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A. C. Silveira, M. A. Morrison, J. W. Miller, I. K. Kim, D. A. Schaumberg, B. W. Hollis, R. Chen, G. S. Hageman, M. M. DeAngelis; Genetic Data Suggest a Novel Association Between the Vitamin D Pathway and Neovascular Age-Related Macular Degeneration. Invest. Ophthalmol. Vis. Sci. 2010;51(13):2478. doi: https://doi.org/.
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Preliminary data from our laboratory suggest a protective role for lifetime UV exposure in susceptibility to age-related macular degeneration (AMD). Thus, we evaluated the genetic contribution of variation in vitamin D pathway genes and serum vitamin D levels to neovascular AMD.
Fifty-nine tagging SNPs in the vitamin D metabolism pathway genes VDR, CYP27B1, CYP24A1, and CYP27A1 were genotyped in 135 extremely discordant sibling pairs (>50 years of age) where one sibling had neovascular disease and the other sibling was AMD-free. Single SNPs and haplotypes were tested for association using FBAT. Haplotypes were constructed in a backwards step-wise selection method with SNPs that were p<0.12. Significant variation was tested for interaction with CFH, ARMS2/HTRA1, and smoking. A subset of 50 pairs from this cohort were ascertained for vitamin D serum levels.
Sera analyses showed a slight trend of higher vitamin D levels in unaffected siblings. After controlling for age, sex, smoking, CFH, and ARMS2/HTRA1 only variation in CYP24A1 influenced AMD risk. After permutation testing, the most significantly associated haplotype increased risk for neovascular AMD (p = 2 x 10-5). No interaction was found between variation in CYP24A1 and CFH, ARMS2/HTRA1, and smoking.
This is the first report that demonstrates a genetic association between the vitamin D pathway gene CYP24A1 and neovascular AMD. Based on the slight trend towards higher serum vitamin D levels in unaffected patients, vitamin D serum levels are being assayed in an expanded cohort. Studies utilizing next generation sequencing technology to pinpoint disease causality with subsequent validation in unrelated case-control and prospectively based nested case-control cohorts are ongoing.
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