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ABSTRACT: Variations in a locus at chromosome 10q26 are strongly associated with the risk of age-related macular degeneration (AMD). The most significantly associated haplotype includes a nonsynonymous SNP rs10490924 in the exon 1 of ARMS2 and rs11200638 in the promoter region of HTRA1. It is under debate which gene(s), ARMS2, HTRA1 or some other genes are functionally responsible for the genetic association. To verify whether the associated variants correlate with a higher HTRA1 expression level as previously reported, HTRA1 mRNA and protein were measured in a larger human retina-RPE-choroid samples (n = 82). Results show there is no significant change of HTRA1 mRNA level among genotypes at rs11200638, rs10490924 or an indel variant of ARMS2. Furthermore, two AMD-associated synonymous SNPs rs1049331 and rs2293870 in HTRA1 exon 1 do not change its protein level either. These results suggest that the AMD-associated variants in the chromosome 10q26 locus do not significantly affect the expression of HTRA1.
Experimental Eye Research 05/2013; · 3.26 Impact Factor
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ABSTRACT: PURPOSE OF REVIEW: Update on controversies in the surgical management of rhegmatogenous retinal detachment. RECENT FINDINGS: There are multiple new reports regarding the development and management of retinal detachment. Current use of oral fluoroquinolones may be associated with onset of retinal detachment, although the clinical relevance of this correlation is uncertain at this time and the finding has not been replicated in subsequent studies. Pars plana vitrectomy (PPV) continues to demonstrate efficacy as a primary treatment for retinal detachment, especially in pseudophakic patients. In many patients with macula-on retinal detachment, scheduling surgery after a short time delay is not necessarily deleterious and may actually be beneficial. Novel surgical tools, including bioerodible scleral buckling materials and artificial vitreous substitutes, are being investigated. SUMMARY: Retinal detachment remains an important cause of visual loss. Although current surgical techniques demonstrate high rates of anatomic and visual success, further advances will probably benefit patients with retinal detachment.
Current opinion in ophthalmology 02/2013; · 2.49 Impact Factor
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ABSTRACT: Members of the large G protein-coupled receptor (GPCR) clan are implicated in many physiological and disease processes, making them important therapeutic drug targets. In the present study, we follow up on results of a pilot study suggesting a functional relationship between glucocorticoid (GC)-induced ocular hypertension and GPR158, one of three orphan members of the GPCR Family C. GC treatment increases levels of GPR158 mRNA and protein through transcriptional mechanisms, in cultured trabecular meshwork (TBM) cells derived from the eye's aqueous outflow pathway. Like treatment with GCs, transient overexpression of GPR158 stimulates cell proliferation, while siRNA knockdown of endogenous GPR158 has the opposite effect. Both endogenous and overexpressed GPR158 show an unusual subcellular localization pattern, being found almost entirely in the nucleus. However, when cells are treated with inhibitors of clathrin-mediated endocytosis, GPR158 is shifted to the plasma membrane. Mutation of a bipartite nuclear localization signal (NLS) in the 8 helix also shifts GPR158 out of the nucleus, but in this case the protein is found in vesicles localized in the cytoplasm. These results suggest that newly synthesized GPR158 first traffics to the plasma membrane, where it rapidly undergoes endocytosis and translocation to the nucleus. Significantly, mutation of the NLS abrogates GPR158-mediated enhancement of cell proliferation, indicating a functional requirement for nuclear localization. GPR158 overexpression upregulates levels of the cell cycle regulator cyclin D1, but mutation of the NLS reverses this. Overexpression of GPR158 enhances the barrier function of a TBM cell monolayer, which is associated with an increase in the levels of tight junction proteins ZO-1 and occludin, similar to reported studies on GC treatment. Regulated paracellular permeability controls aqueous outflow facility . Since GCs stimulate GPR158 expression, the result is consistent with a role for elevation of GPR158 expression in GC-induced ocular hypertension.
PLoS ONE 01/2013; 8(2):e57843. · 4.09 Impact Factor
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ABSTRACT: There are many reasons to suspect a genetic influence on the development and progression of diabetic retinopathy, including substantial variability in disease severity among patients with similar risk factors. Linkage studies have suggested associations with chromosomes 1, 3, 12 and others. The most studied individual genes are those encoding vascular endothelial growth factor, aldose reductase, and the receptor for advanced glycation end products, all of which have shown statistically significant associations in multiple series from various parts of the world. At this time, no definite genetic associations with diabetic retinopathy have been consistently reported.This may be due to small sample sizes, differences in study design, underlying genetic differences between study populations, or other factors. As we continue to collect data, these relationships may become more clear.
Current diabetes reviews 08/2012;
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Stephen G Schwartz,
Anita Agarwal,
Jaclyn L Kovach,
Paul J Gallins,
William Cade,
Eric A Postel,
Gaofeng Wang,
Juan Ayala-Haedo,
Kylee M Spencer,
Jonathan L Haines,
Margaret A Pericak-Vance,
William K Scott
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ABSTRACT: To identify genetic associations between specific risk genes and bilateral advanced age-related macular degeneration (AMD) in a retrospective, observational case series of 1,003 patients: 173 patients with geographic atrophy in at least 1 eye and 830 patients with choroidal neovascularization in at least 1 eye.
Patients underwent clinical examination and fundus photography. The images were subsequently graded using a modified grading system adapted from the Age-Related Eye Disease Study. Genetic analysis was performed to identify genotypes at 4 AMD-associated variants (ARMS2 A69S, CFH Y402H, C3 R102G, and CFB R32Q) in these patients.
There were no statistically significant relationships between clinical findings and genotypes at CFH, C3, and CFB. The genotype at ARMS2 correlated with bilateral advanced AMD using a variety of comparisons: unilateral geographic atrophy versus bilateral geographic atrophy (P = 0.08), unilateral choroidal neovascularization versus bilateral choroidal neovascularization (P = 9.0 × 10(-8)), and unilateral late AMD versus bilateral late AMD (P = 5.9 × 10(-8)).
In this series, in patients with geographic atrophy or choroidal neovascularization in at least 1 eye, the ARMS2 A69S substitution strongly associated with geographic atrophy or choroidal neovascularization in the fellow eye. The ARMS2 A69S substitution may serve as a marker for bilateral advanced AMD.
Retina (Philadelphia, Pa.) 04/2012; 32(8):1486-91. · 2.93 Impact Factor
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ABSTRACT: To record ocular vascular events following injections of vascular endothelium growth factor (VEGF) antagonists.
Collaborative multicenter case series (48 cases), literature reviews (32 cases), and reports to the FDA (64 cases) of patients that had vascular occlusions during anti-VEGF therapy were collected and analyzed.
A total of 144 cases of ocular vascular events were identified, with these diagnosed a median of 15 days after anti-VEGF injection. The majority of patients had pre-existing risk factors for cardiovascular events and nine patients had a prior history of glaucoma. Mean visual acuity dropped by 6.4 lines with severe visual loss after injection to NLP (five eyes), LP (six eyes), and HM (two eyes). The overall risk of ocular vascular events following a VEGF antagonist injection was 0.108% in the general population and 2.61% in the diabetic population. Mean retinal arterial constriction after intravitreal bevacizumab in 13 eyes was 21% (standard deviation = 27%), and mean retinal venous constriction was 8% (standard deviation = 30%).
Ocular vascular events are rare during anti-VEGF therapy, but can lead to severe visual loss and may be caused by a number of factors including the vasoconstrictor effect of the drug, a post-injection rise of intraocular pressure, patient stress as a result of the procedure, and the patient's natural history of underlying ocular or systemic diseases. The diabetic population appears to have a tendency towards ocular vascular occlusions.
Clinical Ophthalmology 01/2012; 6:343-63.
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ABSTRACT: Over the past few years, antivascular endothelial growth factor (VEGF) therapy has become a standard treatment for neovascular age-related macular degeneration (AMD). During this time, treatment strategies have evolved from a monthly dosing schedule to individualized regimens. This paper will review the currently available anti-VEGF agents and evidence-based treatment strategies.
Journal of Ophthalmology 01/2012; 2012:786870.
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ABSTRACT: Purpose. To analyze risk factors for endophthalmitis and retinal detachment (RD) in patients with retained intraocular foreign bodies (IOFBs). Design. A retrospective, interventional, consecutive case series. Participants. All patients treated at Bascom Palmer Eye Institute for traumatic IOFBs between 1999 and 2008. Methods. Analysis of visual outcome, mechanism of injury, management, and postoperative course. Results. 108 eyes with IOFBs were identified. Endophthalmitis occurred in 7 eyes (6.4%) at presentation, and risk was higher with vegetable matter exposure (P = 0.003). All eyes with posterior segment IOFBs received intravitreal antibiotics and there were no cases of endophthalmitis after initial management. RD was identified in 6 of 108 eyes (5.5%) at presentation. Risk factors were entry more than 5 mm behind the limbus (P < 0.001) and posterior segment IOFB (P = 0.028). Postoperative RD occurred in 11 of 102 eyes (10.7%). Risk factors for postoperative RD were preoperative endophthalmitis (P = 0.001), posterior segment IOFB (P = 0.008), and retinal impact sites (P = 0.028). Conclusions. Risk factors for endophthalmitis included vegetable matter exposure and delay to initial management. Risk factors for RD were posterior entry site, posterior segment IOFB, endophthalmitis, and retinal impact sites. No eyes developed endophthalmitis after presentation.
Journal of Ophthalmology 01/2012; 2012:758526.
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ABSTRACT: Diabetic macular edema (DME) remains an important cause of visual loss in patients with diabetes mellitus. Although photocoagulation and intensive control of systemic metabolic factors have been reported to achieve improved outcomes in large randomized clinical trials (RCTs), some patients with DME continue to lose vision despite treatment. Pharmacotherapies for DME include locally and systemically administered agents. We review several agents that have been studied for the treatment of DME.
Experimental Diabetes Research 01/2012; 2012:548732. · 1.20 Impact Factor
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Experimental Eye Research 11/2011; 94(1):187-91. · 3.26 Impact Factor
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Andrew A Moshfeghi,
Philip J Rosenfeld,
Harry W Flynn, Stephen G Schwartz,
Janet L Davis,
Timothy G Murray,
William E Smiddy,
Audina M Berrocal,
Sander R Dubovy,
Wen-Hsiang Lee,
Thomas A Albini,
Geeta A Lalwani,
Jaclyn L Kovach,
Carmen A Puliafito
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ABSTRACT: To assess the rate of infectious endophthalmitis and to describe the clinical and microbiological features of eyes that develop clinically suspected endophthalmitis after an intravitreal injection of vascular endothelial growth factor antagonists.
The medical records of patients undergoing intravitreal injections of anti-vascular endothelial growth factor agents from January 1, 2005, through December 31, 2010, at a single university referral center and associated satellite clinics were retrospectively analyzed to determine the rate of infectious endophthalmitis after intravitreal anti-vascular endothelial growth factor injections.
Twelve cases (11 patients) of clinically suspected endophthalmitis were identified after a total of 60,322 injections (0.02%; 95% confidence interval, 0.0114%-0.0348%). Of the 12 cases, 11 presented within 3 days of the injection. Of the 7 culture-positive cases, 5 were because of Streptococcus species. In 4 of the 5 Streptococcus cases, final visual acuity was hand motions or worse. The rate of clinically suspected endophthalmitis was 0.018% after bevacizumab and 0.027% after ranibizumab injections.
A very low rate of endophthalmitis after intravitreal injections of anti-vascular endothelial growth factor agents was observed. Patients typically presented within 3 days of injection. Streptococcus species was the most common bacteria isolated, and it was generally associated with poor visual outcomes.
Retina (Philadelphia, Pa.) 04/2011; 31(4):662-8. · 2.93 Impact Factor
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ABSTRACT: Pharmacogenetics seeks to explain interpatient variability in response to medications by investigating genotype-phenotype correlations. There is a small but growing body of data regarding the pharmacogenetics of both nonexudative and exudative age-related macular degeneration. Most reported data concern polymorphisms in the complement factor H and age-related maculopathy susceptibility 2 genes. At this time, the data are not consistent and no definite conclusions may be drawn. As clinical trials data continue to accumulate, these relationships may become more apparent.
Journal of Ophthalmology 01/2011; 2011:252549.
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ABSTRACT: Diabetic retinopathy remains a major worldwide cause of preventable visual loss. Although photocoagulation and improved metabolic control are effective for patients with diabetic macular edema and proliferative diabetic retinopathy, some patients continue to lose vision despite treatment. Various classes of pharmacotherapy have shown promise in the treatment of diabetic retinopathy, including corticosteroids, anti-vascular endothelial growth factor agents, and others. Off-label intravitreal corticosteroids are associated with short-term anatomic and visual improvement in some patients, but these patients may require repeated intravitreal injections with cumulative risks of cataract formation, intraocular pressure elevation, and endophthalmitis. Various sustained-release corticosteroid delivery systems have been investigated for this purpose. The first to become widely available is the fluocinolone acetonide intravitreal implant (Retisert, Bausch & Lomb, Rochester, NY), which received U.S. Food and Drug Administration approval to treat chronic, noninfectious posterior segment uveitis in 2005. This device also has been investigated as a treatment for diabetic macular edema. Multiple randomized clinical trials have demonstrated medium-term anatomic and visual improvement, but the device is associated with high risks of cataract formation and intraocular pressure elevation. At this time, the device is not widely used in the treatment of diabetic retinopathy. A smaller device, designed to be injected in a clinic setting (Iluvien, Alimera Sciences, Alpharetta, GA) is currently being investigated for the treatment of diabetic macular edema. Results from a phase 3 randomized controlled trial have recently reported medium-term efficacy and safety in the treatment of diabetic macular edema. Combination photocoagulation and pharmacotherapy with these devices has not yet been reported.
Current pharmaceutical biotechnology 11/2010; 12(3):347-51. · 3.40 Impact Factor
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Dermatologic Surgery 09/2010; 36(9):1466-8. · 1.80 Impact Factor
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ABSTRACT: To study the effect of the duration from initial evaluation to repair on outcomes for fovea-sparing rhegmatogenous retinal detachment (RRD).
Retrospective, single-surgeon, consecutive case series.
Medical records were reviewed for preoperative and intraoperative factors possibly associated with visual and anatomic outcomes for all patients undergoing scleral buckling procedure (SBP) for fovea-sparing, primary RRD between 1989 and 2004.
Fifty-five percent of 199 patients had symptoms for < or = 7 days, 83% had best-corrected visual acuity (BCVA) > or = 20/40, and 33% had a RRD that had extended to within the macular arcade vessels. Eighty-five percent were operated within 3 days, including 56% within 24 hours. One case progressed to fovea-off status before surgery 4 days after initial evaluation (0.5%). The single-operation success rate was 88% and final anatomic success was 99.5% (1 patient refused reoperation). Eighty-six percent were examined postoperatively for at least 2 months; 73% had > or = 20/40 vision. The strongest predictor of postoperative BCVA was initial BCVA (r = 0.47; P < .001). There was no statistically significant difference in postoperative BCVA or single-operation success rate at any point within 3 days of initial examination. No statistically significant correlation was found between postoperative BCVA and duration of symptoms, RRD location, direction of the closest approach of the RRD to the fovea, or need for reoperation.
Progression to fovea-off status was rare in this series when a selectively urgent, but not strictly emergent, surgical approach was employed for fovea-sparing RRD.
American journal of ophthalmology 08/2010; 150(2):205-210.e2. · 3.83 Impact Factor
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Wei Chen,
Dwight Stambolian,
Albert O Edwards,
Kari E Branham,
Mohammad Othman,
Johanna Jakobsdottir,
Nirubol Tosakulwong,
Margaret A Pericak-Vance,
Peter A Campochiaro,
Michael L Klein, [......],
John R Heckenlively,
Nagahisa Yoshimura,
Sudha K Iyengar,
Peter J Francis,
Nicholas Katsanis,
Johanna M Seddon,
Jonathan L Haines,
Michael B Gorin,
Gonçalo R Abecasis,
Anand Swaroop
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ABSTRACT: We executed a genome-wide association scan for age-related macular degeneration (AMD) in 2,157 cases and 1,150 controls. Our results validate AMD susceptibility loci near CFH (P < 10(-75)), ARMS2 (P < 10(-59)), C2/CFB (P < 10(-20)), C3 (P < 10(-9)), and CFI (P < 10(-6)). We compared our top findings with the Tufts/Massachusetts General Hospital genome-wide association study of advanced AMD (821 cases, 1,709 controls) and genotyped 30 promising markers in additional individuals (up to 7,749 cases and 4,625 controls). With these data, we identified a susceptibility locus near TIMP3 (overall P = 1.1 x 10(-11)), a metalloproteinase involved in degradation of the extracellular matrix and previously implicated in early-onset maculopathy. In addition, our data revealed strong association signals with alleles at two loci (LIPC, P = 1.3 x 10(-7); CETP, P = 7.4 x 10(-7)) that were previously associated with high-density lipoprotein cholesterol (HDL-c) levels in blood. Consistent with the hypothesis that HDL metabolism is associated with AMD pathogenesis, we also observed association with AMD of HDL-c-associated alleles near LPL (P = 3.0 x 10(-3)) and ABCA1 (P = 5.6 x 10(-4)). Multilocus analysis including all susceptibility loci showed that 329 of 331 individuals (99%) with the highest-risk genotypes were cases, and 85% of these had advanced AMD. Our studies extend the catalog of AMD associated loci, help identify individuals at high risk of disease, and provide clues about underlying cellular pathways that should eventually lead to new therapies.
Proceedings of the National Academy of Sciences 04/2010; 107(16):7401-6. · 9.68 Impact Factor
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Wei Chen,
Dwight Stambolian,
Albert O. Edwards,
Kari E. Branham,
Mohammad Othman,
Johanna Jakobsdottir,
Nirubol Tosakulwong,
Margaret A. Pericak-Vance,
Peter A. Campochiaro,
Michael L. Klein, [......],
John R. Heckenlively,
Nagahisa Yoshimura,
Sudha K. Iyengar,
Peter J. Francis,
Nicholas Katsanis,
Johanna M. Seddon,
Jonathan L. Haines,
Michael B. Gorin,
Gonçalo R. Abecasis,
Anand Swaroop
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ABSTRACT: We executed a genome-wide association scan for age-related macular degeneration (AMD) in 2,157 cases and 1,150 controls. Our
results validate AMD susceptibility loci near CFH (P < 10−75), ARMS2 (P < 10−59), C2/CFB (P < 10−20), C3 (P < 10−9), and CFI (P < 10−6). We compared our top findings with the Tufts/Massachusetts General Hospital genome-wide association study of advanced AMD
(821 cases, 1,709 controls) and genotyped 30 promising markers in additional individuals (up to 7,749 cases and 4,625 controls).
With these data, we identified a susceptibility locus near TIMP3 (overall P = 1.1 × 10−11), a metalloproteinase involved in degradation of the extracellular matrix and previously implicated in early-onset maculopathy.
In addition, our data revealed strong association signals with alleles at two loci (LIPC, P = 1.3 × 10−7; CETP, P = 7.4 × 10−7) that were previously associated with high-density lipoprotein cholesterol (HDL-c) levels in blood. Consistent with the hypothesis
that HDL metabolism is associated with AMD pathogenesis, we also observed association with AMD of HDL-c—associated alleles
near LPL (P = 3.0 × 10−3) and ABCA1 (P = 5.6 × 10−4). Multilocus analysis including all susceptibility loci showed that 329 of 331 individuals (99%) with the highest-risk genotypes
were cases, and 85% of these had advanced AMD. Our studies extend the catalog of AMD associated loci, help identify individuals
at high risk of disease, and provide clues about underlying cellular pathways that should eventually lead to new therapies.
Proceedings of the National Academy of Sciences 04/2010; 107(16):7401-7406. · 9.68 Impact Factor
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ABSTRACT: The role of intravitreal triamcinolone acetonide (IVTA) for patients with diabetic macular edema is controversial. Three diabetic macular edema case studies are presented to illustrate short-term outcomes. The main outcome measures included visual acuity (VA), optical coherence tomography (OCT), macular thickening (in microns), and improvement in visual acuity. IVTA appears to have short-term efficacy in selected patients with diabetic macular edema, and it is a reasonable treatment option for patients with very poor presenting VA. A controlled prospective study to evaluate the emerging role of IVTA in combination with other treatment options for diabetic macular edema, especially among patients with poor VA at presentation, is underway through the Diabetic Retinopathy Clinical Research network.
Ophthalmic Surgery Lasers and Imaging 03/2010; · 0.62 Impact Factor
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Juan A Ayala-Haedo,
Paul J Gallins,
Patrice L Whitehead, Stephen G Schwartz,
Jaclyn L Kovach,
Eric A Postel,
Anita Agarwal,
Gaofeng Wang,
Jonathan L Haines,
Margaret A Pericak-Vance,
William K Scott
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ABSTRACT: Age-related macular degeneration (AMD) is a complex degenerative retinal disease influenced by both genetic and environmental risk factors. We assessed whether single nucleotide polymorphisms (SNPs) in the NOS2A gene increase risk and modulate the effect of smoking in AMD. 998 Caucasian subjects (712 AMD cases and 286 controls) were genotyped for 17 SNPs in NOS2A. Multivariable logistic regression models containing SNP genotypes, age, sex, smoking status and genotype/smoking interaction were constructed. SNP rs8072199 was significantly associated with AMD (OR = 1.3; 95% CI : 1.02, 1.65; P = 0.035). A significant interaction with smoking was detected at rs2248814 (P = 0.037). Stratified data by genotypes demonstrated that the association between AMD and smoking was stronger in carriers of AA genotypes (OR = 35.98; 95% CI: 3.19, 405.98) than in carriers of the AG genotype (OR = 3.05; 95% CI: 1.36, 6.74) or GG genotype (OR = 2.1; 95% CI: 0.91, 4.84). The results suggest a possible synergistic interaction of AA genotype with smoking, although the result bears replication in larger samples. Our data suggests that SNPs in the NOS2A gene are associated with increased risk for AMD and might modulate the effect of smoking on AMD.
Annals of Human Genetics 03/2010; 74(3):195-201. · 2.57 Impact Factor
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Gaofeng Wang,
Kylee L Spencer,
William K Scott,
Patrice Whitehead,
Brenda L Court,
Juan Ayala-Haedo,
Ping Mayo, Stephen G Schwartz,
Jaclyn L Kovach,
Paul Gallins,
Monica Polk,
Anita Agarwal,
Eric A Postel,
Jonathan L Haines,
Margaret A Pericak-Vance
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ABSTRACT: Controversy remains as to which gene at the chromosome 10q26 locus confers risk for age-related macular degeneration (AMD) and statistical genetic analysis is confounded by the strong linkage disequilibrium (LD) across the region. Functional analysis of related genetic variations could solve this puzzle. Recently, Fritsche et al. reported that AMD is associated with unstable ARMS2 transcripts possibly caused by a complex insertion/deletion (indel; consisting of a 443 bp deletion and an adjacent 54 bp insertion) in its 3'UTR (untranslated region). To validate this indel, we sequenced our samples. We found that this indel is even more complex and is composed of two side-by-side indels separated by 17 bp: (1) 9 bp deletion with 10 bp insertion; (2) 417 bp deletion with 27 bp insertion. The indel is significantly associated with the risk of AMD, but is also in strong LD with the non-synonymous single nucleotide polymorphism rs10490924 (A69S). We also found that ARMS2 is expressed not only in placenta and retina but also in multiple human tissues. Using quantitative PCR, we found no correlation between the indel and ARMS2 mRNA level in human retina and blood samples. The lack of functional effects of the 3'UTR indel, the amino acid substitution of rs10490924 (A69S), and strong LD between them suggest that A69S, not the indel, is the variant that confers risk of AMD. To our knowledge, it is the first time it has been shown that ARMS2 is widely expressed in human tissues. Conclusively, the indel at 3'UTR of ARMS2 actually contains two side-by-side indels. The indels are associated with risk of AMD, but not correlated with ARMS2 mRNA level.
Human Genetics 02/2010; 127(5):595-602. · 5.07 Impact Factor
