EXCLUSION OF TIMP3 AS A CANDIDATE LOCUS IN AGE-RELATED MACULAR DEGENERATION

Purpose. Age-related macular degeneration (AMD) is a genetically compl ex disorder. Tissue inhibitor of metalloproteinases-3 (TIMP3) on chrom osome 22 has been identified as a gene that is mutated in Sorsby's fun dus dystrophy, an autosomal-dominant macular dystrophy that phenotypic ally resembles AMD. The purpose of this study iras to determine whethe r TIMP3 is a major susceptibility gene for the AMD phenotype. Methods. Thirty-eight multiplex families with AMD were identified in Massachus etts and North Carolina. The macular findings were graded according to a modification of the grading system used in the Age-Related Eye Dise ase Study, and persons with extensive intermediate drusen, any large d rusen, geographic atrophy, or evidence of exudative maculopathy were c oded as affected for the purpose of the analysis. Linkage analysis was performed using both model-dependent (led score) and model-independen t (sibpair) methods. For the lod score analysis, both autosomaldominan t as well as recessive low penetrance ''affecteds only'' analyses were examined. Three markers, D22S280, D22S529, and D22568, linked tightly and flanking the TIMP3 locus, were chosen for the analysis. Associati on studies were performed by examining one randomly chosen affected pe rson per family and comparing the patients with AMD with a series of a ge, gender, and ethnically matched control subjects with no known hist ory of AMD. Results. Lod score analysis excluded linkage in these data for an approximately 10-cm interval surrounding the TIMP3 gene for al l models tested. In addition, no significant findings were observed wi th either the sibpair or the association study. Conclusions. No eviden ce of linkage or association or both was found between AMD and TIMP3 i n these 38 families. These data suggest that although clinically simil ar, the genetic defect in Sorsby's fundus dystrophy is of a different cause than the majority of the genetic causes of AMD.