Influence of TIMP3/SYN3 polymorphisms on the phenotypic presentation of age-related macular degeneration

Published Feb 21, 2013European journal of human genetics : EJHG

How TIMP3 and SYN3 gene variations relate to symptoms of age-related macular degeneration

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Abstract

The allele rs9621532 may lower the risk of developing neovascular age-related macular degeneration (nAMD).

No overall association between rs9621532 and age-related macular degeneration (AMD) was observed in three independent study cohorts.
Stratified analyses revealed a moderate protective role of rs9621532 in neovascular AMD with an odds ratio of 0.32.
A similar trend was noted in the Blue Mountains Eye Study data, although it did not reach statistical significance.
Polychotomous logistic regression suggested that carriers of rs9621532 may experience less severe forms of AMD.
In cultured retinal pigment epithelial cells, carriers of the protective rs9621532 allele showed reduced TIMP3 mRNA expression.

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Age-related macular degeneration (AMD) is a leading cause of irreversible central visual loss in the elderly. A recent genome-wide association studies (GWAS) reported that rs9621532 near the tissue inhibitor of metalloproteinase 3 (TIMP3)/synapsin III (SYN3) region of 22q12.3 is associated with AMD. In this study, we characterize its phenotypic influence on AMD using three independent study cohorts: case-control studies from the National Eye Institute Clinical Center (NEI, n=397) and the Age-Related Eye Disease Study (n=523) as well as a nested case-control study from Blue Mountains Eye Study (BMES, n=852). Comparisons between cases and controls show no association between rs9621532 and AMD in the three sample sets. However, stratifying NEI cases uncovers a moderate protective role of rs9621532 in neovascular AMD (nAMD) and the association adhered to a dominant model (odds ratios=0.32; 95% CI: 0.11-0.89; P=0.02). The BMES data followed the same pattern of association with nAMD as that seen in the NEI sample but did not reach statistical significance. Polychotomous logistic regression showed a trend that rs9621532 correlates with less severe disease, for example, with the majority of carriers having intermediate AMD rather than nAMD/geographic atrophy AMD. Functionally, rs9621532 influences TIMP3 mRNA expression in cultured primary human fetal retinal pigment epithelium (hfRPE) cells. In hfRPE donors carrying the protective rs9625132 allele, we measured a reduction in TIMP3 mRNA by quantitative RT-PCR. Our data suggest that rs9621532 carriers have a lower risk of developing nAMD, potentially because of decreased transcription of TIMP3.

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Influence of TIMP3/SYN3 polymorphisms on the phenotypic presentation of age-related macular degeneration

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