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1.  Mitochondrial Haplogroups Are Associated With Severity of Diabetic Retinopathy 
To determine if specific mitochondrial haplogroups associate with nonproliferative diabetic retinopathy (NPDR) and proliferative diabetic retinopathy (PDR).
Deidentified medical records for Caucasian patients with diabetic retinopathy (DR; 153 NPDR and 138 PDR) were obtained from BioVU, Vanderbilt University's electronic, deidentified DNA databank. An independent cohort of Caucasian patients with DR (44 NPDR and 57 PDR) from the Vanderbilt Eye Institute (VEI) was used for validation. We tested for an association between mitochondrial haplogroups and PDR among patients with DR.
In the BioVU cohort, PDR frequency among Caucasian DR patients differed significantly by mitochondrial haplogroup (P = 0.027). Replication in the VEI cohort confirmed this association (P = 0.0064). In the combined cohort, patients from the common haplogroup H were more likely to have PDR (odds ratio [OR] = 2.0 [95% confidence interval (CI) = 1.3–3.0], P = 0.0012), while patients from haplogroup Uk were less likely to have PDR (OR = 0.5 [95% CI = 0.3–0.8], P = 0.0049). In logistic regression analyses, the addition of diabetes duration, hemoglobin A1c (HgbA1c) levels, and hypertension had no effect on the associations of haplogroups H and Uk with PDR.
In this study, DR patients from mitochondrial haplogroup H were more likely to have PDR, while DR patients from haplogroup Uk were less likely to have PDR. The association was independent of the major clinical variables affecting PDR. The mitochondrial haplogroups were as strong a risk factor for PDR as were elevated HgbA1c levels.
Using BioVU, Vanderbilt's deidentified DNA databank, and an independent clinical cohort, the authors demonstrate that among patients with diabetic retinopathy, proliferative retinopathy is positively associated with European mitochondrial haplogroup H and negatively associated with haplogroup Uk.
PMCID: PMC4160073  PMID: 25118268
diabetes; diabetic retinopathy; proliferative diabetic retinopathy; genetics; mitochondrial haplogroup; mitochondrial genetics; mitochondrial DNA
2.  Elevated Transforming Growth Factor β1 in Plasma of Primary Open-Angle Glaucoma Patients 
To test the hypothesis that primary open-angle glaucoma (POAG) patients have a systemic elevation of transforming growth factor β1 (TGFβ1).
Plasma was prepared from blood samples drawn from patients of the Vanderbilt Eye Institute during clinic visits. Concentrations of total TGFβ1 and thrombospondin-1 (TSP1) in plasma were determined by ELISA. Statistical significance of differences between POAG and control samples was evaluated by Mann-Whitney test. Regression analysis was used to evaluate correlations between plasma TGFβ1 and patient age and between plasma TGFβ1 and TSP1.
Plasma samples were obtained from 148 POAG patients and 150 controls. Concentration of total TGFβ1 in the plasma of POAG patients (median = 3.25 ng/mL) was significantly higher (P < 0.0001) than in controls (median = 2.46 ng/mL). Plasma TGFβ1 was not correlated with age of patient (P = 0.17). Thrombospondin-1 concentration was also significantly higher (P < 0.0001) in POAG patients (median = 0.774 μg/mL) as compared to controls (median = 0.567 μg/mL). Plasma total TGFβ1 and TSP1 concentrations were linearly correlated (P < 0.0001).
Plasma samples from POAG patients display elevated total TGFβ1 compared to controls, consistent with elevated systemic TGFβ1 in POAG patients.
Transforming growth factor β1 concentration was determined in plasma samples from 148 control subjects and 150 POAG patients and found to be significantly elevated in plasma from POAG patients.
PMCID: PMC4142830  PMID: 25061114
glaucoma; transforming growth factor beta; plasma; platelet; aqueous humor
3.  Heritability and Genome-wide Association Study To Assess Genetic Differences Between Advanced Age-Related Macular Degeneration Subtypes  
Ophthalmology  2012;119(9):1874-1885.
To investigate whether the two subtypes of advanced age-related macular degeneration (AMD), choroidal neovascularization (CNV) and geographic atrophy (GA), segregate separately in families and to identify which genetic variants are associated with these two subtypes.
Sibling correlation study and genome-wide association study (GWAS)
For the sibling correlation study, we included 209 sibling pairs with advanced AMD. For the GWAS, we included 2594 participants with advanced AMD subtypes and 4134 controls. Replication cohorts included 5383 advanced AMD participants and 15,240 controls.
Participants had AMD grade assigned based on fundus photography and/or examination. To determine heritability of advanced AMD subtypes, we performed a sibling correlation study. For the GWAS, we conducted genome-wide genotyping and imputed 6,036,699 single nucleotide polymorphism (SNPs). We then analyzed SNPs with a generalized linear model controlling for genotyping platform and genetic ancestry. The most significant associations were evaluated in independent cohorts.
Main Outcome Measures
Concordance of advanced AMD subtypes in sibling pairs and associations between SNPs with GA and CNV advanced AMD subtypes.
The difference between the observed and expected proportion of siblings concordant for the same subtype of advanced AMD was different to a statistically significant degree (P=4.2 x 10−5) meaning that siblings of probands with CNV or GA are more likely to develop CNV or GA, respectively. In the analysis comparing participants with CNV to those with GA, we observed a statistically significant association at the ARMS2/HTRA1 locus [rs10490924, odds ratio (OR)=1.47, P=4.3 ×10−9] which was confirmed in the replication samples (OR=1.38, P=7.4 x 10−14 for combined discovery and replication analysis).
Whether a patient with AMD develops CNV vs. GA is determined in part by genetic variation. In this large GWAS meta-analysis and replication analysis, the ARMS2/HTRA1 locus confers increased risk for both advanced AMD subtypes but imparts greater risk for CNV than for GA. This locus explains a small proportion of the excess sibling correlation for advanced AMD subtype. Other loci were detected with suggestive associations which differ for advanced AMD subtypes and deserve follow-up in additional studies.
PMCID: PMC3899891  PMID: 22705344
4.  Metabolome-Wide Association Study of Neovascular Age-Related Macular Degeneration 
PLoS ONE  2013;8(8):e72737.
To determine if plasma metabolic profiles can detect differences between patients with neovascular age-related macular degeneration (NVAMD) and similarly-aged controls.
Metabolomic analysis using liquid chromatography with Fourier-transform mass spectrometry (LC-FTMS) was performed on plasma samples from 26 NVAMD patients and 19 controls. Data were collected from mass/charge ratio (m/z) 85 to 850 on a Thermo LTQ-FT mass spectrometer, and metabolic features were extracted using an adaptive processing software package. Both non-transformed and log2 transformed data were corrected using Benjamini and Hochberg False Discovery Rate (FDR) to account for multiple testing. Orthogonal Partial Least Squares-Discriminant Analysis was performed to determine metabolic features that distinguished NVAMD patients from controls. Individual m/z features were matched to the Kyoto Encyclopedia of Genes and Genomes database and the Metlin metabolomics database, and metabolic pathways associated with NVAMD were identified using MetScape.
Of the 1680 total m/z features detected by LC-FTMS, 94 unique m/z features were significantly different between NVAMD patients and controls using FDR (q = 0.05). A comparison of these features to those found with log2 transformed data (n = 132, q = 0.2) revealed 40 features in common, reaffirming the involvement of certain metabolites. Such metabolites included di- and tripeptides, covalently modified amino acids, bile acids, and vitamin D-related metabolites. Correlation analysis revealed associations among certain significant features, and pathway analysis demonstrated broader changes in tyrosine metabolism, sulfur amino acid metabolism, and amino acids related to urea metabolism.
These data suggest that metabolomic analysis can identify a panel of individual metabolites that differ between NVAMD cases and controls. Pathway analysis can assess the involvement of certain metabolic pathways, such as tyrosine and urea metabolism, and can provide further insight into the pathophysiology of AMD.
PMCID: PMC3754980  PMID: 24015273
5.  The short-term effects of antioxidant and zinc supplements on oxidative stress biomarker levels in plasma: a pilot investigation 
American Journal of Ophthalmology  2012;153(6):1104-1109.e2.
To determine if short-term Age-Related Eye Disease Study (AREDS) antioxidant and zinc supplementation affects biomarkers of oxidative stress, possibly serving as a predictor of their efficacy.
Prospective interventional case series
Nineteen subjects, 12 with intermediate or advanced age-related macular degeneration (AMD) (AREDS categories 3 or 4) and 7 non-AMD controls, were admitted to the Vanderbilt General Clinical Research Center and placed on a controlled diet for 7 days. Antioxidant and zinc supplements were stopped two weeks prior to study enrollment. Dietary supplementation with 500 mg vitamin C, 400 IU vitamin E, 15 mg β-carotene, 80 mg zinc oxide, and 2 mg cupric oxide per day was instituted on Study Day 2. Blood was drawn on Study Days 2 and 7, and plasma concentrations of cysteine (Cys), cystine (CySS), glutathione (GSH), isoprostane (IsoP), and isofuran (IsoF) were determined.
Short-term AREDS supplementation significantly lowered mean plasma levels of CySS in participants on a regulated diet (p = 0.034). No significant differences were observed for Cys, GSH, IsoP, or IsoF. There were no significant differences between AMD patients and controls.
This pilot interventional study shows that a 5-day course of antioxidant and zinc supplements can modify plasma levels of CySS, suggesting that this oxidative stress biomarker could help predict how likely an individual is to benefit from AREDS supplementation. Further, CySS may be useful for the evaluation of new AMD therapies, particularly those hypothesized to affect redox status.
PMCID: PMC3358482  PMID: 22381365
6.  The effect of genetic variants in SERPING1 on the risk of neovascular age-related macular degeneration 
Genetic factors influence an individual’s risk for developing age-related macular degeneration (AMD), a leading cause of irreversible vision loss. Previous studies investigating the potential association between all AMD subtypes and the SERPING1 gene, which encodes a key regulator of the classical complement pathway, have yielded conflicting results. The purpose of this study was to determine whether variations in SERPING1 are associated with the neovascular form of AMD.
A total of 556 patients with neovascular AMD and 256 ethnically-matched controls were genotyped for polymorphisms in SERPING1. A tagging single nucleotide polymorphism (tSNP) approach was used to cover the SERPING1 gene plus 2 kilobases (kb) on each side, spanning the promoter and the 3′ untranslated regions. Ten SNPs with a minimum allele frequency of 0.10 were covered by three tSNPs (rs1005510, rs11603020, rs2511989).
SERPING1 SNPs rs1005510 and rs2511989 were significantly associated with neovascular AMD in our cohort, with rs1005510 conferring an adverse risk effect (OR 1.49, 95% CI 1.18–1.88) and rs2511989 conferring a protective effect (OR 0.73, 95% CI 0.59–0.90). For both tSNPs, logistic regression of individual genotypes demonstrated statistically-significant stepwise changes in the risk of developing AMD. Combined analysis of rs1005510 with variants in CFH and HTRA1 confirmed an independent risk effect. The rs11603020 variant had no effect on AMD susceptibility in this study (OR 0.98, 95% CI 0.78–1.24).
This study comprehensively investigates the SERPING1 gene (using three tSNPs) and evaluates these genetic variants in the largest neovascular AMD cohort to date. Our results support the hypothesis that SERPING1 has a modest effect on the risk of neovascular AMD.
PMCID: PMC3655725  PMID: 20606025
SERPING1; Complement cascade; Age-Related Macular Degeneration; Choroidal Neovascularization
7.  Plasma biomarkers of oxidative stress and genetic variants in age-related macular degeneration 
American journal of ophthalmology  2011;153(3):460-467.e1.
To compare plasma levels of oxidative stress biomarkers in patients with age-related macular degeneration (AMD) and controls and to evaluate a potential relationship between biochemical markers of oxidative stress and AMD susceptibility genotypes.
Prospective case-control study
Plasma levels of oxidative stress biomarkers were determined in 77 AMD patients and 75 controls recruited from a clinical practice. Cysteine (Cys), cystine (CySS), glutathione (GSH), isoprostane (IsoP), and isofuran (IsoF) were measured, and participants were genotyped for polymorphisms in the complement factor H (CFH) and age-related maculopathy susceptibility 2 (ARMS2) genes.
CySS was elevated in cases compared to controls (p = 0.013). After adjustment for age, gender, and smoking, this association was not significant. In all participants, CySS levels were associated with the CFH polymorphism rs3753394 (p = 0.028) as well as an eight-allele CFH haplotype (p = 0.029) after correction for age, gender, and smoking. None of the other plasma markers was related to AMD status in our cohort.
Our investigation of the gene/environment interaction involved in AMD revealed a relationship between a plasma biomarker of oxidative stress (CySS) and CFH genotype. These data suggest a potential association between inflammatory regulators and redox status in AMD pathogenesis.
PMCID: PMC3288635  PMID: 22035603
8.  Pharmacogenetics of Complement Factor H (Y402H) and treatment of exudative age-related macular degeneration with ranibizumab 
To determine whether complement factor H (CFH) genotypes have a pharmacogenetic effect on the treatment of exudative age-related macular degeneration (AMD) with ranibizumab.
A retrospective study of 156 patients with exudative AMD treated with intravitreal ranibizumab monotherapy was conducted. AMD phenotypes were characterized by clinical examination, visual acuity, fundus photography, fluorescein angiography, and injection timing. Patients received intravitreal ranibizumab injections as part of routine ophthalmologic care and were followed for a minimum of nine months. Each patient was genotyped for the single nucleotide polymorphism rs1061170 (Y402H) in the CFH gene.
Baseline lesion size and angiographic type, as well as mean visual acuities at baseline, 6 months, and 9 months were similar among the three CFH genotypes. Over 9 months, patients with both risk alleles received approximately one more injection (p = 0.09). In a recurrent event analysis, patients homozygous for the CFH Y402H risk allele had a 37% significantly higher risk of requiring additional ranibizumab injections (p = 0.04)
In our cohort, response to treatment of AMD with ranibizumab differed according to CFH genotype, suggesting that determining patients' CFH genotype may be helpful in the future in tailoring treatment for exudative AMD with intravitreal ranibizumab.
PMCID: PMC3490485  PMID: 19091853
Complement Factor H; Ranibizumab; Age-Related Macular Degeneration; Pharmacogenetics
9.  Pharmacogenetics and Age-Related Macular Degeneration 
Journal of Ophthalmology  2011;2011:252549.
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.
PMCID: PMC3199209  PMID: 22046503
10.  Common variants near FRK/COL10A1 and VEGFA are associated with advanced age-related macular degeneration 
Human Molecular Genetics  2011;20(18):3699-3709.
Despite significant progress in the identification of genetic loci for age-related macular degeneration (AMD), not all of the heritability has been explained. To identify variants which contribute to the remaining genetic susceptibility, we performed the largest meta-analysis of genome-wide association studies to date for advanced AMD. We imputed 6 036 699 single-nucleotide polymorphisms with the 1000 Genomes Project reference genotypes on 2594 cases and 4134 controls with follow-up replication of top signals in 5640 cases and 52 174 controls. We identified two new common susceptibility alleles, rs1999930 on 6q21-q22.3 near FRK/COL10A1 [odds ratio (OR) 0.87; P = 1.1 × 10−8] and rs4711751 on 6p12 near VEGFA (OR 1.15; P = 8.7 × 10−9). In addition to the two novel loci, 10 previously reported loci in ARMS2/HTRA1 (rs10490924), CFH (rs1061170, and rs1410996), CFB (rs641153), C3 (rs2230199), C2 (rs9332739), CFI (rs10033900), LIPC (rs10468017), TIMP3 (rs9621532) and CETP (rs3764261) were confirmed with genome-wide significant signals in this large study. Loci in the recently reported genes ABCA1 and COL8A1 were also detected with suggestive evidence of association with advanced AMD. The novel variants identified in this study suggest that angiogenesis (VEGFA) and extracellular collagen matrix (FRK/COL10A1) pathways contribute to the development of advanced AMD.
PMCID: PMC3159552  PMID: 21665990
11.  Optic Nerve Dysfunction in a Mouse Model of Neurofibromatosis-1 Optic Glioma 
Individuals with neurofibromatosis type 1 (NF1) are prone to develop optic pathway gliomas that can result in significant visual impairment. To explore the cellular basis for the reduced visual function resulting from optic glioma formation, we employed a genetically engineered mouse model of Nf1 optic glioma (Nf1+/−GFAPCKO mice). We performed multi-modal functional and structural analyses both before and after the appearance of macroscopic tumors. At 6 weeks of age, prior to obvious glioma formation, Nf1+/−GFAPCKO mice had decreased visual evoked potential amplitudes and increased optic nerve axon calibers. By 3 months of age, Nf1+/−GFAPCKO mice exhibited pronounced optic nerve axonopathy and apoptosis of neurons in the retinal ganglion cell layer. Magnetic resonance diffusion tensor imaging showed a progressive increase in radial diffusivity between 6 weeks and 6 months of age in the optic nerve proximal to the tumor indicating ongoing deterioration of axons. These data suggest that optic glioma formation results in early axonal disorganization and damage that culminates in retinal ganglion cell death. The Nf1+/−GFAPCKO mice provide a useful model for defining mechanisms of visual abnormalities in children with NF1 and lay the foundations for future interventional studies aimed at reducing visual loss.
PMCID: PMC2746323  PMID: 19525901
Apoptosis; Magnetic resonance imaging; Neurofibromatosis-1; Optic pathway glioma; Retinal ganglion cell; Visual evoked potential
12.  Neurturin-mediated Ret activation is required for retinal function 
The GDNF family ligands (GFLs: GDNF, NRTN, ARTN, and PSPN), interact with GDNF family receptors (GFRαs) and activate intracellular signaling through the Ret receptor tyrosine kinase. To characterize the role of Ret signaling in retinal activity, we examined Ret hypomorphic and Ret conditional mice using electroretinography. We found that aberrant Ret function resulted in markedly diminished scotopic and photopic responses. Using mice deficient in individual GFLs, we found that only NRTN deficiency led to reduced retinal activity. To determine the potential target cell-type for NRTN, we examined the retinal expression of its coreceptors (GFRα1 and GFRα2) and Ret using mice expressing fluorescence reporter EGFP from their respective loci. We found robust GFRα1 and Ret expression in horizontal, amacrine, and ganglion cells, whereas GFRα2 expression was only detected in a subset of amacrine and ganglion cells. In contrast to previous studies, no expression of GFRα1, GFRα2, or Ret was detected in photoreceptors or Müller cells, suggesting these cells are not directly affected by Ret. Finally, detailed morphologic analyses of retinas from NRTN- and Ret-deficient mice demonstrated a reduction in normal horizontal cell dendrites and axons, abnormal extensions of horizontal cell and bipolar cell processes into the outer nuclear layer, and mislocalized synaptic complexes. These anatomic abnormalities indicate a possible basis for the abnormal retinal activity in the Ret and NRTN mutant mice.
PMCID: PMC2704905  PMID: 18417692
RET; Neurturin; retina; ERG; horizontal; outer plexiform layer
13.  Clinical phenotypes associated with the Complement Factor H Y402H variant in age-related macular degeneration 
American journal of ophthalmology  2007;144(3):404-408.
To determine whether the complement factor H (CFH) Y402H variant is associated with specific age-related macular degeneration (AMD) clinical phenotypes.
Retrospective, case-control study.
188 Caucasian subjects with AMD and 189 control subjects were genotyped for the T-to-C polymorphism in exon-9 of the CFH gene by restriction-fragment length analysis and DNA sequencing using genomic DNA from mouthwash samples. AMD phenotypes were characterized by clinical examination, fundus photography, and fluorescein angiography.
Heterozygosity for the at-risk genotype (TC) increased the likelihood for AMD 2.1-fold (95% CI 1.3–3.3) while homozygosity for the genotype (CC) increased the likelihood for AMD 6.5-fold (95% CI 3.4–12.5) in our population. The C allele was significantly associated with predominantly classic choroidal neovascularization (OR 2.01, 95% CI 1.34–3.30). Neovascular lesion size was similar among the three genotypes (p=0.67).
The Y402H CFH variant carried a significantly increased risk for developing AMD in our population. Genotype/phenotype correlations regarding choroidal neovascular lesion type were observed
PMCID: PMC2140051  PMID: 17631852

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