The Relationship Between the A69S Variant With the Indel (372_815delins54) in the ARMS2 Gene, and Its Association With Age-Related Macular Degeneration

Abstract

Purpose: : The SNP rs10490924 (A69S variant) in the ARMS2 gene is associated with AMD. Recently a deletion-insertion (*372_815delins54) polymorphism in the 3’UTR of the gene has beendemonstrated to reside on the same high-risk haplotype as the SNP. The purpose of our study is to confirm the relationship between the A69S polymorphism and the indel.

Methods: : Our case-control sample consisted of 205 subjects with AMD and 123 control individuals. All individuals underwent a clinical examination by a retina specialist. Those with AMD were classified further (grade 1-4) based on the severity of their disease. Controls had a grade 0 and were ≥ 65 years old. We developed a PCR-based assay, in conjunction with a commercially available SNP assay, to genotype the indel and the A69S SNP. Standard genetic-association statistical methods were used to analyze the relationship between the indel and SNP, and their association with AMD.

Results: : We confirmed that the indel variant showed a highly significant association with AMD versus controls (40.24% vs. 23.17%, p=8.57x10-6) as did the A69S mutation (40.09% vs. 20.90%, p=3.29x10-7). The indel variant resided in most cases on the same high risk haplotype as the A69S mutation, however, 3 individuals were discordant for the indel and A69S variant.

Conclusions: : Our results replicate the previously reported association between the ARMS2 A69S variant and AMD, and independently confirm the association of AMD with the indel polymorphism. We have found exceptions, however, to the previously reported concordance between the genotypes of the indel and the A69S polymorphism suggesting an incomplete linkage between the two loci. It will be important to further define the linkage structure of the region with a focus on phenotypic effects of possible haplotypes in AMD. Future work should also focus on identifying the role of the normal ARMS2 protein, and how its absence is involved in the pathogenesis of AMD.

Keywords: age-related macular degeneration • genetics • candidate gene analysis