Samaneh Davoudi

Whole exome sequencing identification of novel candidate genes in patients with proliferative diabetic retinopathy

&NA; Rare or novel gene variants in patients with proliferative diabetic retinopathy may contribute to disease development. We performed whole exome sequencing (WES) on patients at the phenotypic extremes of diabetic retinal complications: 57 patients diagnosed with proliferative diabetic retinopathy (PDR) as cases and 13 patients with no diabetic retinopathy despite at least 10 years of type 2 diabetes as controls. Thirty‐one out of the 57 cases and all 13 controls were from the African American Proliferative Diabetic Retinopathy Study (AA). The rest of the cases were of mixed ethnicities (ME). WES identified 721 candidate genes with rare or novel non‐synonymous variants found in at least one case with PDR and not present in any controls. After filtering for genes with null alleles in greater than two cases, 28 candidate genes were identified in our ME cases and 16 genes were identified in our AA cases. Our analysis showed rare and novel variants within these genes that could contribute to the development of PDR, including rare non‐synonymous variants in FAM132A, SLC5A9, ZNF600, and TMEM217. We also found previously unidentified variants in VEGFB and APOB. We found that VEGFB, VPS13B, PHF21A, NAT1, ZNF600, PKHD1L1 expression was reduced in human retinal endothelial cells (HRECs) cultured under high glucose conditions. In an exome sequence analysis of patients with PDR, we identified variants in genes that could contribute to pathogenesis. Six of these genes were further validated and found to have reduced expression in HRECs under high glucose conditions, suggestive of an important role in the development of PDR.

Association of Low Vitamin D Levels With Noninfectious Anterior Uveitis

Importance Vitamin D plays an important role in both the innate and adaptive immune systems. It has been shown to contribute to the etiology of T-cell–mediated autoimmune diseases through the upregulation of type 2 anti-inflammatory T helper cells and the suppression of type 1 T helper cells. Noninfectious uveitis is postulated to be caused by immune dysfunction. Objective To determine whether there is an association between vitamin D levels and noninfectious anterior uveitis. Design, Setting, and Participants This was a case-control study. We identified patients with and without noninfectious uveitis using the Massachusetts Eye and Ear Infirmary Ocular Inflammation Database and electronic medical records from March 1, 2008, to December 12, 2015, at the Massachusetts Eye and Ear Infirmary Uveitis and Comprehensive Ophthalmology Clinics. One hundred patients with noninfectious anterior uveitis and 100 patients without uveitis were recruited. Patients with noninfectious uveitis were diagnosed by fellowship-trained uveitis specialists after exclusion of infectious causes and neoplastic masquerades of uveitis. All patients included had a total 25-hydroxyvitamin D level recorded. Multivariate regression models were constructed to determine the association between vitamin D levels and the presence of uveitis. Main Outcome and Measure Presence of noninfectious anterior uveitis. Results We identified 100 patients (64 white, 8 African American, 25 Asian, and 3 Hispanic) with a mean (SD) age of 51.8 (15.9) years (26 men) and 100 control individuals (58 white, 23 African American, 8 Asian, and 11 Hispanic) with a mean (SD) age of 53.6 (16.2) years (27 men). Hypovitaminosis D was associated with noninfectious uveitis in the univariate analysis (odds ratio, 2.53; 95% CI, 1.42-4.51; P = .002). The association in multivariate regression after adjusting for age, sex, and race/ethnicity was 2.96 (95% CI, 1.60-5.50; P = .001). The odds of developing uveitis were 4% lower for every 1–ng/mL increase in vitamin D level (odds ratio, 0.96; 95% CI, 0.93-0.99; P = .01) in the main multivariate analysis. Conclusions and Relevance In this retrospective study, lower vitamin D levels were associated with an increased risk of noninfectious anterior uveitis. However, this does not confirm a causal effect.

OPTICAL COHERENCE TOMOGRAPHY CHARACTERISTICS OF MACULAR EDEMA AND HARD EXUDATES AND THEIR ASSOCIATION WITH LIPID SERUM LEVELS IN TYPE 2 DIABETES.

Purpose: To determine whether hyperreflective foci (HF) and macular thickness on spectral domain ocular coherence tomography are associated with lipid levels in patients with Type 2 diabetes. Methods: Two hundred and thirty-eight participants from four sites had fundus photographs and spectral domain ocular coherence tomography images graded for hard exudates and HF, respectively. Regression models were used to determine the association between serum lipid levels and 1) presence of HF and hard exudates and 2) central subfield macular thickness, central subfield macular volume, and total macular volume. Results: All patients with hard exudates on fundus photographs had corresponding HF on spectral domain ocular coherence tomography, but 57% of patients with HF on optical coherence tomography did not have hard exudates detected in their fundus photographs. Presence of HF was associated with higher total cholesterol (odds ratio = 1.13, 95% confidence interval = 1.01–1.27, P = 0.03) and higher low-density lipoprotein levels (odds ratio = 1.17, 95% confidence interval = 1.02–1.35, P = 0.02) in models adjusting for other risk factors. The total macular volume was also associated with higher total cholesterol (P = 0.009) and triglyceride (P = 0.02) levels after adjusting for other risk factors. Conclusion: Higher total and low-density lipoprotein cholesterol were associated with presence of HF on spectral domain ocular coherence tomography. Total macular volume was associated with higher total cholesterol and triglyceride levels.

A retrospective study on the outcomes of Ahmed valve versus Ahmed valve combined with fluocinolone implant in uveitic glaucoma

Purpose To compare the intraocular pressure (IOP) outcomes of Ahmed glaucoma valve (AGV) surgery alone versus AGV with fluocinolone implant in uveitic glaucoma patients. Methods We identified uveitic glaucoma patients with AGV surgery alone and AGV surgery combined with fluocinolone implant from the Massachusetts Eye and Ear Ocular Inflammation Database. Demographic information, visual acuity, and IOP were recorded at preoperative visits and 1, 6, and 12 months after surgery. Incidence of hypertensive phase, defined as an IOP of >21 mm Hg or use of additional treatment to lower IOP occurring any time between 7 days to 6 months postoperatively, was investigated. Multilevel mixed effects models were performed to compare the outcomes between groups. Results Eighteen eyes of 13 uveitic glaucoma patients with 1-year follow-up data were included. There were 11 eyes of 9 patients (mean age, 56.5 years; 63.6% male) in the AGV group and 7 eyes of 4 patients (mean age, 61.3 years; 71.4% male) in the AGV + fluocinolone group. There was no significant difference in visual acuity change at 1 year after surgery between groups (P = 0.25), although visual acuity improvement was significant in the AGV group (P = 0.01). The hypertensive phase occurred in 91% of AGV patients and 43% of AGV + fluocinolone patients (P = 0.30), with onset of 8-40 days (mean, 18 days) after surgery. IOP and number of glaucoma medications decreased at the 1-year postoperative visits in both the AGV group (P < 0.0001, P < 0.0001) and the AGV + fluocinolone group (P = 0.001, P < 0.0001). Compared to the AGV group, the AGV + fluocinolone group used fewer glaucoma medications (0.28 vs 1.30 [P = 0.01]) and had better inflammation control (P = 0.02). The surgical complication rates were similar between groups. Conclusions In uveitic glaucoma, AGV with fluocinolone achieves a similar, desired IOP control but with fewer glaucoma medications than AGV alone.

Ocular Manifestations, Conventional Fundus Fluorescein Angiographic Findings, and Relationship Between Angiographic Findings and Visual Acuity in Behçet’s Disease

ABSTRACT Purpose: Evaluating the ocular manifestation and fundus fluorescein angiography (FA) findings of patients with Behçet’s disease as well as the relationship between visual acuity and angiographic findings. Methods: Retrospective chart review of patients with Behçet’s disease seen at the Farabi Eye Hospital. Results: Forty-six patients (92 eyes) with mean age of 33.41 ± 10.67 were included. The most frequent presenting symptom and sign were reduced vision (76%) and uveitis (87%), respectively. Panuveitis was the most frequent type of uveitis (76%). Among patients with FA, vasculitis was the most common finding (87%) and it was significantly more severe among patients with visual acuity less than 20/200. Macular leakage (P = 0.001), arterial narrowing (P = 0.000), and posterior retinal vasculitis (P = 0.002) on FA were all associated with worsening final visual acuity. Conclusion: The most common ocular findings in Behçet’s disease were panuveitis and vasculitis. Location of vasculitis, arterial narrowing, and macular leakage on initial FA may predict visual prognosis.

Novel Genetic Actors of Diabetes-Associated Microvascular Complications: Retinopathy, Kidney Disease and Neuropathy.

Both type 1 and type 2 diabetes mellitus can lead to the common microvascular complications of diabetic retinopathy, kidney disease, and neuropathy. Diabetic patients do not universally develop these complications. Long duration of diabetes and poor glycemic control explain a lot of the variability in the development of microvascular complications, but not all. Genetic factors account for some of the remaining variability because of the heritability and familial clustering of these complications. There have been a large number of investigations, including linkage studies, candidate gene studies, and genome-wide association studies, all of which have sought to identify the specific variants that increase susceptibility. For retinopathy, several genome-wide association studies have been performed in small or midsize samples, but no reproducible loci across the studies have been identified. For diabetic kidney disease, genome-wide association studies in larger samples have been performed, and loci for this complication are beginning to emerge. However, validation of the existing discoveries, and further novel discoveries in larger samples is ongoing. The amount of genetic research into diabetic neuropathy has been very limited, and much is dedicated to the understanding of genetic risk factors only. Collaborations that pool samples and aim to detect phenotype classifications more precisely are promising avenues for a better explanation of the genetics of diabetic microvascular complications.

High Reliability of Cone Cell Measurements With Adaptive Optics Scanning Laser Ophthalmoscopy in a Simulated Real-Life Clinical Setting

BACKGROUND AND OBJECTIVE The authors evaluated adaptive optics scanning laser ophthalmoscopy (AO-SLO) in a simulated real-life clinical setting to identify factors that impact its reliability in this setting. PATIENTS AND METHODS For this prospective study, macular cones were imaged in five healthy eyes using an AO-SLO prototype machine. Multilevel mixed-effect regression was used to compare the cone densities across different analysis parameters. Intergrader, intragrader, interphotographer, and intersession reliabilities were determined with intraclass correlation coefficients (ICCs). RESULTS Cone densities in the largest measurement window size, 150 μm × 150 μm, were most consistent. Image quality strongly impacted cone analysis. Intragrader and intergrader ICCs were 0.99 and 0.98, respectively. Intersession and interphotographer reliability both had an ICC of 0.72. CONCLUSIONS Larger measurement window sizes and higher image quality improve the reliability of cone density measurement. Although there were excellent intergrader and intragrader reliabilities, intersession and interphotographer reliabilities were not as robust. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:228-235.].

Phage Immunoprecipitation Sequencing of Autoantigens in Autoimmune Retinopathy

ABSTRACT Purpose: To identify autoantigens in autoimmune retinopathy patients by phage immunoprecipitation sequencing (PhIP-Seq), a new technique for autoantigen discovery. Methods: PhIP-Seq was used to sequence putative autoantibodies in plasma from 11 patients with autoimmune retinopathy and eight controls. We compared the autoantibodies’ molecular weights with those of proteins detected by Western blot. Results: Several autoantigens were found in cases and not detected in the controls. Autoantigens RTN3, PRPF6, TRPC6, and B3GNT8, four proteins expressed in the retina, were detected in plasma as autoantibodies from one patient each and no controls. Only one patient had an autoantibody, B3GNT8 (43.4 kDa), within a similar weight range as that detected by antiretinal antibody Western blot (42 kDa). Autoantibody POLR3A, which has a well-characterized role in scleroderma, was detected in two cases and no controls. Conclusion: PhIP-Seq detected autoantigens that are expressed in the retina as well as scleroderma-related autoantigens in autoimmune retinopathy patients.

Treatment of Serpiginous Choroiditis with Chlorambucil: A Report of 17 Patients

ABSTRACT Purpose: To evaluate the efficacy of chlorambucil in the treatment of serpiginous choroiditis. Methods: Patient records from the Massachusetts Eye Research and Surgery Institution (MERSI) were reviewed from over the past 10 years. In total, 17 patients with the diagnosis of serpiginous choroiditis treated with chlorambucil were identified. QuantiFERON gold was negative in all of them. Chlorambucil was started at 0.15 mg/kg and dosage was titrated up using weekly white blood cell (WBC) count to achieve a target cell number of 3.0–4.5 × 109 cells/L. The goal of therapy was to maintain this value for at least 6–9 months. Adverse effects, recurrence, rate of new choroidal neovascularization (CNVM), and visual acuity before and after treatment were recorded. Results: The mean age of the 17 patients with the diagnosis of serpiginous choroiditis treated with chlorambucil was 46 years, and six patients (35%) were male. The mean duration of treatment for chlorambucil was 8.4 months. None of them developed cancer or persistent side-effects, with a mean follow-up of 53 months. Of the patients, 12 (71%) achieved an average of 45 (5–120) months drug-free remission in their last follow-up. Visual acuity of 33 treated eyes remained within two lines of Snellen acuity in 27 eyes (82%), improved in one eye (3%), and deteriorated in five eyes (15%). Leukopenia was the most common side-effect, which was reversible in all cases. Conclusions: Chlorambucil in a relatively short duration of time, with an escalating dose guided by weekly WBC was well tolerated, as well as effective in preventing recurrence and maintaining vision in patients with serpiginous choroiditis.

Association of Low Vitamin D Levels with Noninfectious Uveitis and Scleritis

ABSTRACT Purpose: To determine whether an association between Vitamin D and noninfectious ocular inflammation exists. Methods: Retrospective case-control study with 765 patients (333 uveitis cases, 103 scleritis cases, 329 controls). Logistic regression models examined the relationship between hypovitaminosis D and ocular inflammation. Results: The odds of having uveitis were 1.92 times higher for patients with hypovitaminosis D compared to patients with normal Vitamin D levels in the multivariate analysis [odds ratio (OR) = 1.92, 95% Confidence Interval (CI) = 1.36–2.72, p = 2.32 × 10–4]. A secondary analysis demonstrated that the odds of developing uveitis or scleritis were 5% lower and 4% lower, respectively, for every unit increase in Vitamin D level (uveitis: OR = 0.95, 95% CI = 0.94–0.97, p = 9.87 × 10–6; scleritis: OR = 0.96, 95% CI = 0.93–0.99, p = 0.009). Conclusion: Hypovitaminosis D was associated with increased risk of ocular inflammation in this retrospective study.