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C.M. Bojanowski, C.C. Chan, E.Y. Chew, D.F. Shen, W.R. Green, J. Tuo; A Non–synonymous Variation Within Apolipoprotein E (ApoE) Is Associated With Decreased Risk of Age–Related Macular Degeneration . Invest. Ophthalmol. Vis. Sci. 2005;46(13):3001.
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Purpose: Age–related macular degeneration (AMD) is marked by an accumulation of lipid–containing drusen within Bruch’s membrane. ApoE, a CNS apolipoprotein important in lipid metabolism, is found in high levels in soft drusen and damaged neuroretina. The aim of this study is to verify the previously proposed role of ApoE single nucleotide polymorphisms (SNPs) in AMD development using an independent data set, a multiple control study design, and more advanced and precise molecular biology techniques. Methods: Genomic DNA extracted from 192 screened age–matched controls, 194 random unscreened healthy volunteers with a younger mean age, and 128 advanced AMD patients was amplified by PCR. DNA was also collected, following microdissection and whole genome amplification, from 40 archived paraffin–embedded ocular slides of pathologically diagnosed AMD patients. ApoE Cys130Arg (rs#429358) and Arg176Cys (rs#7412) (previously reported at positions 112 and 158) SNP typing was performed using both restriction fragment length polymorphism (RFLP) and Taqman techniques. Serum profiles were obtained and analyzed for the AMD patients and screened controls. Results: ApoE130R SNP distribution differed significantly between AMD patients and controls. ApoE130R allele frequency was 11.2% (27/242) in the AMD group as compared to 14.9 % (58/388) in the random controls and 19.1% (66/346) in the screened controls. The pathologically diagnosed AMD cases had the lowest allele frequency of 5% (4/80). This association is in a gene dosage effect manner. The lowest odds ratio of ApoE130R allele carrier was 0.44, p=0.001. For the ApoE176C allele frequencies: 7.3% (19/262) was found in the AMD cases, 8.6 % (33/382) in the random controls, and 9.5% (35/368) in the screened controls. Both serum cholesterol levels and ApoE130R carrier frequency were higher (217 to 198 and 34% to 28%, respectively) in the controls as compared to the AMD cases. Conclusions: The results of our study suggest that an association exists between ApoE130R and a decreased risk of AMD development. We propose that despite elevated serum cholesterol levels in the control subjects, the high ApoE130R frequency may exert a protective effect against AMD. These findings support the previously proposed role of this variant in AMD etiology. No statistically significant evidence was obtained to suggest an association between ApoE 176C and AMD although a trend was observed.
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