Document Detail

Influence of TIMP3/SYN3 polymorphisms on the phenotypic presentation of age-related macular degeneration.
MedLine Citation:
PMID:  23422939     Owner:  NLM     Status:  MEDLINE    
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.
Daniel Ardeljan; Catherine B Meyerle; Elvira Agron; Jie Jin Wang; Paul Mitchell; Emily Y Chew; Jing Zhao; Arvydas Maminishkis; Chi-Chao Chan; Jingsheng Tuo
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Intramural; Research Support, Non-U.S. Gov't     Date:  2013-02-20
Journal Detail:
Title:  European journal of human genetics : EJHG     Volume:  21     ISSN:  1476-5438     ISO Abbreviation:  Eur. J. Hum. Genet.     Publication Date:  2013 Oct 
Date Detail:
Created Date:  2013-09-19     Completed Date:  2014-05-01     Revised Date:  2014-10-12    
Medline Journal Info:
Nlm Unique ID:  9302235     Medline TA:  Eur J Hum Genet     Country:  England    
Other Details:
Languages:  eng     Pagination:  1152-7     Citation Subset:  IM    
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MeSH Terms
Aged, 80 and over
Case-Control Studies
Cell Line
Genetic Predisposition to Disease
Geographic Atrophy / diagnosis,  genetics*,  metabolism
Middle Aged
Pigment Epithelium of Eye / metabolism
Polymorphism, Single Nucleotide*
RNA, Messenger / genetics,  metabolism
Synapsins / genetics*
Tissue Inhibitor of Metalloproteinase-3 / genetics*,  metabolism
Wet Macular Degeneration / diagnosis,  genetics*,  metabolism
Reg. No./Substance:
0/RNA, Messenger; 0/SYN3 protein, human; 0/Synapsins; 0/TIMP3 protein, human; 0/Tissue Inhibitor of Metalloproteinase-3

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