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M. A. Morrison, H. P. Zhang, S. M. Adams, M. T. Andreoli, N. Huynh, J. W. Miller, I. K. Kim, J. Hoh, M. M. DeAngelis; Independent Validation of the Nei/Ncbi Dbgap Database: Genotypes and Haplotypes Associated With Risk of Advanced Age-Related Macular Degeneration in a Caucasian Population of European Descent. Invest. Ophthalmol. Vis. Sci. 2008;49(13):1705.
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To examine if the significantly associated SNPs derived from the genome wide allelelic association study on the AREDS cohort at the NEI (dbGAP) confer risk for neovascular age-related macular degeneration (AMD).
We ascertained 134 unrelated patients with neovascular AMD who had one sibling with normal maculae and was past the age at which the affected sibling was diagnosed, i.e., 134 extremely discordant sibpairs. Genotyping was performed by both direct sequencing and Sequenom iPLEX system technology. Smoking history was obtained via a standardized questionnaire and measured in pack-years. Single SNP analyses were conducted with McNemar’s Test (both 2 X 2 and 3 X 3 tests) and likelihood ratio tests (LRT). Conditional logistic regression was used to determine significant gene-gene interactions. LRT was used to determine the best fit for each genotypic model tested (Additive, Dominant and Recessive).
Of the 35 variants we examined (including the previously genotyped CFH rs1061170 SNP), 23 significantly modified risk of neovascular AMD. Many variants on 1q32-q22 including those in CFH, CFHR4, CFHR2, CFHR5, F13B, ASPM and ZBTB were significantly associated with AMD risk. Of these variants, single SNP analysis revealed that CFH rs572515 was the most significantly associated (P < 10-8) with AMD risk. Haplotype analysis supported our findings of single SNP analyses, demonstrating that the most significant haplotype, GATAGTTCTC, spanning CFH, CFHR4, and CFHR2 was associated with the greatest risk of developing neovascular AMD (P < 10-6). Only one SNP, rs2014307, on 10q26 (equidistant between the end of PLEKHA1 and the beginning of HTRA1) was significantly associated with AMD status (P < 10-6). After controlling for smoking history, gender and age, the most significant gene-gene interaction appears to be between rs10801575 (CFH) and rs2014307 (PLEKHA1/HTRA1) (P < 10-9). The best genotypic fit for rs10801575 and rs2014307 was the additive model based on the LRT. After applying a Bonferonni correction, no other significant interactions were identified between any other SNPs.
This is the first independent validation of the NEI dbGAP SNPs, demonstrating that alleles on 1q and 10q may predispose an individual specifically to neovascular AMD.
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