Coding Variants In The ARMS2 Gene And The Risk Of Age-related Macular Degeneration

Abstract

Purpose: : Genetic variation at the chromosome 10q26 locus is strongly linked to and associated with the risk of AMD. However, it is under debate which potentially functional variants at the locus biologically contribute to the development of AMD. Recently, a common coding variant R38X in ARMS2 was reported to be inversely associated with AMD. Herein, we examined the association of AMD with three common coding variants in the ARMS2 locus: R3H, R38X and A69S with the risk of AMD.

Methods: : The case-control sample contains 1169 AMD cases and 707 controls. All participants are unrelated non-Hispanic Caucasians. Taqman SNP assays were applied for genotyping. The allelic association of each variant with AMD was assessed by 2 × 2 Χ² test and age and sex-adjusted odds ratios were estimated using logistic regression. The association of three-SNP haplotype with AMD was evaluated by the haplo.stats software package.

Results: : The variant A69S was strongly associated with the risk of AMD, whereas variants R3H and R38X were inversely associated with risk of AMD. From 4 observed haplotypes, the most frequent R-R-A was chosen as baseline neutral haplotype. Compared to haplotype R-R-A, only haplotype R-R-S was significantly associated with risk of AMD (OR = 2.09, P = 8.27x10^-16), Haplotype H-R-A exhibited a small protective effect on AMD (OR = 0.92, P = 0.001) and haplotype R-X-A has a negligible effect on AMD (OR = 0.99, P = 0.02). Further conditional analysis of sample stratification showed that once the strong effect of A69S was removed, the inverse associations of R3H and R38X were no longer significant.

Conclusions: : The inverse association of variants R3H and R38X with the risk of AMD is dependent on genotypes at A69S, suggesting that A69S could be a variant underlying the association with AMD in the ARMS2 gene.

Keywords: age-related macular degeneration • retina • genetics