Proteomic and Genomic Biomarkers for Age-Related Macular Degeneration
Toward early detection of susceptibility to age-related macular degeneration (AMD), we quantified plasma carboxyethylpyrrole (CEP) oxidative protein modifications and CEP autoantibodies by ELISA in 916 AMD and 488 control donors. Mean CEP adduct and autoantibody levels were elevated in AMD plasma by ∼60 and ∼30%, respectively, and the odds ratio for both CEP markers elevated was ∼3-fold greater in AMD than in control patients. Genotyping was performed for AMD risk polymorphisms associated with age-related maculopathy susceptibility 2 (ARMS2), high-temperature requirement factor A1 (HTRA1), complement factor H (CFH), and complement C3. The AMD risk predicted for those exhibiting elevated CEP markers and risk genotypes was 2- to 3-fold greater than the risk based on genotype alone. AMD donors carrying the ARMS2 and HTRA1 risk alleles were the most likely to exhibit elevated CEP markers. Receiver operating characteristic curves suggest that CEP markers alone can discriminate between AMD and control plasma donors with ∼76% accuracy and in combination with genomic markers, provide up to ∼80% discrimination accuracy. CEP plasma biomarkers, particularly in combination with genomic markers, offer a potential early warning system for predicting susceptibility to this blinding disease.
KeywordsRisk Genotype Genomic Marker Autoantibody Titer Oxidative Protein Modification Compare Receiver Operating Characteristic Curve
This work was supported in part by US National Institute of Health grants EY015638, EY014239, GM21249, EY016072, BRTT 05–29 from the State of Ohio, a Foundation Fighting Blindness Center Grant, a Research to Prevent Blindness (RPB) Center Grant, a RPB Senior Investigator Award to JWC, a Steinbach Award to JWC, the VA Medical Research Service and the Cleveland Clinic Foundation. We thank Drs Joe G Hollyfield and Bela Anand-Apte for valuable discussions. The Clinical Genomic and Proteomic AMD Study Group was composed of the following individuals: David Barnhart OD1, William J Dupps MD1, Froncie A Gutman MD1, Peter K Kaiser MD1, Hilel Lewis MD1,5, Richard E Gans MD1,5, Bennie H Jeng MD1, Gregory S Kosmorsky DO1, Ronald R Krueger MD1,5, Ann Laurenzi OD1, Roger HS Langston, MD1, Edward J Rockwood MD1,5, William E Sax MD1, Andrew P Schachat MD1, Jonathan E Sears MD1,5, Rishi Singh MD1, Scott D Smith MD1,5, Mindy Toabe OD1, Elias I Traboulsi MD1,5, Nadia Waheed MD1, Steven E Wilson MD1,5, and Stacia S. Yaniglos OD4,6, Elisa Bala MD1,4, Sonya Bamba MD1, Sue Crowe BS1, Patrice Nerone RN1, Tiffany Ruez RN1, and Ellen Simpson RN1. JWC is a consultant for Alcon Research Ltd and Allergan, Inc. and has received funding for this research from Merck & Co and Johnson and Johnson. JWC and RGS each have a license for CEP as an inventor with Frantz Biomarkers, LLC.
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