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G. J. Pauer, G. M. Sturgill, N. S. Peachey, S. A. Hagstrom, Clinical Genomic and Proteomic AMD Study Group; Protective Effect of a Paraoxonase 1 Gene Variant in Age-Related Macular Degeneration. Invest. Ophthalmol. Vis. Sci. 2009;50(13):2822.
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Paraoxonases are a family of three enzymes involved in the metabolism of oxidized lipids. Two polymorphisms in the PON1 gene (Leu55Met and Gln192Arg) have been implicated in protection against oxidative stress in aging diseases. Because oxidative damage appears to play a role in age-related macular degeneration (AMD), we evaluated PON1 as a candidate gene for AMD.
A screen for mutations in 1037 unrelated patients with AMD was performed using SSCP. Variant bands detected by SSCP were further analyzed by direct genomic sequencing. In silico analysis of mutations were evaluated using the PolyPhen and PMut algorithms.
Six missense changes (Leu55Met, Met127Arg, His155Arg, Gln192Arg, Gln192Glu, Ala252Gly) were identified in PON1. Compared with controls, the Leu55Met allele frequency was not significantly higher in all AMD cases combined or in individual categories defined by AREDS criteria. However, when only exudative AMD patients were considered, the minor allele frequency was significantly different than controls (P = 0.02). The Gln192Arg allele frequency was significantly higher in controls than in all AMD patients combined (P < 0.0001) and when individually comparing subgroups. The heterozygous missense changes, Met127Arg, His155Arg, Gln192Glu, and Ala252Gly, showed no significant difference between patients and controls. However, Met127Arg and His155Arg are predicted to be pathogenic by computational methods, while Gln192Glu and Ala252Gly are predicted to be benign.
Our data suggest weak evidence of an association between the Leu55Met polymorphism with an increased risk of exudative AMD. Interestingly, our results indicate that the Arg192 allele may have a protective effect or a decreased susceptibility to AMD. Functional studies are needed to confirm whether this variant is an actual source of decreased AMD susceptibility and to unravel the mechanism behind these results.
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