title: Influence of TIMP3/SYN3 polymorphisms on the phenotypic presentation of age-related macular degeneration.
abstract: 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.
authors: Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, MD, USA.
authors: Daniel
authors: D
authors: Ardeljan
authors: Catherine B
authors: CB
authors: Meyerle
authors: Elvira
authors: E
authors: Agron
authors: Jie Jin
authors: JJ
authors: Wang
authors: Paul
authors: P
authors: Mitchell
authors: Emily Y
authors: EY
authors: Chew
authors: Jing
authors: J
authors: Zhao
authors: Arvydas
authors: A
authors: Maminishkis
authors: Chi-Chao
authors: CC
authors: Chan
authors: Jingsheng
authors: J
authors: Tuo
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D002460:Cell Line; D005260:Female; D020022:Genetic Predisposition to Disease; D057092:Geographic Atrophy / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D010857:Pigment Epithelium of Eye / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016704:Synapsins / Q000235:genetics*; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000235:genetics* / Q000378:metabolism; D057135:Wet Macular Degeneration / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism
chemical_list: D012333:RNA, Messenger; C111812:SYN3 protein, human; D016704:Synapsins; C088390:TIMP3 protein, human; D019717:Tissue Inhibitor of Metalloproteinase-3