title: Analysis of the indel at the ARMS2 3'UTR in age-related macular degeneration.
abstract: 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. Functional analysis of related genetic variations could solve this puzzle. Recently, Fritsche et al. 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). To validate this indel, we sequenced our samples. 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 10 bp insertion; (2) 417 bp deletion with 27 bp insertion. The indel is significantly associated with the risk of AMD, but is also in strong LD with the non-synonymous single nucleotide polymorphism rs10490924 (A69S). We also found that ARMS2 is expressed not only in placenta and retina but also in multiple human tissues. Using quantitative PCR, we found no correlation between the indel and ARMS2 mRNA level in human retina and blood samples. 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. To our knowledge, it is the first time it has been shown that ARMS2 is widely expressed in human tissues. Conclusively, the indel at 3'UTR of ARMS2 actually contains two side-by-side indels. The indels are associated with risk of AMD, but not correlated with ARMS2 mRNA level.
authors.affiliation: Dr. John T. Macdonald Foundation Department of Human Genetics, John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL 33136, USA. gwang@med.miami.edu
authors.forename: Gaofeng
authors.initials: G
authors.lastname: Wang
authors.forename: Kylee L
authors.initials: KL
authors.lastname: Spencer
authors.forename: William K
authors.initials: WK
authors.lastname: Scott
authors.forename: Patrice
authors.initials: P
authors.lastname: Whitehead
authors.forename: Brenda L
authors.initials: BL
authors.lastname: Court
authors.forename: Juan
authors.initials: J
authors.lastname: Ayala-Haedo
authors.forename: Ping
authors.initials: P
authors.lastname: Mayo
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Schwartz
authors.forename: Jaclyn L
authors.initials: JL
authors.lastname: Kovach
authors.forename: Paul
authors.initials: P
authors.lastname: Gallins
authors.forename: Monica
authors.initials: M
authors.lastname: Polk
authors.forename: Anita
authors.initials: A
authors.lastname: Agarwal
authors.forename: Eric A
authors.initials: EA
authors.lastname: Postel
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Haines
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Pericak-Vance
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics*; D000368:Aged; D000369:Aged, 80 and over; D001483:Base Sequence; D016022:Case-Control Studies; D005260:Female; D005786:Gene Expression Regulation; D005838:Genotype; D006801:Humans; D054643:INDEL Mutation; D008268:Macular Degeneration / Q000235:genetics*; D008297:Male; D016133:Polymerase Chain Reaction; D011506:Proteins / Q000235:genetics*; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D014018:Tissue Distribution
chemical_list: D020413:3' Untranslated Regions; C514392:ARMS2 protein, human; D011506:Proteins; D012333:RNA, Messenger