Publications by authors named "Gwen M Sturgill-Short"

5 Publications

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VEGFA and VEGFR2 gene polymorphisms and response to anti-vascular endothelial growth factor therapy: comparison of age-related macular degeneration treatments trials (CATT).

JAMA Ophthalmol 2014 May;132(5):521-7

Importance: Individual variation in response and duration of anti-vascular endothelial growth factor (VEGF) therapy is seen among patients with neovascular age-related macular degeneration. Identification of genetic markers that affect clinical response may result in optimization of anti-VEGF therapy.

Objective: To evaluate the pharmacogenetic relationship between genotypes of single-nucleotide polymorphisms (SNPs) in the VEGF signaling pathway and response to treatment with ranibizumab or bevacizumab for neovascular age-related macular degeneration.

Design, Setting, And Participants: In total, 835 of 1149 patients (72.7%) participating in the Comparison of Age-Related Macular Degeneration Treatments Trials (CATT) at 43 CATT clinical centers.

Intervention: Each patient was genotyped for 7 SNPs in VEGFA (rs699946, rs699947, rs833069, rs833070, rs1413711, rs2010963, and rs2146323) and 1 SNP in VEGFR2 (rs2071559) using TaqMan SNP genotyping assays.

Main Outcomes And Measures: Genotypic frequencies were compared with clinical measures of response to therapy at 1 year, including the mean visual acuity, mean change in visual acuity, at least a 15-letter increase, retinal thickness, mean change in total foveal thickness, presence of fluid on optical coherence tomography, presence of leakage on fluorescein angiography, mean change in lesion size, and mean number of injections administered. Differences in response by genotype were evaluated with tests of linear trend calculated from logistic regression models for categorical outcomes and linear regression models for continuous outcomes. The method of controlling the false discovery rate was used to adjust for multiple comparisons.

Results: For each of the measures of visual acuity evaluated, no association was observed with any of the genotypes or with the number of risk alleles. Four VEGFA SNPs demonstrated an association with retinal thickness: rs699947 (P = .03), rs833070 (P = .04), rs1413711 (P = .045), and rs2146323 (P = .006). However, adjusted P values for these associations were all statistically nonsignificant (range, P = .24 to P = .45). Among the participants in 2 as-needed groups, no association was found in the number of injections among the different genotypes or for the total number of risk alleles. The effect of risk alleles on each clinical measure did not differ by treatment group, drug, or dosing regimen (P > .01 for all).

Conclusions And Relevance: This study provides evidence that no pharmacogenetic associations exist between the studied VEGFA and VEGFR2 SNPs and response to anti-VEGF therapy.

Trial Registration: clinicaltrials.gov Identifier: NCT00593450.
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http://dx.doi.org/10.1001/jamaophthalmol.2014.109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4162123PMC
May 2014

Identification of three ABCA4 sequence variations exclusive to African American patients in a cohort of patients with Stargardt disease.

Am J Ophthalmol 2013 Dec 4;156(6):1220-1227.e2. Epub 2013 Sep 4.

Cole Eye Institute, Cleveland, Ohio.

Purpose: To describe the clinical and molecular findings in ten unrelated African American patients with Stargardt disease.

Design: Retrospective, observational case series.

Methods: We reviewed the clinical histories, examinations, and genotypes of 85 patients with molecular diagnoses of Stargardt disease. Three ABCA4 sequence variations identified exclusively in African Americans were evaluated in 300 African American controls and by in silico analysis.

Results: ABCA4 sequence changes were identified in 85 patients from 80 families, of which 11 patients identified themselves as African American. Of these 11 patients, 10 unrelated patients shared 1 of 3 ABCA4 sequence variations: c.3602T>G (p.L1201R); c.3899G>A (p.R1300Q); or c.6320G>A (p.R2107H). The minor allele frequencies in the African American control population for each variation were 7.5%, 6.3%, and 2%, respectively. This is comparable to the allele frequency in African Americans in the Exome Variant Server. In contrast, the allele frequency of all three of these variations was less than or equal to 0.05% in European Americans. Although both c.3602T>G and c.3899G>A have been reported as likely disease-causing variations, one of our control patients was homozygous for each variant, suggesting that these are nonpathogenic. In contrast, the absence of c.6320G>A in the control population in the homozygous state, combined with the results of bioinformatics analysis, support its pathogenicity.

Conclusions: Three ABCA4 sequence variations were identified exclusively in 10 unrelated African American patients: p.L1201R and p.R1300Q likely represent nonpathogenic sequence variants, whereas the p.R2107H substitution appears to be pathogenic. Characterization of population-specific disease alleles may have important implications for the development of genetic screening algorithms.
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http://dx.doi.org/10.1016/j.ajo.2013.07.008DOI Listing
December 2013

Seven new loci associated with age-related macular degeneration.

Nat Genet 2013 Apr 3;45(4):433-9, 439e1-2. Epub 2013 Mar 3.

Institute of Human Genetics, University of Regensburg, Regensburg, Germany.

Age-related macular degeneration (AMD) is a common cause of blindness in older individuals. To accelerate the understanding of AMD biology and help design new therapies, we executed a collaborative genome-wide association study, including >17,100 advanced AMD cases and >60,000 controls of European and Asian ancestry. We identified 19 loci associated at P < 5 × 10(-8). These loci show enrichment for genes involved in the regulation of complement activity, lipid metabolism, extracellular matrix remodeling and angiogenesis. Our results include seven loci with associations reaching P < 5 × 10(-8) for the first time, near the genes COL8A1-FILIP1L, IER3-DDR1, SLC16A8, TGFBR1, RAD51B, ADAMTS9 and B3GALTL. A genetic risk score combining SNP genotypes from all loci showed similar ability to distinguish cases and controls in all samples examined. Our findings provide new directions for biological, genetic and therapeutic studies of AMD.
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http://dx.doi.org/10.1038/ng.2578DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3739472PMC
April 2013

Pharmacogenetics for genes associated with age-related macular degeneration in the Comparison of AMD Treatments Trials (CATT).

Ophthalmology 2013 Mar 18;120(3):593-599. Epub 2013 Jan 18.

Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio.

Purpose: To evaluate the pharmacogenetic relationship between genotypes of single nucleotide polymorphisms (SNPs) known to be associated with age-related macular degeneration (AMD) and response to treatment with ranibizumab (Lucentis; Genentech, South San Francisco, CA) or bevacizumab (Avastin; Genentech) for neovascular AMD.

Design: Clinical trial.

Participants: Eight hundred thirty-four (73%) of 1149 patients participating in the Comparison of AMD Treatments Trials (CATT) were recruited through 43 CATT clinical centers.

Methods: Each patient was genotyped for SNPs rs1061170 (CFH), rs10490924 (ARMS2), rs11200638 (HTRA1), and rs2230199 (C3), using TaqMan SNP genotyping assays (Applied Biosystems, Foster City, CA).

Main Outcomes Measures: Genotypic frequencies were compared with clinical measures of response to therapy at one year, including mean visual acuity (VA), mean change in VA, 15-letter or more increase in VA, retinal thickness, mean change in total foveal thickness, presence of fluid on OCT, presence of leakage on fluorescein angiography (FA), mean change in lesion size, and mean number of injections administered. Differences in response by genotype were evaluated with tests of linear trend calculated from logistic regression models for categorical outcomes and linear regression models for continuous outcomes. To adjust for multiple comparisons, P≤0.01 was considered statistically significant.

Results: No statistically significant differences in response by genotype were identified for any of the clinical measures studied. Specifically, there were no high-risk alleles that predicted final VA or change in VA, the degree of anatomic response (fluid on OCT or FA, retinal thickness, change in total foveal thickness, change in lesion size), or the number of injections. Furthermore, a stepwise analysis failed to show a significant epistatic interaction among the variants analyzed; that is, response did not vary by the number of risk alleles present. The lack of association was similar whether patients were treated with ranibizumab or bevacizumab or whether they received monthly or pro re nata dosing.

Conclusions: Although specific alleles for CFH, ARMS2, HTRA1, and C3 may predict the development of AMD, they did not predict response to anti-vascular endothelial growth factor therapy.
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http://dx.doi.org/10.1016/j.ophtha.2012.11.037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3633658PMC
March 2013

Response properties of slow PIII in the Large (vls) mutant.

Doc Ophthalmol 2012 Dec 4;125(3):203-9. Epub 2012 Aug 4.

Louis Stokes Cleveland VA Medical Center, 10701 East Boulevard, Cleveland, OH, 44106, USA.

Purpose: Mouse mutants for proteins expressed in the dystrophin-glycoprotein complex at the photoreceptor terminal have electroretinogram (ERG) b-waves with a delayed onset and time course. The b-wave is defined by the sum of PII generated by depolarizing bipolar cells and slow PIII generated by Müller glial cells. In this study, we evaluated the hypothesis that the abnormalities observed in one of these mutants, Large (vls) , are caused by abnormal response properties of slow PIII.

Methods: To isolate slow PIII, we crossed the Large (vls) mutant to a mouse line (Gpr179 (nob5) ) that lacks the ERG b-wave but maintains normal photoreceptor function and in which retinal degeneration does not occur. ERGs were recorded to strobe flash stimuli after overnight dark adaptation.

Results: In comparison with control responses, the a-wave and slow PIII had comparable waveforms but were reduced in amplitude in Large (vls) mice. The magnitude of this reduction was comparable for these components, and across stimulus luminance. There was no stimulus condition where the amplitude of slow PIII was larger than control.

Conclusions: The data obtained are inconsistent with the idea that the b-wave abnormalities noted in Large (vls) mutant mice are caused by abnormal response properties of slow PIII.
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http://dx.doi.org/10.1007/s10633-012-9347-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6706866PMC
December 2012