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Gayle J. Pauer, Craig D. Beight, Gwen M. Sturgill-Short, Neal S. Peachey, Emma M. Lessieur, Bela Anand-Apte, Stephanie A. Hagstrom; Exclusion Of TIMP3 As A Susceptibility Locus In Age-related Macular Degeneration. Invest. Ophthalmol. Vis. Sci. 2011;52(14):5265.
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A recent report from a genome-wide association scan (GWAS) for age-related macular degeneration (AMD) identified a susceptibility locus near TIMP3, a matrix metalloproteinase inhibitor that is mutated in an early onset maculopathy, Sorsby fundus dystrophy (SFD). Given this result and the phenotypic similarities between SFD and AMD, we evaluated the coding region of TIMP3 for genetic risk variants in a case-control association study.
Direct genomic sequencing of the entire TIMP3 coding region was performed on 1329 patients with AMD and 951 control subjects. All cases and controls were a subset of the original GWAS study.
Three isocoding changes (His60, Ser64, and Phe149) and one missense change (Val74Ile) were identified in TIMP3. His60 and Ser64 have been previously reported in both controls and patients with various maculopathies. The minor allele frequencies for His60 or Ser64 in our patient population was not significantly different than controls (P = 0.12 and P = 0.10, respectively). The Phe149 isocoding change was identified heterozygously in eight patients and no control subjects yielding a minor allele frequency of 0.33% (P = 0.06). The Val74Ile missense change was identified heterozygously in one control and no patients yielding a minor allele frequency of 0.054%. None of the isocoding variants are predicted to create or eliminate splice donor or acceptor sites or exonic splicing enhancer sites based on the prediction software RESCUE-ESE, NNSPLICE and Splice View.
No evidence of an association was found between AMD and the coding region of TIMP3 in our patient population.
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