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G. J. Pauer, P. Nerone, S. Bamba, S. A. Hagstrom, Cleveland AMD Study Group; A Strong Association Between the Complement C3 Arg80Gly Polymorphism and Advanced AMD. Invest. Ophthalmol. Vis. Sci. 2008;49(13):1707. doi: https://doi.org/.
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Age-related macular degeneration (AMD) is the leading cause of severe visual impairment in the elderly. It affects the macular region of the retina which provides detailed central vision. Polymorphisms in genes coding for key regulators of the complement pathway, including CFH and CFB, have been shown to be predictors of risk for AMD. Most recently, a single nucleotide polymorphism (SNP) in a central protein within the cascade, C3, has shown an association with AMD. To test whether the Arg80Gly SNP is associated with AMD in our Cleveland cohort, we genotyped our cases and controls.
Restriction analysis was performed on 811 patients with AMD and 274 control subjects for the C3 SNP rs2230199 which is predicted to result in a substitution of glycine for arginine at position 80. The chi-square test was used for comparisons of categorical variables and allele and genotype frequencies and to check for Hardy-Weinberg equilibrium. All P values were calculated with two-sided tests. Logistic-regression analysis was used to estimate odds ratios and 95% confidence intervals.
The Arg80Gly polymorphism in the C3 gene was strongly associated with advanced AMD in our patient cohort. Compared with controls the frequency of the G allele was significantly higher in cases than controls (p <0.0005). In addition, the frequency of the GG genotype was significantly higher in cases as compared with controls (p < 0.0005). Subgroup analysis that was confined to category 4 AMD or advanced AMD (n = 615) also showed a highly significant association (p< 0.0005). The odds ratio for all AMD associated with the GG genotype compared to the CC genotype was 2.7 (95% CI 1.8 - 4.0) or twice that associated with the genotype CG. Similarly, the odds ratio for advanced AMD associated with the GG genotype compared to the CC genotype was 2.6 (95% CI 1.7 - 3.9) or twice that associated with the genotype CG.
Our results confirm a strong association between the C3 Arg80Gly polymorphism and advanced AMD, verifying the importance of C3 in the pathogenesis of AMD. It is evident that the complement pathway plays a key role in the pathogenesis of this blinding disease.
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