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Molecular & Cellular Proteomics 8:1921-1933, 2009.
© 2009 by The American Society for Biochemistry and Molecular Biology, Inc.

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Research

Plasma Protein Pentosidine and Carboxymethyllysine, Biomarkers for Age-related Macular Degeneration^*,

Jiaqian Ni^,,¶, Xianglin Yuan^,, Jiayin Gu^,,||, Xiuzhen Yue^,, Xiaorong Gu^,, Ram H. Nagaraj^**, John W. Crabb^,,¶,||,, and The Clinical Genomic and Proteomic AMD Study Group

From the Cole Eye Institute and
Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio 44195,
¶Department of Chemistry, Cleveland State University, Cleveland, Ohio 44115,
Departments of ||Chemistry and
**Ophthalmology and Visual Sciences, Case Western Reserve University, Cleveland, Ohio 44106, and
Department of Ophthalmology, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio 44195

Age-related macular degeneration (AMD) causes severe vision loss in the elderly; early identification of AMD risk could help slow or prevent disease progression. Toward the discovery of AMD biomarkers, we quantified plasma protein N-carboxymethyllysine (CML) and pentosidine from 58 AMD and 32 control donors. CML and pentosidine are advanced glycation end products that are abundant in Bruch membrane, the extracellular matrix separating the retinal pigment epithelium from the blood-bearing choriocapillaris. We measured CML and pentosidine by LC-MS/MS and LC-fluorometry, respectively, and found higher mean levels of CML (54%) and pentosidine (64%) in AMD (p < 0.0001) relative to normal controls. Plasma protein fructosyl-lysine, a marker of early glycation, was found by amino acid analysis to be in equal amounts in control and non-diabetic AMD donors, supporting an association between AMD and increased levels of CML and pentosidine independent of other diseases like diabetes. Carboxyethylpyrrole (CEP), an oxidative modification from docosahexaenoate-containing lipids and also abundant in AMD Bruch membrane, was elevated 86% in the AMD cohort, but autoantibody titers to CEP, CML, and pentosidine were not significantly increased. Compellingly higher mean levels of CML and pentosidine were present in AMD plasma protein over a broad age range. Receiver operating curves indicate that CML, CEP adducts, and pentosidine alone discriminated between AMD and control subjects with 78, 79, and 88% accuracy, respectively, whereas CML in combination with pentosidine provided 89% accuracy, and CEP plus pentosidine provided 92% accuracy. Pentosidine levels appeared slightly altered in AMD patients with hypertension and cardiovascular disease, indicating further studies are warranted. Overall this study supports the potential utility of plasma protein CML and pentosidine as biomarkers for assessing AMD risk and susceptibility, particularly in combination with CEP adducts and with concurrent analyses of fructosyl-lysine to detect confounding factors.

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