Protective effect of paraoxonase 1 gene variant Gln192Arg in age-related macular degeneration.
OBJECTIVE
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.


METHODS
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).


CONCLUSIONS
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.
Pauer
Gayle J T
GJ
Department of Ophthalmic Research, Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA.
Sturgill
Gwen M
GM
Peachey
Neal S
NS
Hagstrom
Stephanie A
SA
D000368:Aged; D000369:Aged, 80 and over; D043303:Aryldialkylphosphatase / Q000235:genetics*; D016022:Case-Control Studies; D004252:DNA Mutational Analysis; D017931:DNA Primers / Q000737:chemistry; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D018384:Oxidative Stress; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D018807:Polymorphism, Single-Stranded Conformational; D017422:Sequence Analysis, DNA; D057135:Wet Macular Degeneration / Q000235:genetics*
D017931:DNA Primers; D043303:Aryldialkylphosphatase; C468406:PON1 protein, human