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

Daniel Ardeljan, Catherine B. Meyerle, Elvira Agron, Jie Jin Wang, Paul Mitchell, Emily Y. Chew, Jing Zhao, Arvydas Maminishkis, Chi Chao Chan, Jingsheng Tuo

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Pages (from-to)1152-1157
Number of pages6
JournalEuropean Journal of Human Genetics
Issue number10
StatePublished - Oct 2013
Externally publishedYes


  • Age-Related Eye Diseases Study
  • Blue Mountains Eye Study
  • TIMP3
  • age-related macular degeneration
  • phenotype
  • single-nucleotide polymorphism

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


Dive into the research topics of 'Influence of TIMP3/SYN3 polymorphisms on the phenotypic presentation of age-related macular degeneration'. Together they form a unique fingerprint.

Cite this