Exclusion of TIMP3 as a candidate locus in age-related macular degeneration

Monica A. De La Paz, Margaret A. Pericak-Vance, Felicia Lennon, Jonathan L. Haines, Johanna M. Seddon

Research output: Contribution to journalArticlepeer-review

93 Scopus citations


Purpose. Age-related macular degeneration (AMD) is a genetically complex disorder. Tissue inhibitor of metalloproteinase-3 (TIMP3) on chromosome 22 has been identified as a gene that is mutated in Sorsby's fundus dystrophy, an autosomal-dominant macular dystrophy that phenotypically resembles AMD. The purpose of this study was to determine whether TIMP3 is a major susceptibility gene for the AMD phenotype. Methods. Thirty-eight multiplex families with AMD were identified in Massachusetts and North Carolina. The macular findings were graded according to a modification of the grading system used in the Age-Related Eye Disease Study, and persons with extensive drusen, any large drusen, geographic atrophy, or evidence of exudative maculopathy were coded as affected for the purpose of the analysis. Linkage analysis was performed using both model-dependent (lod score) and model- independent (sibpair) methods. For the lod score analysis, both autosomal- dominant as well as recessive low penetrance 'affected only' analyses were examined. Three markers, D22S280, D22S529, and D225268, linked tightly and flanking TIMP3 locus, were chosen for the analysis. Association studies were performed by examining one randomly chosen affected person per family and comparing the patients with AMD with a series of age, gender, and ethnically matched control subjects with no known history of AMD. Results. Lod score analysis excluded linkage in these data for an approximately 10-cm interval surrounding the TIMP3 gene for all models tested. In addition, no significant findings were observed with either the sibpair or the association study. Conclusions. No evidence of linkage or association or both was found between AMD and TIMP3 in these 38 families. These data suggest that although clinically similar, the genetic defect in Sorsby's fundus dystrophy is of a different cause than the majority of the genetic causes of AMD.

Original languageEnglish (US)
Pages (from-to)1060-1065
Number of pages6
JournalInvestigative Ophthalmology and Visual Science
Issue number6
StatePublished - 1997
Externally publishedYes


  • age-related macular degeneration
  • Sorsby's fundus dystrophy
  • tissue inhibitor of metalloproteinases-3

ASJC Scopus subject areas

  • Ophthalmology


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