ARMS2 rs10490924, CFH rs800292, CFH rs12144939, CFI rs10033900, COL8A1 rs13081855, COL10A1 rs3812111, GLI3 rs2049622, and SKIV2L rs4296082 revealed an AUC of 0.871. Considering all possible predictors, backward selection revealed a slightly different set of genetic factors, as well as the following nongenetic risk factors: smoking, rheumatoid arthritis, steroids, antiglaucomatous drugs, and past sunlight exposure; the results showed an AUC of 0.886. CONCLUSIONS: RPD share a variety of genetic and nongenetic risk factors with AMD. Future AMD grading systems should integrate RPD as an important risk phenotype.

Novel Programmed Cell Death as Therapeutic Targets in Age-Related Macular Degeneration?

Age-related macular degeneration (AMD) is a leading cause of severe visual loss among the elderly. AMD patients are tormented by progressive central blurring/loss of vision and have limited therapeutic options to date. Drusen accumulation causing retinal pigment epithelial (RPE) cell damage is the hallmark of AMD pathogenesis, in which oxidative stress and inflammation are the well-known molecular mechanisms. However, the underlying mechanisms of how RPE responds when exposed to drusen are still poorly understood. Programmed cell death (PCD) plays an important role in cellular responses to stress and the regulation of homeostasis and diseases. Apart from the classical apoptosis, recent studies also discovered novel PCD pathways such as pyroptosis, necroptosis, and ferroptosis, which may contribute to RPE cell death in AMD. This evidence may yield new treatment targets for AMD. In this review, we summarized and analyzed recent advances on the association between novel PCD and AMD, proposing PCD's role as a therapeutic new target for future AMD treatment.

Genetic and environmental risk factors for extramacular drusen.

PURPOSE: To analyze risk factors for extramacular drusen (EMD) in patients with age-related macular degeneration (AMD) and healthy control individuals. METHODS: This case-control study included 1,520 patients from the prospective multicenter European Genetic Database (EUGENDA). Color fundus photographs and optical coherence tomography scans were evaluated for the presence of AMD and EMD. EMD was considered present if ten or fewer drusen including at least one intermediate-sized drusen were detected outside the macula. Association of EMD was evaluated with various genetic and non-genetic risk factors (31 single nucleotide polymorphisms, systemic complement activation, smoking, cardiovascular factors, and sunlight exposure) using logistic regression models adjusted for age, gender, and AMD. RESULTS: EMD was found in 608 subjects (40%) and AMD in 763 (50%) of 1,520 participants. EMD was strongly associated with AMD (p = 2.83 × 10-63, odds ratio [OR] 7.63). After adjustment for AMD, age (p = 0.06, OR 1.02), female gender (p = 3.34 × 10-24, OR 4.44), history of sunlight exposure ≥ 8 h /day (p = 0.0004, OR 1.99), serum complement activation (p = 0.004, OR 1.61), and polymorphisms in ARMS2 (p = 0.00016, OR 1.43) and CFI (p = 0.043, OR 1.20) were identified as risk factors for EMD. The final prediction model including these variants showed an area under the curve of 0.820. CONCLUSIONS: The comprehensive analysis of various risk factors revealed a common genetic and pathological pathway of EMD with AMD. Future longitudinal studies are needed to evaluate the role of EMD in otherwise healthy subjects as an expanded phenotype of AMD.

Association Between Perifoveal Drusen Burden Determined by OCT and Genetic Risk in Early and Intermediate Age-Related Macular Degeneration.

Purpose: The purpose of this study was to determine associations between macular drusen parameters derived from an automatic optical coherence tomography (OCT) algorithm, nonadvanced age-related macular degeneration (AMD) stage, and genetic variants. Methods: Eyes classified as early or intermediate AMD with OCT imaging and genetic data were selected (n = 239 eyes). Drusen area and volume measurements were estimated using the Zeiss Cirrus advanced retinal pigment epithelium analysis algorithm in a perifoveal zone centered on the fovea. Associations between drusen measurements and common genetic variants in the complement and high-density lipoprotein (HDL) lipid pathways and the ARMS2/HTRA1 variant were calculated using generalized estimating equations and linear mixed models adjusting for age, sex, smoking, body mass index, and education. Results: Drusen area ≥ the median was independently associated with a higher number of risk alleles for CFH risk score and risk variants in C3 and ARMS2/HTRA1 compared with eyes with no measurable drusen. Similar results were obtained for drusen volume. When all genes were analyzed in the same model, only CFH score and ARMS2/HTRA1 were associated with drusen measurements. HDL pathway genes were not significantly related to drusen parameters. Nonadvanced AMD stages were associated with OCT-derived drusen area and volume. Conclusions: Variants in CFH and ARMS2/HTRA1, commonly associated with advanced AMD, were independently associated with an increase in drusen burden determined by OCT in an allele dose dependent manner, in eyes with early and intermediate AMD. Biomarkers such as a quantitative classification of nonadvanced AMD and other OCT-derived subphenotypes could provide earlier anatomic endpoints for clinical trials and facilitate the development of new therapies for AMD.

Prevalence, Risk, and Genetic Association of Reticular Pseudodrusen in Age-related Macular Degeneration: Age-Related Eye Disease Study 2 Report 21.

PURPOSE: To determine the prevalence of reticular pseudodrusen (RPD) in eyes with age-related macular degeneration (AMD), assess the role of RPD as an independent risk factor for late AMD development, and evaluate genetic association with RPD. DESIGN: Prospective cohort study. PARTICIPANTS: Participants with intermediate AMD in 1 or both eyes enrolled in the Age-Related Eye Disease Study 2 (AREDS2), a 5-year multicenter study of nutritional supplement. METHODS: Fundus autofluorescence (FAF) images from a subset of AREDS2 participants were evaluated at annual visits for presence of RPD. Six single nucleotide polymorphisms-rs10490924 (ARMS2), rs1061170 (CFH), rs2230199 (C3), rs116503776 and rs114254831 (C2/CFB), and rs943080 (VEGF-A)-and the genetic risk score (GRS) were assessed for association with RPD. Development of late AMD, defined as geographic atrophy (GA) or neovascular AMD (NVAMD), was identified. MAIN OUTCOME MEASURES: Prevalence of RPD, odds ratio (OR) of late AMD development, and genetic associations of RPD. RESULTS: The FAF images were evaluated for 5021 eyes (2516 participants). Reticular pseudodrusen were seen in 1186 eyes (24% of eyes, 29% of participants). Prevalence of RPD varied with baseline AREDS AMD severity level: 6% in early AMD (n = 458), 26% in intermediate AMD (n = 2606), 36% in GA (n = 682), and 19% in NVAMD (n = 1246). Mean age of participants with RPD was 79 years (standard deviation [SD], 7) and 75 years (SD, 8) in those without RPD (P < 0.0001). Reticular pseudodrusen were more frequent in female participants (65% RPD vs. 53% no RPD). Odds ratio adjusted for baseline age, gender, race, educational status, smoking, and AMD severity level for 1710 eyes at risk of developing late AMD at the next annual visit was 2.42 (95% confidence interval [CI], 1.80-3.24; P < 0.001) for GA and 1.21 (95% CI, 0.87-1.7; P = 0.26) for NVAMD. Presence of RPD was significantly associated with higher GRS (P < 0.0001) and ARMS2 risk alleles (P < 0.0001) and, at a nominal level, with C3 risk alleles (P = 0.04) and CFH risk alleles (P = 0.048 for homozygotes). CONCLUSIONS: Participants with RPD have an increased risk of progression to GA but not NVAMD. ARMS2 risk alleles and higher GRS were associated with the presence of RPD. This study suggests that RPD are an important risk marker and should be included in classification systems used for patient prognosis.

Clinical and genetic characteristics of pachydrusen in patients with exudative age-related macular degeneration.

We investigated the clinical and genetic characteristics of patients with unilateral exudative age-related macular degeneration (AMD), including typical AMD, polypoidal choroidal vasculopathy, and retinal angiomatous proliferation, in whom pachydrusen was seen. Patients with unilateral exudative AMD with at least a 12-month follow-up period were included. According to the fellow eye condition, 327 consecutive patients were classified into 4 groups: Group 0: no drusen (42.8%), Group 1: pachydrusen (12.2%), Group 2: soft drusen (30.3%), Group 3: pseudodrusen with or without soft drusen (14.7%). Development of exudative AMD in the fellow eye was retrospectively studied for a 60-month period and this inter-group comparisons were performed. Genotyping was performed for ARMS2 A69S and CFH I62V. The thickness of the choroid in the fellow eyes increased significantly in Group 1 than in other groups (all P < 1.0 × 10-7). The development of exudative AMD in the fellow eye was significantly less frequent in Group 1 than in Groups 2 or 3 (P = 0.022 and 0.0015, respectively). Risk allele frequency of ARMS2 A69S was significantly lower in Group 1 than in Group 2 and 3 (all P < 1.0 × 10-4). Patients with pachydrusen have genetic and clinical characteristics distinct from those of soft drusen and pseudodrusen.

Imaging, Genetic, and Demographic Factors Associated With Conversion to Neovascular Age-Related Macular Degeneration: Secondary Analysis of a Randomized Clinical Trial.

Importance: Risk factors associated with the development of neovascular age-related macular degeneration (AMD) have been identified. However, population size and methods to integrate imaging, genetic, and demographic factors associated with conversion to neovascular AMD are limited, specifically when treatment is administered in 1 eye. Objective: To determine the imaging, genetic, and demographic factors associated with conversion from nonneovascular to neovascular AMD in fellow eyes. Design, Setting, and Participants: This post hoc secondary analysis of the 24-month phase 3 multicenter, double-masked, active treatment-controlled HARBOR trial included 686 fellow eyes with nonneovascular AMD at baseline. Imaging features describing the presence, number, extent, density, and relative reflectivity of drusen were automatically extracted from spectral-domain optical coherence tomography scans. Genetic analysis included 34 single-nucleotide polymorphisms. Least absolute shrinkage and selection operator regression was performed to narrow imaging features. Survival analysis and Cox proportional hazards regression were performed to determine the association of the selected imaging features and genetic and demographic factors with conversion to neovascular AMD. Data were collected from November 2016 through October 2017 and analyzed from October 2017 through October 2018. Exposure: Nonneovascular AMD in the fellow eye. Main Outcomes and Measures: Features associated with conversion to neovascular AMD. Hazard ratios (HRs) and their 95% CIs were calculated. Results: Among the 686 fellow eyes included in the analysis (406 [59.2%] women; mean [SD] age, 78.12 [8.28] years), 154 (22.4%) converted to neovascular AMD. Female sex was significantly associated with conversion to neovascular AMD (HR, 1.57; 95% CI, 1.11-2.20; P = .009). After controlling for demographic and treatment effects, drusen area within 3 mm of the fovea (HR, 1.45; 95% CI, 1.24-1.69; HR for 1-SD increase, 1.36 [95% CI, 1.20-1.54]) and mean drusen reflectivity (HR, 3.97; 95% CI, 1.11-14.18; HR for 1-SD increase, 1.32 [95% CI, 1.02-1.71]) were significantly associated with conversion to neovascular AMD. In addition, 1 genetic variant (rs61941274) was found to be associated with conversion to neovascular AMD. Conclusions and Relevance: Two imaging features (total en face area of drusen restricted to a circular area 3 mm from the fovea and mean drusen reflectivity) and 1 genetic variant (ACAD10 locus) were associated with conversion to neovascular AMD. Drusen characteristics may be associated with conversion to neovascular AMD despite treatment in 1 eye. Trial Registration: ClinicalTrials.gov identifier: NCT00891735.

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

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.

Reticular Pseudodrusen in Intermediate Age-Related Macular Degeneration: Prevalence, Detection, Clinical, Environmental, and Genetic Associations.

PURPOSE: To determine the prevalence of reticular pseudodrusen (RPD) and their detection using multimodal imaging in patients with bilateral large drusen, and examine their clinical, demographic, environmental, and genetic associations. METHODS: Three hundred participants with bilateral large drusen (>125 µm) underwent color fundus photography (CFP), near-infrared reflectance (NIR), fundus autofluorescence (FAF), and spectral-domain optical coherence tomography (SD-OCT) imaging. Demographic information, smoking, and medical history were recorded, and a blood sample was obtained and genotyped to identify the risk alleles of the CFH and ARMS2 genes. RESULTS: Reticular pseudodrusen were detected in 28.2% eyes of 29.0% participants using NIR and SD-OCT combined, but CFP and FAF detected only 42% and 89%, respectively, of these eyes with RPD. Participants with RPD were significantly older than those without (P < 0.001), but there was no significant difference in sex distribution, smoking history, cardiovascular factors, and minor allele frequency of the CFH gene (P > 0.173). However, the minor allele frequency of the ARMS2 gene was significantly higher in participants with RPD (P = 0.002). The presence of RPD was also independently associated with the presence of atrophic changes (including nascent geographic atrophy and drusen-associated atrophy detected on SD-OCT; P = 0.043). CONCLUSIONS: Reticular pseudodrusen were detected on NIR and SD-OCT in more than a quarter of participants with bilateral large drusen, being often overlooked with CFP. Those with RPD had a higher frequency of the ARMS2 risk variant, and eyes with RPD were more likely to have atrophic changes. These findings are important to consider when managing patients with intermediate AMD.

[Molecular genetic analysis and clinical phenotype of a pedigree with familial dominant drusen].

OBJECTIVE: To analyze clinical features and mutations of EFEMP1 gene in a Chinese pedigree with familial dominant drusen. METHODS: Clinical features of the pedigree were studied with fundus photography, fundus fluorescein angiography and optical coherence tomography. Molecular genetic analysis was performed on the patients and unaffected individuals from the family. All coding exons of the EFEMP1 gene were amplified by polymerase chain reaction (PCR) and sequenced. The results were compared with wild-type sequences from NCBI. The proband who had suffered from choroidal neovascularization and preretinal hemorrhage received an intravitreal injection of an anti-vascular endothelial growth factor (VEGF) preparation. RESULTS: A heterozygous mutation C>T (R345W) was identified in exon 10 of the EFEMP1 gene in two affected individuals from the family. The same mutation was not detected in unaffected family members and 100 healthy individuals. Postoperative follow-up of the patient receiving intravitreal injection of anti-VEGF drug showed that visual acuity was improved and fundus appeared to be stable. CONCLUSION: The R345W mutation in EFEMP1 is responsible for the dominant drusen in this family. Intravitreal injection of anti-VEGF drug is a promising treatment for the improvement in vision.

Incidence, Progression, and Associated Risk Factors of Medium Drusen in Age-Related Macular Degeneration: Findings From the 15-Year Follow-up of an Australian Cohort.

IMPORTANCE: The natural course and prognosis of medium drusen and risk factors associated with the incidence and progression of this lesion type in age-related macular degeneration (AMD) are not well understood. OBJECTIVE: To assess the 15-year incidence and progression of medium drusen and associated risk factors. DESIGN, SETTING, AND PARTICIPANTS: Population-based cohort in the Blue Mountains region, west of Sydney, Australia. Included in the study were 3654 participants 49 years or older who attended baseline examinations of the Blue Mountains Eye Study (1992-1994), and 75.8%, 76.7%, and 56.1% of survivors who attended the 5-year, 10-year, and 15-year follow-up examinations, respectively. MAIN OUTCOMES AND MEASURES: Color retinal fundus photographs were obtained at each examination. The incidence and progression of medium drusen (maximum diameter, 63 to <125 µm) were assessed using Kaplan-Meier product-limit survival methods, controlling for competing risk of death. Factors associated with a 15-year incidence of medium drusen were assessed using discrete logistic regression models after adjusting for age, sex, smoking status, serum lipid levels, systemic and dietary factors, and CFH rs1061170 and ARMS2 rs10490924 polymorphisms. Associations between lesion characteristics and the progression to late AMD were assessed using generalized estimating equation models and eye-specific data. RESULTS: Among 1317 participants at risk, the 15-year cumulative incidence of medium drusen was 13.9% (n = 281). Increasing age (per decade older) (odds ratio [OR], 1.4; 95% CI, 1.2-1.8) and the presence of at least 3 risk alleles of the CFH rs1061170 or ARMS2 rs10490924 genes (OR, 2.1; 95% CI, 1.1-4.1) were associated with a higher incidence. There was no association between past smoking (OR, 0.8; 95% CI, 0.6-1.1) or current smoking (OR, 0.6; 95% CI, 0.4-1.1) and the development of medium drusen. The progression rate to late AMD in eyes with both medium drusen and retinal pigmentary abnormalities was 4-fold higher than that in eyes with medium drusen alone. Larger total area and central location of medium drusen were associated with a greater likelihood of the progression to worse stages of AMD. CONCLUSIONS AND RELEVANCE: Older age and the presence of CFH and ARMS2 risk alleles are 2 main risk factors associated with the development of medium drusen. The copresence of medium drusen plus retinal pigment epithelium abnormalities signals a greater risk of the progression to late AMD than the presence of medium drusen alone.

Analysis of rare variants in the CFH gene in patients with the cuticular drusen subtype of age-related macular degeneration.

PURPOSE: Age-related macular degeneration (AMD) and cuticular drusen (CD), a clinical subtype of AMD, have been linked to genetic variants in the complement factor H (CFH) gene. In this study, we aimed to investigate the frequency of rare variants in the CFH gene in 180 cases with CD. In addition, we aimed to determine the frequency of a previously reported rare, highly penetrant CFH variant (p.Arg1210Cys) in a Dutch-German non-CD-type AMD case-control cohort, and to describe the phenotype of patients carrying the p.Arg1210Cys variant. METHODS: Study subjects were selected from the European Genetic Database (EUGENDA), a joint AMD database of the Radboud University Medical Centre and the University Hospital of Cologne, and graded at the Cologne Image Reading Centre and Laboratory (CIRCL). Additionally, two CD cases were recruited from the VU Medical Centre in Amsterdam. The CFH gene was analyzed in 180 CD cases with Sanger sequencing. All identified variants were analyzed for potential damaging effects with prediction software tools Sorting Intolerant from Tolerant (SIFT) and Polymorphism Phenotyping (PolyPhen). In addition, we genotyped the p.Arg1210Cys variant in 813 non-CD type AMD cases and 1175 controls. RESULTS: Sequencing identified 11 rare, heterozygous missense variants, one frameshift variant, and one splice acceptor site variant in 16 CD cases. The p.Arg1210Cys variant was identified in two CD cases but was not identified in our Dutch-German non-CD-type AMD case-control cohort. CONCLUSIONS: The present study identified the presence of rare variants in the CFH gene in 16 (8.8%) of 180 patients with the CD subtype of AMD. The carriers of rare CFH variants displayed a significantly earlier age at onset than non-carriers (p=0.016). The rare missense variant p.Arg1210Cys was identified in two CD cases, but was not detected in 813 non-CD type AMD cases or in the 1,175 controls of our Dutch-German cohort. The current study suggests that the p.Arg1210Cys variant may be restricted to a subset of patients with the CD subtype of AMD. Detailed clinical phenotyping, including fluorescein angiography, of patients with AMD carrying the p.Arg1210Cys variant in other cohorts is required to confirm this finding.

Genetic and clinical factors associated with reticular pseudodrusen in exudative age-related macular degeneration.

BACKGROUNDS: Reticular pseudodrusen (RPD) is considered to be a distinct entity from soft drusen and a risk factor for age-related macular degeneration (AMD). In the present study, we investigate the genetic and clinical factors associated with reticular pseudodrusen (RPD) in patients with exudative AMD, including polypoidal choroidal vasculopathy (PCV), typical neovascular AMD, and retinal angiomatous proliferation (RAP). METHODS: The presence or absence of RPD was studied among 408 patients with exudative AMD in at least one eye, and the clinical characteristics of those with RPD were investigated as well as genetic polymorphisms of ARMS2 A69S (rs10490924) and CFH I62V (rs800292). Subfoveal choroidal thickness was also evaluated in a limited number of subjects using the EDI mode of spectral-domain optical coherence tomography. RESULTS: The prevalence of RPD was significantly higher in RAP eyes than in typical neovascular AMD or in PCV eyes (38.2% of 26 eyes, 13.6% of 132 eyes and 0% of 250 eyes respectively, P < 0.0001). RPD was significantly more prevalent in the elderly (P < 0.0001) and female (P < 0.0001) subjects. The subfoveal choroidal thickness was thinner in eyes with RPD than in those without (129.7 ± 61.7 µm vs 42.6 ± 84.9 µm, P < 0.0001). The frequency of risk variants of ARMS2 A69S was significantly higher in eyes with RPD than in those without RPD (85.7% vs 63.8%, P = 0.0009), although the frequency of CFH I62V was not significantly different between those with and without RPD. Logistic regression analysis revealed that age (odds ratio [OR]:1.10; 95% confidence interval [CI]: 1.04-1.18; p = 0.002), female gender (OR:4.26; 95%CI: 1.72-10.4; p = 0.002), T-allele at ARMS2 A69S (OR: 3.23; 95%CI: 1.36-7.68; p = 0.008) and RAP (OR: 4.25; 95%CI:1.49-12.1; p = 0.007) were risk factors for RPD. CONCLUSIONS: Among eyes with exudative AMD, RPD is more common in eyes with RAP having a thin choroid at the fovea, especially in old, female patients with the risk variant of ARMS2 A69S.

Risk factors associated with reticular pseudodrusen versus large soft drusen.

PURPOSE: To investigate genetic, environmental, and systemic risk factors in prospectively identified subjects with the age-related macular degeneration (AMD) phenotypes of (1) reticular pseudodrusen without large soft drusen and (2) large soft drusen without reticular pseudodrusen. DESIGN: Prospective case-case comparison. METHODS: In a clinical practice setting, patients with AMD were sequentially screened using clinical examination and scanning laser ophthalmoscopy imaging to prospectively identify subjects (n = 73) with the phenotypes of (1) reticular pseudodrusen without large soft drusen (n = 30) or (2) large soft drusen without reticular pseudodrusen (n = 43). Subjects were genotyped for 2 alleles associated with AMD, age-related maculopathy susceptibility 2 (ARMS2) and complement factor H (CFH). A questionnaire was administered to collect history of smoking, hypertension, diabetes, and hyperlipidemia, as well as personal and family history of AMD. RESULTS: The reticular pseudodrusen group was older (median age 87 vs 81 years, P = .04) and had more female subjects (83.3% vs 48.8%, P = .003), later ages of AMD onset (83 vs 70 years, P = .0005), and a greater frequency of hypertension (76.7% vs 55.8%, P = .08). No significant differences were found in the distribution of the ARMS2 risk allele (P = .4) between the reticular pseudodrusen (homozygous = 20.0%; heterozygous = 56.7%) and large soft drusen (homozygous = 19.0%; heterozygous = 42.9%) phenotypes, or in the distribution of the CHF risk allele (P = .7) between the reticular pseudodrusen (homozygous = 26.7%; heterozygous = 56.7%) and large soft drusen (homozygous = 21.4%; heterozygous = 66.7%) phenotypes. CONCLUSIONS: The reticular pseudodrusen phenotype was associated with increased age, later age of AMD onset, and female sex.

Incidence and progression of reticular drusen in age-related macular degeneration: findings from an older Australian cohort.

PURPOSE: To assess the 15-year incidence and progression of reticular drusen and associations of this lesion with age-related macular degeneration (AMD) risk factors. DESIGN: Population-based cohort. PARTICIPANTS: Blue Mountains Eye Study participants (n = 3654) 49 years of age and older attended baseline examinations; of these, 75.8%, 76.7%, and 56.1% of survivors attended 5-year, 10-year, and 15-year follow-up examinations, respectively. METHODS: Color retinal photographs were obtained and comprehensive questionnaires were administered at each visit, and DNA samples were genotyped. Fundus autofluorescence images were not available. Reticular drusen identified from photographs were confirmed with side-by-side grading using the Wisconsin AMD grading protocol. Incidence was assessed using Kaplan-Meier product limit survival methods, controlling for competing risk of death. Associations between smoking, fish consumption, serum lipids, systemic and dietary factors, the CFH single nucleotide polymorphism (SNP) rs1061170 and ARMS2 SNP rs10490924, and the 15-year incidence of reticular drusen were analyzed in discrete logistic regression models. Generalized estimating equation models were used to analyze eye-specific relationships between these risk factors and 5-year progression from reticular drusen to late AMD. MAIN OUTCOME MEASURES: Incidence and progression of reticular drusen. RESULTS: The 15-year cumulative incidence of reticular drusen was 4.0% (n = 95). Increasing age (per decade increase; odds ratio [OR], 3.4; 95% confidence interval [CI], 2.6-4.4), female sex (OR, 2.0; 95% CI, 1.3-3.2), and presence of risk alleles of CFH-rs1061170 (OR, 1.8; 95% CI, 1.3-2.4) or ARMS2-rs10490924 (OR, 3.0; 95% CI, 2.1-4.4) were associated with higher reticular drusen incidence. Current smoking at baseline predicted higher reticular drusen incidence (OR 2.1, 95% CI 1.0-4.5) after adjusting for age, sex, CFH-rs1061170 and ARMS2-rs10490924 polymorphisms. Of 118 eyes with reticular drusen, 40 (33.9%) developed late AMD over 5 years. A higher proportion of eyes with reticular drusen located outside versus within the macular area progressed to late AMD (50.0% vs. 37.8%). Dietary lutein-zeaxanthin intake was associated with decreased likelihood of progression from reticular drusen to late AMD (adjusted OR, 0.5; 95% CI, 0.3-1.0). CONCLUSIONS: Known AMD risk factors were associated with greater long-term risk of reticular drusen. Neither total area nor central location of reticular drusen predicted 5-year progression to late AMD. Increased consumption of lutein-zeaxanthin predicted a lower risk of progression.

Prevalence and genomic association of reticular pseudodrusen in age-related macular degeneration.

PURPOSE: To survey the prevalence of reticular pseudodrusen in late age-related macular degeneration (AMD) using multiple imaging methods, and to investigate the association between reticular pseudodrusen and polymorphisms in complement factor H (CFH) and age-related maculopathy susceptibility 2 (ARMS2) genes. DESIGN: Retrospective case series. METHODS: This study included 216 consecutive patients with late AMD (typical AMD, polypoidal choroidal vasculopathy [PCV], retinal angiomatous proliferation [RAP], or geographic atrophy). Eyes were assessed for reticular pseudodrusen using the blue channel of color fundus photography, infrared reflectance, fundus autofluorescence, and spectral-domain optical coherence tomography. The major AMD-associated single nucleotide polymorphisms (CFH Y402 rs1061170, CFH I62V rs800292, and ARMS2 A69S rs10490924) were genotyped. RESULTS: Forty-nine eyes of 30 patients had a reticular pattern in ≥2 imaging modalities and were diagnosed with reticular pseudodrusen. Of these, 16 had bilateral late AMD, whereas 32 of 186 patients without reticular pseudodrusen had bilateral late AMD (P < .001). The prevalence of reticular pseudodrusen was 83% in RAP, 50% in geographic atrophy, 9% in typical AMD, and 2% in PCV. The frequency of the T allele in ARMS2 A69S in patients with and without reticular pseudodrusen was 78.6% and 59.9%, respectively (P=.007). CONCLUSIONS: The prevalence of reticular pseudodrusen was low in PCV cases. About 50% of patients with reticular pseudodrusen had bilateral late AMD. The connection of ARMS2 risk allele and reticular pseudodrusen was confirmed in a Japanese population.

Association analysis of genetic and environmental risk factors in the cuticular drusen subtype of age-related macular degeneration.

PURPOSE: To assess the association of gender, cigarette smoking, body-mass index, and nine genetic risk variants with cuticular drusen (CD), a well recognized subtype of age-related macular degeneration (AMD). METHODS: A total of 757 patients with AMD, including 217 patients with CD, and 553 control individuals were interviewed with a questionnaire and underwent an ophthalmic examination. Venous blood samples were obtained for genomic DNA extraction, and genotyping was performed of single nucleotide polymorphisms previously associated with AMD. Odds ratios were calculated for patients with CD, using unaffected control individuals as a reference. Furthermore, odds ratios in patients with CD were compared to those in patients with "non-CD" AMD. RESULTS: The CD subtype of AMD was significantly associated with current smoking as well as variants in the complement factor H (CFH), age-related maculopathy susceptibility 2 (ARMS2), complement factor B/complement component 2 (CFB/C2), complement component 3 (C3), and apolipoprotein E (APOE) genes. In patients with CD, the association with the CFH Y402H risk allele was significantly higher (p=0.022), whereas the association with current smoking was significantly lower (p<0.001) than in the heterogeneous group of patients with "non-CD" AMD. CONCLUSIONS: The AMD subtype of CD was associated with previously identified genetic AMD risk factors. However, the association with the CFH Y402H risk allele appeared to be stronger, whereas the association with smoking was less pronounced when compared to AMD as a whole. This study suggests a more important role for genetic factors than environmental factors in the development of this well defined subtype of AMD. These findings stress the importance of detailed phenotyping in AMD to identify homogeneous AMD subtypes, which may be associated with different risk factors and disease mechanisms. Such studies will improve the accuracy of predictive models and the effectiveness of preventive and therapeutic options in AMD.

C-reactive protein and CFH, ARMS2/HTRA1 gene variants are independently associated with risk of macular degeneration.

PURPOSE: Genetic variants CFH and ARMS2/HTRA1 gene regions as well as high-sensitivity C-reactive protein (CRP) levels are related to age-related macular degeneration (AMD). We evaluated their independent and combined effects on risk of AMD, as well as their interactions. DESIGN: Case-control study. PARTICIPANTS: Subjects with AMD (n = 244) or no or minimal maculopathy (n = 209) in the Age Related Eye Disease Ancillary Study. METHODS: Risk factors, genotypes, and biomarkers were assessed by questionnaire, direct measurement, and analyses of blood specimens. The independent and joint effects of serum CRP and CFH (rs1061170) and ARMS2/HTRA1 (rs10490924) genotypes were assessed using logistic regression analyses, adjusting for age, gender, education, smoking, body mass index, and vitamin/mineral supplementation. MAIN OUTCOME MEASURES: We defined AMD as large drusen, geographic atrophy, or neovascular disease. RESULTS: Higher CRP levels were associated with a higher risk of AMD, controlling for genotype and demographic and behavioral risk factors, with odds ratio 2.6 for levels of 3.0 mg/L and above versus below 1.0 mg/L (95% confidence interval, 1.01-6.7). Single nucleotide polymorphisms (SNPs) in both genes were also independently associated with risk of AMD, controlling for the level of CRP and other factors. Presence of both highest level of CRP together with risk genotypes for both SNPs, conferred the highest risk of AMD (OR 5.4, 95% CI 1.4-21.1). CONCLUSIONS: High-sensitivity CRP and polymorphisms in the CFH and ARMS2/HTRA1 genes are independently associated with risk of AMD. Higher CRP level tends to confer a higher risk of AMD within most genotype groups.