Conclusively, the indel at 3′UTR of ARMS2 actually contains two side-by-side indels. To our knowledge, it is the first time it's been shown that ARMS2 is widely expressed in human tissues. The lack of functional effects of the 3′UTR indel, the amino acid substitution of rs10490924 (A69S) and strong LD between them suggest that A69S, not the indel is the variant that confers risk of AMD. Using quantitative PCR, we found no correlation between the indel and ARMS2 mRNA level in human retina and blood samples. We also found that ARMS2 is expressed not only in placenta and retina but also in multiple human tissues. The indel is significantly associated with the risk of AMD, but is also in strong LD with the non-synonymous single nucleotide polymorphism (SNP) rs10490924 (A69S). We found that this indel is even more complex and is composed of two side-by-side indels separated by 17 bp: (1) 9 bp deletion with 10bp insertion (2) 417 bp deletion with 27 bp insertion. To validate this indel, we sequenced our samples. reported that AMD is associated with unstable ARMS2 transcripts possibly caused by a complex insertion/deletion (indel consisting of a 443 bp deletion and an adjacent 54 bp insertion) in its 3′UTR (untranslated region).
Functional analysis of related genetic variations could solve this puzzle. Controversy remains as to which gene at the chromosome 10q26 locus confers risk for age-related macular degeneration (AMD) and statistical genetic analysis is confounded by the strong linkage disequilibrium (LD) across the region.
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