Proteomic Profiles in Advanced Age-Related Macular Degeneration Using an Aptamer-Based Proteomic Technology

Lynch, Anne M.; Wagner, Brandie D.; Weiss, Sophie; Wall, Kirsten; Palestine, Alan G.; Mathias, Marc T; Siringo, Frank S; Cathcart, Jennifer N.; Patnaik, Jennifer L; Drolet, Daniel; Janjić, Nebojša; Mandava, Naresh

doi:10.1167/tvst.8.1.14

Cited by 21 publications

(22 citation statements)

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“…The recruitment, exclusion/inclusion criteria and informed consent of each participant are described in detail elsewhere 35 45 46. In summary, each case and control is consented for: (1) review of the medical history, (2) collection of an ethylenediaminetetraacetic acid (EDTA) plasma sample (collected from controls at least 1 month after cataract surgery) and (3) review and disease phenotype classification of image data to include a colour fundus photo, fundus autofluorescence (FAF), near-infrared fundus reflectance (NIR) and spectral domain optical coherence tomography (SD-OCT).…”

Section: Methodsmentioning

confidence: 99%

Complement factors and reticular pseudodrusen in intermediate age-related macular degeneration staged by multimodal imaging

et al. 2020

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ObjectiveSystemic activation of the complement system in intermediate age-related macular degeneration (AMD) is understudied. Moreover, links between the presence of reticular pseudodrusen (RPD) and systemic complement dysregulation have not been studied. The aim of this study was to determine if there is a difference in plasma complement factor levels in intermediate AMD compared with controls, and if complement levels are related to the presence of RPD.Methods and analysisLevels of complement factors C1q (µg/mL), C4 (µg/mL), C2 (µg/mL), Mannose Binding Lectin (ng/mL), C4b (µg/mL), C3 (µg/mL), factor B (µg/mL), factor D (µg/mL), properdin (µg/mL), C3a (ng/mL), iC3b/C3b (ng/mL), Ba (ng/mL), factor H (µg/mL), factor I (µg/mL), C5 (µg/mL), C5a (pg/mL) and SC5b-9 (ng/mL) were measured in plasma.Results109 cases and 65 controls were included in the study. Thirty-nine (36%) cases had RPD. Significantly lower systemic levels of: C1q (OR 0.96, 95% CI 0.94 to 0.98), factor B (OR 0.98, 95% CI 0.96 to 0.99), iC3b/C3b (OR 0.97, 95% CI 0.95 to 0.98), factor H (OR 0.99, 95% CI 0.98 to 0.99), factor I (OR 0.83, 95% CI 0.77 to 0.89) and C5 (OR 0.94, 95% CI 0.90 to 0.98) were found in cases versus controls. Significantly elevated levels of: C2 (OR 1.29, 95% CI 1.07 to 1.59), C3a (OR 1.03, 95% CI 1.01 to 1.05) Ba (OR 1.03, 95% CI 1.01 to 1.05) and C5a (OR 1.04, 95% CI 1.02 to 1.07) were found in cases versus controls. Systemic levels of complement factors measured were not related to the presence of RPD.ConclusionsLevels of several systemic complement pathway factors were found to be altered in intermediate AMD. Systemic levels of complement factors were not related to RPD.

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Section: Methodsmentioning

confidence: 99%

Complement factors and reticular pseudodrusen in intermediate age-related macular degeneration staged by multimodal imaging

et al. 2020

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“…In this study we document how serum proteins report on and influence AMD appearance and progression in the eye. Previous studies of AMD patient plasma and urine reveal changes in lipid and energy metabolites however sample size has limited detection of serological protein changes, or stratification of late AMD into GA and nAMD [45][46][47][48][49][50] . The population-based AGES study with its array of biomarkers, clinical profiles, and genetic risk factors collected prospectively from participants who were aged >67 at baseline visit, and a follow up visit after five-years has enabled us to identify circulating proteins and protein networks in patients that associate with AMD stage and progression.…”

Section: Discussionmentioning

confidence: 99%

“…Two independent variants at 1q31.3, rs1061170 and intronic variant rs1410996, account for 17% of AMD risk 9 . In the most recent GWAS examining 16,144 patients with advanced AMD, 52 independent variants were found at 34 different genomic loci explaining 46.7% of the variability in AMD risk 10 . The risk variants with the largest difference between late AMD patients and healthy controls reside within the ARMS2/HTRA1 and CFH genomic loci, although for most variants, the effect size was small 10 .…”

Section: Introductionmentioning

confidence: 99%

A Proteogenomic Signature of Age-related Macular Degeneration in Blood

Emilsson

Gudmundsson

Jonmundsson

et al. 2021

Preprint

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Age-related macular degeneration (AMD) is one of the most frequent causes of visual impairment in the elderly population. The overall etiology of AMD is complex and still poorly understood, though age, obesity, smoking, and high-density lipoprotein are known risk factors. In one of the first successful reported genome-wide association studies (GWAS), common genetic variants were strongly associated with AMD, including variants within the complement factor H (CFH) gene. To date, 34 genomic regions have been linked to AMD; however, the genes that mediate the risk remain largely unknown, indicating that novel approaches to identifying causal candidates are needed. Recent advances in proteomic technology have exposed the serum proteome's depth and complexity. In the Age, Gene/Environment Susceptibility Reykjavik Study (AGES-RS), a broad population-based study of the elderly (N = 5764), levels of 4137 human serum proteins and associated networks were integrated with established genetic risk loci for AMD, revealing many predicted as well as novel proteins and pathways, linked to the disease. Serum proteins were also found to reflect AMD severity independent of genetics and predict progression from early to advanced AMD after five years in this population. A two-sample Mendelian randomization study of five proteins associated with AMD found CFHR1, CFHR5, and FUT5 to be causally related to the disease, all of which were directionally consistent with the observational estimates. This study provides a robust and unique framework for elucidating the pathobiology of AMD.

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“…We conducted this cohort study by using records and samples from an AMD research registry and repository (described in detail elsewhere [21][22][23][24] ) developed by the Department of Ophthalmology at the University of Colorado School of Medicine. For this study, we focused on patients in the registry with the intermediate form of AMD.…”

Section: Overview Of the Colorado Amd Registrymentioning

confidence: 99%

“…Moreover, the presence of RPD has been shown to be associated with an increased risk of progression to advanced AMD, specifically GA. 20 The focus of research from our group has been to investigate systemic biomarkers related to AMD. Using our AMD registry and biorepository, 21 we have recently reported several proteins linked with the presence of advanced AMD 22,23 and intermediate AMD. 24 In the present study, we build on our biomarker research and focus on a cohort of patients with the intermediate phenotype of AMD.…”

Section: Introductionmentioning

confidence: 99%

Plasma Biomarkers of Reticular Pseudodrusen and the Risk of Progression to Advanced Age-Related Macular Degeneration

Lynch

Wagner

Palestine

et al. 2020

Trans. Vis. Sci. Tech.

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Purpose To determine, using an aptamer-based technology in patients with intermediate age-related macular degeneration (AMD), (1) if there is a difference in plasma levels of 4979 proteins in patients with and without reticular pseudodrusen (RPD), and (2) if plasma levels of proteins are related to time to conversion to advanced AMD. Methods Patients with intermediate AMD and RPD were identified from an AMD registry. Relative concentrations of each protein were log (base 2) transformed and compared between patients with and without RPD using linear regression. A Cox proportional hazards survival model was fit to each aptamer to quantify associations with time to conversion. A pathway analysis was conducted in converters versus non-converters using the Reactome database. Results Of the 109 intermediate AMD patients, 39 had bilateral RPD (36%). Two proteins, TCL1A and CNDP1, were lower in patients in the intermediate AMD group with RPD. Twenty-one patients converted to advanced AMD with a median time to conversion of 25.2 months (range, 2.3–48.5 months) and median follow-up time in non-converters of 26.4 months (range, 0.03–49.7 months). Several proteins (lysozyme C, TFF3, RNAS6, and SAP3) distinguished patients who converted from those who did not convert to advanced AMD. The top conversion pathways included tumor necrosis factors bind their physiological receptors, digestion and absorption, signaling by activin, and signaling by TGF-β family members. Conclusions We identified a protein signature related to RPD, as well as to conversion to advanced AMD. The pathway analysis suggests that dysfunction of critical systemic pathways may have links to conversion to advanced AMD. Translational Relevance Biomarkers identified in plasma likely reflect systemic alterations in protein expression in patients with intermediate AMD.

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Proteomic Profiles in Advanced Age-Related Macular Degeneration Using an Aptamer-Based Proteomic Technology

Cited by 21 publications

References 43 publications

Complement factors and reticular pseudodrusen in intermediate age-related macular degeneration staged by multimodal imaging

Complement factors and reticular pseudodrusen in intermediate age-related macular degeneration staged by multimodal imaging

A Proteogenomic Signature of Age-related Macular Degeneration in Blood

Plasma Biomarkers of Reticular Pseudodrusen and the Risk of Progression to Advanced Age-Related Macular Degeneration

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