Protective Effect of Paraoxonase 1 Gene Variant Gln192Arg in Age-Related Macular Degeneration
Accepted 30 September 2009. published online 30 December 2009.
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.
aDepartment of Ophthalmic Research, Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio
bLouis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, Ohio
cDepartment of Ophthalmology, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio
dDepartment of Ophthalmology, School of Medicine, Case Western Reserve University, Cleveland, Ohio
Inquiries to Stephanie A. Hagstrom, PhD, Ophthalmic Research - i31, Cole Eye Institute, Cleveland Clinic, 9500 Euclid Ave, Cleveland, OH 44195
ABSTRACT