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B. J. Kim, M. T. Andreoli, M. A. Morrison, S. M. Adams, J. W. Miller, M. M. DeAngelis, I. K. Kim; Correlation of Advanced Age-Related Macular Degeneration Phenotype With Variants in the LOC387715/ARMS2/HTRA1 Region. Invest. Ophthalmol. Vis. Sci. 2008;49(13):2668.
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To examine if AMD risk associated SNPs in CFH and LOC387715/ARMS2/HTRA1 correlated with specific phenotypes in a neovascular age-related macular degeneration (AMD) cohort.
We ascertained 86 unrelated patients with neovascular AMD. Genotyping of CFH Y402H and 6 variants (rs10490924, rs10664316, rs11200638, rs2672598, rs1049331, rs2293870) on 10q26 was performed by direct sequencing. Parameters analyzed included unilateral vs. bilateral disease, visual acuity, age of onset, pigmentary changes, drusen size, and lesion type. The study eye was defined as the eye with active choroidal neovascularization at the time of recruitment. The mean follow-up was 3.6 years. Statistical analyses were conducted with Fisher’s exact test, a two-tailed chi-square test and ANOVA.
The most significant association was between HTRA1 SNP rs1049331 and best visual acuity recorded for the study eye during the follow-up period, the risk allele being associated with higher rates of vision worse than 20/200 (Fisher’s exact test p < .0001; Yates correction X2 p= .005). The minor variant at LOC387715/ARMS2 SNP rs10664316, which is associated with reduced risk of neovascular AMD, was significantly associated with visual acuity better than 20/200 at time of diagnosis (Fisher’s exact test p = .0104; Yates correction X2 p= .011) and throughout the follow-up period (Fisher’s exact test p = .009; Yates correction X2 p= .009). The triallelic SNP HTRA1 rs2293870 was associated with study eye RPE hyperpigmentation (Fisher’s exact test p = .026; Yates correction X2 p= .04). ANOVA demonstrated that the minor alleles of the two SNPs in linkage disequilibrium, LOC387715/ARMS2 rs10490924 and HTRA1 rs11200638, were significantly associated with an earlier age of onset (71.3 years versus 75.4 years) when compared to the homozygous state of the common allele for both of these SNPs (p = .02 and p = .03, respectively). No other significant interactions were found.
Variants in the chromosome 10q26 region shown to be associated with risk of neovascular AMD also appear to correlate with phenotypic characteristics including visual acuity outcomes, age of onset, and RPE hyperpigmentation. No association between CFH genotype and neovascular AMD phenotypes were detected. These data support the stronger influence of chromosome 10 genotypes in the pathogenesis of neovascular AMD.
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