title: Serum levels of lipid metabolites in age-related macular degeneration.
abstract: Age-related macular degeneration (AMD) is a neurodegenerative disease that causes adult-onset blindness. There are 2 forms of this progressive disease: wet and dry. Currently there is no cure for AMD, but several treatment options have started to emerge making early detection critical for therapeutic success. Analysis of the eyes of Abca4(-/-)Rdh8(-/-) mice that display light-induced retinal degeneration indicates that 11-cis-retinal and docosahexaenoic acid (DHA) levels were significantly decreased as compared with the eyes of control dark-adapted C57BL/6J mice. In addition, exposure to intense light correlated with higher levels of prostaglandin G2 in the eyes of Abca4(-/-)Rdh8(-/-) mice. Intense light exposure also lowered DHA levels in the eyes of wild-type C57BL/6J mice without discernible retinal degeneration. Analysis of human serum from patients with AMD recapitulated these dysregulated DHA levels and revealed dysregulation of arachidonic acid (AA) levels as well (∼32% increase in patients with AMD compared with average levels in healthy individuals). From these observations, we then built a statistical model that included levels of DHA and AA from human serum. This model had a 74% probability of correctly identifying patients with AMD from controls. Addition of a genetic analysis for one of the most prevalent amino acid substitutions in the age-related maculopathy susceptibility 2 gene linked to AMD, Ala(69)→Ser, did not improve the statistical model. Thus, we have characterized a reliable method with the potential to detect AMD without a genetic component, paving the way for a larger-scale clinical evaluation. Our studies on mouse models along with the analysis of human serum suggest that our small molecule-based model may serve as an effective tool to estimate the risk of developing AMD.
authors.affiliation: *Department of Pharmacology and Department of Ophthalmology and Visual Sciences, School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA; Polgenix, Incorporated, Cleveland, Ohio, USA; Department of Ophthalmology, Jikei University School of Medicine, Tokyo, Japan; and Louis Stokes Veterans Affairs Medical Research Center, Cleveland, Ohio, USA.
authors.forename: Tivadar
authors.initials: T
authors.lastname: Orban
authors.affiliation: *Department of Pharmacology and Department of Ophthalmology and Visual Sciences, School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA; Polgenix, Incorporated, Cleveland, Ohio, USA; Department of Ophthalmology, Jikei University School of Medicine, Tokyo, Japan; and Louis Stokes Veterans Affairs Medical Research Center, Cleveland, Ohio, USA.
authors.forename: William M
authors.initials: WM
authors.lastname: Johnson
authors.affiliation: *Department of Pharmacology and Department of Ophthalmology and Visual Sciences, School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA; Polgenix, Incorporated, Cleveland, Ohio, USA; Department of Ophthalmology, Jikei University School of Medicine, Tokyo, Japan; and Louis Stokes Veterans Affairs Medical Research Center, Cleveland, Ohio, USA.
authors.forename: Zhiqian
authors.initials: Z
authors.lastname: Dong
authors.affiliation: *Department of Pharmacology and Department of Ophthalmology and Visual Sciences, School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA; Polgenix, Incorporated, Cleveland, Ohio, USA; Department of Ophthalmology, Jikei University School of Medicine, Tokyo, Japan; and Louis Stokes Veterans Affairs Medical Research Center, Cleveland, Ohio, USA.
authors.forename: Tadao
authors.initials: T
authors.lastname: Maeda
authors.affiliation: *Department of Pharmacology and Department of Ophthalmology and Visual Sciences, School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA; Polgenix, Incorporated, Cleveland, Ohio, USA; Department of Ophthalmology, Jikei University School of Medicine, Tokyo, Japan; and Louis Stokes Veterans Affairs Medical Research Center, Cleveland, Ohio, USA.
authors.forename: Akiko
authors.initials: A
authors.lastname: Maeda
authors.affiliation: *Department of Pharmacology and Department of Ophthalmology and Visual Sciences, School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA; Polgenix, Incorporated, Cleveland, Ohio, USA; Department of Ophthalmology, Jikei University School of Medicine, Tokyo, Japan; and Louis Stokes Veterans Affairs Medical Research Center, Cleveland, Ohio, USA.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Sakai
authors.affiliation: *Department of Pharmacology and Department of Ophthalmology and Visual Sciences, School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA; Polgenix, Incorporated, Cleveland, Ohio, USA; Department of Ophthalmology, Jikei University School of Medicine, Tokyo, Japan; and Louis Stokes Veterans Affairs Medical Research Center, Cleveland, Ohio, USA.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Tsuneoka
authors.affiliation: *Department of Pharmacology and Department of Ophthalmology and Visual Sciences, School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA; Polgenix, Incorporated, Cleveland, Ohio, USA; Department of Ophthalmology, Jikei University School of Medicine, Tokyo, Japan; and Louis Stokes Veterans Affairs Medical Research Center, Cleveland, Ohio, USA.
authors.forename: John J
authors.initials: JJ
authors.lastname: Mieyal
authors.affiliation: *Department of Pharmacology and Department of Ophthalmology and Visual Sciences, School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA; Polgenix, Incorporated, Cleveland, Ohio, USA; Department of Ophthalmology, Jikei University School of Medicine, Tokyo, Japan; and Louis Stokes Veterans Affairs Medical Research Center, Cleveland, Ohio, USA kxp65@case.edu.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Palczewski
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000328:Adult; D000368:Aged; D000429:Alcohol Oxidoreductases / Q000235:genetics / Q000378:metabolism; D019943:Amino Acid Substitution; D000818:Animals; D004281:Docosahexaenoic Acids / Q000097:blood* / Q000235:genetics; D005260:Female; D006801:Humans; D008268:Macular Degeneration / Q000097:blood* / Q000235:genetics; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D008954:Models, Biological; D020125:Mutation, Missense; D012172:Retinaldehyde / Q000097:blood* / Q000235:genetics
chemical_list: D018528:ATP-Binding Cassette Transporters; D000429:Alcohol Oxidoreductases; D004281:Docosahexaenoic Acids; D012172:Retinaldehyde; C512841:Abca4 protein, mouse; C525880:HSD17B6 protein, mouse
keywords: arachidonic acid; docosahexaenoic acid; mouse model; risk evaluation; serum