Abstract:
PURPOSE:Current understanding of the genetic risk factors for age-related macular degeneration (AMD) is not sufficiently predictive of the clinical course. The VEGF pathway is a key therapeutic target for treatment of neovascular AMD; however, risk attributable to genetic variation within pathway genes is unclear. We sought to identify single nucleotide polymorphisms (SNPs) associated with AMD within the VEGF pathway. METHODS:Using a tagSNP, direct sequencing and meta-analysis approach within four ethnically diverse cohorts, we identified genetic risk present in FLT1, though not within other VEGF pathway genes KDR, VEGFA, or VASH1. We used ChIP and ELISA in functional analysis. RESULTS:The FLT1 SNPs rs9943922, rs9508034, rs2281827, rs7324510, and rs9513115 were significantly associated with increased risk of neovascular AMD. Each association was more significant after meta-analysis than in any one of the four cohorts. All associations were novel, within noncoding regions of FLT1 that do not tag for coding variants in linkage disequilibrium. Analysis of soluble FLT1 demonstrated higher expression in unaffected individuals homozygous for the FLT1 risk alleles rs9943922 (P = 0.0086) and rs7324510 (P = 0.0057). In silico analysis suggests that these variants change predicted splice sites and RNA secondary structure, and have been identified in other neovascular pathologies. These data were supported further by murine chromatin immunoprecipitation demonstrating that FLT1 is a target of Nr2e3, a nuclear receptor gene implicated in regulating an AMD pathway. CONCLUSIONS:Although exact variant functions are not known, these data demonstrate relevancy across ethnically diverse genetic backgrounds within our study and, therefore, hold potential for global efficacy.
journal_name
Invest Ophthalmol Vis Scijournal_title
Investigative ophthalmology & visual scienceauthors
Owen LA,Morrison MA,Ahn J,Woo SJ,Sato H,Robinson R,Morgan DJ,Zacharaki F,Simeonova M,Uehara H,Chakravarthy U,Hogg RE,Ambati BK,Kotoula M,Baehr W,Haider NB,Silvestri G,Miller JW,Tsironi EE,Farrer LA,Kim IK,Park Kdoi
10.1167/iovs.14-14047subject
Has Abstractpub_date
2014-05-08 00:00:00pages
3543-54issue
6eissn
0146-0404issn
1552-5783pii
iovs.14-14047journal_volume
55pub_type
杂志文章abstract::During the healing of a total corneal epithelial defect extending beyond the limbus, conjunctival transdifferentiation can be inhibited by corneal vascularization as evidenced by the lack of morphological transformation of the conjunctival epithelium into a cornea-like epithelium and the persistence of goblet cells on...
journal_title:Investigative ophthalmology & visual science
pub_type: 杂志文章
doi:
更新日期:1987-03-01 00:00:00
abstract:PURPOSE:To evaluate the importance of lens epithelial cell death in age-related cataract. To determine whether the large percentage of terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick-end labeling (TUNEL)-positive lens epithelial cells previously reported in human capsulotomy specimens results from apopto...
journal_title:Investigative ophthalmology & visual science
pub_type: 杂志文章
doi:
更新日期:1998-12-01 00:00:00
abstract:Purpose:This study quantified the thickness and depth of the lamina cribrosa (LC) and peripapillary scleral thickness in high-resolution three-dimensional (3D) fluorescent reconstructions of the optic nerve head (ONH) in eyes from donors of African (AD) and European descent (ED). Methods:A total of 64 eyes (45 ED, 19 ...
journal_title:Investigative ophthalmology & visual science
pub_type: 杂志文章
doi:10.1167/iovs.17-21842
更新日期:2017-07-01 00:00:00
abstract:PURPOSE:To assess the variability in choroidal laser Doppler flowmetry (LDF). METHODS:Five measurements of choroidal blood flow were obtained on 5 days in both eyes of 10 subjects. Reliability, sensitivity, and sample size calculations were performed. Yield, the intensity of the returning light (direct current [DC]) d...
journal_title:Investigative ophthalmology & visual science
pub_type: 杂志文章
doi:
更新日期:2002-03-01 00:00:00
abstract:PURPOSE:To determine whether integrin-linked kinase (ILK) controls the organization of the actin cytoskeleton in the trabecular meshwork (TM) by regulating integrin co-signaling. METHODS:The cell binding domain and the Heparin II (Hep II) domain of fibronectin were used to activate α5β1 and α4β1 integrin signaling, re...
journal_title:Investigative ophthalmology & visual science
pub_type: 杂志文章
doi:10.1167/iovs.10-6397
更新日期:2011-03-25 00:00:00
abstract::To investigate the pathogenesis of ocular cytomegalovirus infections, 3-week-old BALB/c mice were inoculated with 10(4) plaque-forming units of murine cytomegalovirus (MCMV) by the right anterior chamber and studied sequentially with the use of virus assays and in situ nucleic acid hybridization methods. During acute ...
journal_title:Investigative ophthalmology & visual science
pub_type: 杂志文章
doi:
更新日期:1990-08-01 00:00:00
abstract:PURPOSE:To identify the underlying mechanisms by which lipid mediator lysophosphatidic acid (LPA) acts as a growth factor in stimulating extracellular signal-regulated kinase (ERK) and phosphatidylinositol 3'-kinase (PI3K) during corneal epithelial wound healing. METHODS:Epithelial debridement wounds in cultured porci...
journal_title:Investigative ophthalmology & visual science
pub_type: 杂志文章
doi:10.1167/iovs.06-0203
更新日期:2007-02-01 00:00:00
abstract:Purpose:The purpose of this study was to establish and analyze a cell model of Leber congenital amaurosis type 16 (LCA16), which is caused by mutations in the KCNJ13 gene encoding Kir7.1, an inward-rectifying potassium ion channel. Methods:The two guide RNAs specific to the target sites in the KCNJ13 gene were designe...
journal_title:Investigative ophthalmology & visual science
pub_type: 杂志文章
doi:10.1167/iovs.61.5.38
更新日期:2020-05-11 00:00:00
abstract:PURPOSE:To localize and identify the gene and mutations causing autosomal dominant retinitis pigmentosa in a Chinese Family. METHODS:Families were ascertained and patients underwent complete ophthalmic examinations. Blood samples were collected and DNA was extracted. A linkage scan of genomic regions containing known ...
journal_title:Investigative ophthalmology & visual science
pub_type: 杂志文章
doi:10.1167/iovs.09-3725
更新日期:2010-02-01 00:00:00
abstract:PURPOSE:To test the effects of subconjunctival topotecan (TPT) in fibrin sealant (FS) in transgenic murine retinoblastoma (RB). METHODS:Growth inhibitory, apoptotic, and cell cycle effects of TPT were assayed in human RB cell lines. In a dose-escalation study, eight groups of three 10- to 14-week-old wild-type mice we...
journal_title:Investigative ophthalmology & visual science
pub_type: 杂志文章
doi:10.1167/iovs.07-0653
更新日期:2008-02-01 00:00:00
abstract:PURPOSE:To investigate macular photoreceptor structure in patients with inherited retinal degeneration using high-resolution images and to correlate the findings with clinical phenotypes and genetic mutations. METHODS:Adaptive optics scanning laser ophthalmoscopy (AOSLO) images of photoreceptors were obtained in 16 ey...
journal_title:Investigative ophthalmology & visual science
pub_type: 杂志文章
doi:10.1167/iovs.06-1422
更新日期:2007-07-01 00:00:00
abstract:Purpose:To investigate the difference in intraocular vascular endothelial growth factor (VEGF) concentration between pachychoroid neovasculopathy and neovascular age-related macular degeneration (nAMD) and its associations with responses to three monthly anti-VEGF injections as an initial treatment for the two conditio...
journal_title:Investigative ophthalmology & visual science
pub_type: 杂志文章
doi:10.1167/iovs.16-20967
更新日期:2017-01-01 00:00:00
abstract:PURPOSE:Obstructive sleep apnea (OSA) syndrome generates hypertension, atherosclerosis, and endothelial and autonomic dysfunction, which may mutually interact with ocular vascular regulation. Exercise and posture changes can be used to manipulate blood pressure, ocular perfusion pressure (OPP), or both. It was hypothes...
journal_title:Investigative ophthalmology & visual science
pub_type: 杂志文章,随机对照试验
doi:10.1167/iovs.11-7936
更新日期:2011-12-16 00:00:00
abstract:PURPOSE:The purpose of this study was to examine ocular surface and tear film, contact lens, care solution, medical, and patient-related factors that are associated with corneal staining in contact lens wearers. METHODS:In this cross-sectional/nested case-control study, in addition to the assessment of corneal stainin...
journal_title:Investigative ophthalmology & visual science
pub_type: 杂志文章
doi:10.1167/iovs.10-5757
更新日期:2011-02-28 00:00:00
abstract:PURPOSE:The increase of nerve growth factor (NGF) plasma levels in vernal keratoconjunctivitis (VKC) patients has been demonstrated previously. Results of numerous studies in vitro and in vivo have shown that NGF modulates the synthesis of substance P (SP), a neuropeptide involved in the pathogenesis of human allergic ...
journal_title:Investigative ophthalmology & visual science
pub_type: 杂志文章
doi:
更新日期:1997-09-01 00:00:00
abstract:PURPOSE:To characterize the outward chloride currents (Cl(OR)) in single acinar cells isolated from the rabbit superior lacrimal gland (RSLG) to investigate the hypothesis that Cl(OR) may have a role in regulating the volume of RSLG acini. METHODS:Cl(OR) was characterized by using patch-clamp electrophysiology. Confoc...
journal_title:Investigative ophthalmology & visual science
pub_type: 杂志文章
doi:10.1167/iovs.07-0435
更新日期:2008-12-01 00:00:00
abstract:PURPOSE:It is known that the pattern electroretinogram (PERG) of normal subjects is reduced temporarily after short-term elevation of intraocular pressure (IOP). The authors evaluated PERG changes in ocular hypertension during and after transient IOP elevation. METHODS:Steady state (8 Hz) PERGs to sinusoidal gratings ...
journal_title:Investigative ophthalmology & visual science
pub_type: 杂志文章
doi:
更新日期:1996-12-01 00:00:00
abstract::The effect of systemic hypoxia on the maintained firing rate (MFR) of single retinal ganglion cells has been measured in the cat at a constant luminance level. Systemic hypoxia was produced by reducing the percentage of oxygen in the respiratory mixture under forced ventilation so that arterial PCO2 and pH were consta...
journal_title:Investigative ophthalmology & visual science
pub_type: 杂志文章
doi:
更新日期:1981-09-01 00:00:00
abstract:PURPOSE:Corneal confocal microscopy is a reiterative, rapid, noninvasive in vivo clinical examination technique capable of imaging corneal nerve fibers. Nerve fiber tortuosity may indicate a degenerative and attempted regenerative response of nerve fibers to diabetes. The purpose of this study was to define alterations...
journal_title:Investigative ophthalmology & visual science
pub_type: 杂志文章
doi:10.1167/iovs.03-0637
更新日期:2004-02-01 00:00:00
abstract::The histological distribution of R-cognin in chick retinas was determined from embryonic day 8 through 13 wk post-hatching by indirect immunofluorescence using polyclonal anticognin. On embryonic day 8, at a developmental stage without distinct retina layers, most of the cells within the tissue exhibited fluorescence....
journal_title:Investigative ophthalmology & visual science
pub_type: 杂志文章
doi:
更新日期:1986-03-01 00:00:00
abstract::Newborn stump-tail monkeys were continuously exposed to 400 f-c of cool, white, fluorescent light for periods varying from 12 hr to 7 days. The right eye of each monkey was occluded by a patch of black velour material to serve as a control. The protected eyes retained normal ultrastructure; the exposed eyes showed pro...
journal_title:Investigative ophthalmology & visual science
pub_type: 杂志文章
doi:
更新日期:1978-02-01 00:00:00
abstract::The unscarified corneas of rabbits were inoculated with 50 microliter of 2-4 X 10(6) PFU/ml of herpes simplex virus, type 1 (HSV-1), McKrae strain in 10 separate experiments over a 12-month period. Sixty of 104 (57.7%) rabbits survived to postinoculation (PI) day 20. These sixty rabbits were swabbed with dacron-tipped...
journal_title:Investigative ophthalmology & visual science
pub_type: 杂志文章
doi:
更新日期:1985-04-01 00:00:00
abstract:PURPOSE:Photodynamic therapy (PDT) and the administration of compounds acting against vascular endothelial growth factor (anti-VEGF) are approved for the treatment of choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD). Experimental evidence that the combined use of both treatment opt...
journal_title:Investigative ophthalmology & visual science
pub_type: 杂志文章
doi:10.1167/iovs.06-1224
更新日期:2007-04-01 00:00:00
abstract:Purpose:To determine if there is structural and functional recovery of the retina from light induced retinal degeneration, and to evaluate the role of the oxidative stress response elements Nrf2, SOD1, DJ-1, and Parkin in such a recovery process. Methods:Eyes from C57BL/6J (B6J) mice and from oxidative stress response...
journal_title:Investigative ophthalmology & visual science
pub_type: 杂志文章
doi:10.1167/iovs.18-25751
更新日期:2019-03-01 00:00:00
abstract:Purpose:We investigated the accumulation of amyloid β (Aβ1-40, Aβ1-42, Aβ1-43) in the lens epithelium of patients with opacification of five different types (cortical cataract [COR]; nuclear cataract [NUC]; posterior subcapsular cataract [PSC]; retrodots [RD]; and water clefts [WC]). Methods:Samples were collected fro...
journal_title:Investigative ophthalmology & visual science
pub_type: 杂志文章
doi:10.1167/iovs.17-22065
更新日期:2017-06-01 00:00:00
abstract::Treatment of human skin and corneal fibroblasts with prednisolone-21-phosphate did not increase the capacity of these cells to replicate type I herpes simplex virus (HSV). The steroid however was found to (1) inhibit human lymphocytes from mediating antibody-dependent cell-mediated cytotoxicity (ADCC) against HSV-infe...
journal_title:Investigative ophthalmology & visual science
pub_type: 杂志文章
doi:
更新日期:1978-04-01 00:00:00
abstract:PURPOSE:To determine whether changes in the retinal blood flow in light and darkness occur in humans. METHODS; The systolic and diastolic flow velocities were measured by color Doppler in the ophthalmic and the central retinal arteries in 12 healthy individuals in light and darkness. RESULTS:In the ophthalmic artery t...
journal_title:Investigative ophthalmology & visual science
pub_type: 杂志文章
doi:
更新日期:1999-07-01 00:00:00
abstract:PURPOSE:Contraction of fibroblasts and the resultant tractional force is a contributing factor to fibrotic diseases of the eye, such as proliferative vitreoretinopathy (PVR). Transforming growth factor (TGF)-beta is abundant in the eye, and is one of the growth factors thought to contribute to the development of PVR. A...
journal_title:Investigative ophthalmology & visual science
pub_type: 杂志文章
doi:
更新日期:2002-01-01 00:00:00
abstract:PURPOSE:Subtle structural and functional neuroretinal changes have been described in human immunodeficiency virus (HIV)-infected adults without retinitis treated with combination antiretroviral therapy (cART). However, studies on this subject in HIV-infected children are scarce. This study aimed to assess the presence ...
journal_title:Investigative ophthalmology & visual science
pub_type: 杂志文章
doi:10.1167/iovs.15-16855
更新日期:2015-06-01 00:00:00
abstract::PURPOSE. To solve the shortage of donor corneas, a decellularizing method based on hypertonic saline treatment was introduced, and a favorable outcome was observed in pig-to-rabbit lamellar corneal transplantation. This study was an investigation of the efficacy of pig-to-nonhuman primate lamellar corneal transplantat...
journal_title:Investigative ophthalmology & visual science
pub_type: 杂志文章
doi:10.1167/iovs.11-7273
更新日期:2011-08-22 00:00:00