PURPOSE: Age-related macular degeneration (AMD) is the leading cause of blindness among older adults, in which oxidative damage may play a pivotal role. Paraoxonase 1 (PON1) protects against oxidative damage and has been evaluated for its involvement in aging diseases including AMD. This study investigated whether PON1 gene polymorphisms associate with AMD. DESIGN: Case-control association study. METHODS: We studied 1037 individuals with AMD subcategorized using AREDS criteria and 370 control subjects without retinal disease. Participants were primarily Caucasian of European descent. All exons of PON1 were evaluated by single-strand conformation polymorphism and direct sequence analysis. RESULTS: Six missense changes (Leu55Met, Met127Arg, His155Arg, Gln192Arg, Gln192Glu, Ala252Gly) were identified in PON1. We observed a weak association of Leu55Met with an increased risk of wet AMD (P = .02), but not with dry AMD or when combining all patient categories. A significantly higher allele frequency for Gln192Arg was detected in controls than in the combined AMD patient population (P < .0001), and when category 2, 3, and 4 patients were separately considered (P = .004, P = .002, and P < .0001, respectively). For category 4 AMD, the Arg192 allele was significantly less prevalent in the wet form (P < .0001), but not in the dry form (P = .377). CONCLUSION: We report a weak association of PON1 Leu55Met with an increased risk of wet AMD, replicating previous reports. Our findings indicate a protective role for Gln192Arg, particularly for patients with the wet form. Gln192Glu warrants consideration, as this variant alters the same amino acid as Gln192Arg and was identified only in category 4 AMD patients. We believe that Met127Arg, His155Arg, and Ala252Gly play minor roles in AMD susceptibility because of their limited frequency and/or location within the PON1 gene. The functional and biological mechanism by which Gln192Arg is acting to decrease AMD susceptibility remains to be determined. (c) 2010 Elsevier Inc. All rights reserved.
PURPOSE: Age-related macular degeneration (AMD) is the leading cause of blindness among older adults, in which oxidative damage may play a pivotal role. Paraoxonase 1 (PON1) protects against oxidative damage and has been evaluated for its involvement in aging diseases including AMD. This study investigated whether PON1 gene polymorphisms associate with AMD. DESIGN: Case-control association study. METHODS: We studied 1037 individuals with AMD subcategorized using AREDS criteria and 370 control subjects without retinal disease. Participants were primarily Caucasian of European descent. All exons of PON1 were evaluated by single-strand conformation polymorphism and direct sequence analysis. RESULTS: Six missense changes (Leu55Met, Met127Arg, His155Arg, Gln192Arg, Gln192Glu, Ala252Gly) were identified in PON1. We observed a weak association of Leu55Met with an increased risk of wet AMD (P = .02), but not with dry AMD or when combining all patient categories. A significantly higher allele frequency for Gln192Arg was detected in controls than in the combined AMDpatient population (P < .0001), and when category 2, 3, and 4 patients were separately considered (P = .004, P = .002, and P < .0001, respectively). For category 4 AMD, the Arg192 allele was significantly less prevalent in the wet form (P < .0001), but not in the dry form (P = .377). CONCLUSION: We report a weak association of PON1Leu55Met with an increased risk of wet AMD, replicating previous reports. Our findings indicate a protective role for Gln192Arg, particularly for patients with the wet form. Gln192Glu warrants consideration, as this variant alters the same amino acid as Gln192Arg and was identified only in category 4 AMDpatients. We believe that Met127Arg, His155Arg, and Ala252Gly play minor roles in AMD susceptibility because of their limited frequency and/or location within the PON1 gene. The functional and biological mechanism by which Gln192Arg is acting to decrease AMD susceptibility remains to be determined. (c) 2010 Elsevier Inc. All rights reserved.
Authors: David S Friedman; Benita J O'Colmain; Beatriz Muñoz; Sandra C Tomany; Cathy McCarty; Paulus T V M de Jong; Barbara Nemesure; Paul Mitchell; John Kempen Journal: Arch Ophthalmol Date: 2004-04
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