Genome-wide association studies for diabetic macular edema and proliferative diabetic retinopathy

Background: Diabetic macular edema (DME) and proliferative diabetic retinopathy (PDR) are sight threatening complications of diabetes mellitus and leading causes of adult onset blindness worldwide. Genetic risk factors for diabetic retinopathy (DR) have been described previously, but have been difficult to replicate between studies, which have often used composite phenotypes and been conducted in different populations. This study aims to identify genetic risk factors for DME and PDR as separate complications in Australians of European descent with type 2 diabetes. Methods: Caucasian Australians with type 2 diabetes were evaluated in a genome wide association study (GWAS) to compare 270 DME cases and 176 PDR cases with 435 non retinopathy controls. All participants were genotyped by SNP array and after data cleaning, cases were compared to controls using logistic regression adjusting for relevant covariates. Results: The top ranked SNP for DME was rs1990145 (p = 4.10 x 10(-6), OR = 2.02 95%CI [1.50, 2.72]) on chromosome 2. The top-ranked SNP for PDR was rs918519 (p = 3.87 x 10(-6), OR = 0.35 95%CI [0.22, 0.54]) on chromosome 5. A trend towards association was also detected at two SNPs reported in the only other reported GWAS of DR in Caucasians; rs12267418 near MALRD1 (p = 0.008) in the DME cohort and rs16999051 in the diabetes gene PCSK.2 (p = 0.007) in the PDR cohort. Conclusion: This study has identified loci of interest for DME and PDR, two common ocular complications of diabetes. These findings require replication in other Caucasian cohorts with type 2 diabetes and larger cohorts will be required to identify genetic loci with statistical confidence. There is considerable overlap in the patient cohorts with each retinopathy subtype, complicating the search for genes that contribute to PDR and DME biology

Genetic study of Diabetic Retinopathy: recruitment methodology and analysis of baseline characteristics

ARC and NHMRC funded authors may self-archive the author accepted version of their paper (authors manuscript) after a 12-month embargo period from publication in an open access institutional repository.BACKGROUND: Diabetic retinopathy (DR) is a blinding disease of increasing prevalence, caused by a complex interplay of genetic and environmental factors. Here we describe the patient recruitment methodology, case and control definitions, and clinical characteristics of a study sample to be used for genome-wide association (GWAS) analysis to detect genetic risk variants of DR. METHODS: 1669 participants with either type 1 (T1) or type 2 (T2) diabetes mellitus (DM) aged 18 to 95 years were recruited in Australian hospital clinics. Individuals with T2DM had disease duration of at least 5 years, and were taking oral hypoglycemic medication, and/or insulin therapy. Participants underwent ophthalmic examination. Medical history and biochemistry results were collected. Venous blood was obtained for genetic analysis. RESULTS: 683 diabetic cases (178 T1DM and 505 T2DM participants) with sight-threatening DR, defined as severe non-proliferative DR (NPDR), proliferative DR (PDR) or diabetic macular edema (DME) were included in this analysis. 812 individuals with DM but no DR or minimal NPDR were recruited as controls (191 with T1DM and 621 with T2DM). The presence of sight-threatening DR was significantly correlated with DM duration, hypertension, nephropathy, neuropathy, HbA1C and BMI. DME was associated with T2DM (p<0.001), whereas PDR was associated with T1DM (p<0.001). CONCLUSIONS: Adoption of a case-control study design involving extremes of the DR phenotype makes this a suitable cohort, for a well-powered GWAS to detect genetic risk variants for DR.This work was funded by a grant from the Ophthalmic Research Institute of Australia, and Project Grant #595918 from the National Health and Medical Research Council (NHMRC) of Australia. JEC is supported in part by a NHMRC Practitioner Fellowship and KPB by a Career Development Fellowship. Research conducted at Moorfields Eye Hospital was funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology

Central Serous Chorioretinopathy Associated with Desmopressin Nasal Spray: Causality or Unfortunate Association

Purpose: To describe the possible association between central serous chorioretinopathy (CSCR) and desmopressin use. Methods: The case histories of 2 middle-aged men with CSCR using desmopressin nasal spray were studied. Results: The diagnosis of CSCR was made on the basis of clinical features and ancillary testing (fluorescein angiography and optical coherence tomography). Both patients were using desmopressin nasal spray for polyuria when they developed the first ocular symptoms. Both of them also had an independent risk factor for developing CSCR. Conclusion: We suggest that desmopressin-induced hypercortisolism might implicate the development of CSCR in some patients. A larger study on patients using desmopressin nasal spray would be beneficial to confirm the possible association between this form of therapy and the development of CSCR

Clinical Phenotypes of Poppers Maculopathy and Their Links to Visual and Anatomic Recovery

SCOPUS: cp.jinfo:eu-repo/semantics/publishe

Vitreomacular traction affects anti-vascular endothelial growth factor treatment outcomes for exudative age-related macular degeneration

Purpose: To evaluate the effect of vitreomacular traction (VMT) on visual acuity outcomes and central retinal thickness (CRT) measurements after intravitreal anti-vascular endothelial growth factor (anti-VEGF) therapy for treatment of exudative age-related macular degeneration (AMD).Methods: In this retrospective series, the authors evaluate the clinical records and optical coherence tomography of 34 eyes of 32 patients, with VMT confirmed on optical coherence tomography at baseline, to assess the effects of VMT on anti-VEGF therapy for newly diagnosed exudative wet AMD. Best-corrected visual acuity at baseline, 1, 3, 6, 9, and 12 months and CRT at baseline, 3, 6, and 12 months were assessed. Comparison was made with a control group of 29 eyes of 28 patients with wet AMD and no VMT on optical coherence tomography and with key variable-dosing studies for anti-VEGF in exudative AMD (CATT, HARBOR, PrONTO, SUSTAIN, and Gupta et al).Results: Best-corrected visual acuity results showed a visual acuity improvement that peaked at 3 months with 2.47 letters, well below other variable-dosing studies for anti-VEGF therapy in exudative AMD. This was then followed by a steady decline with mean best-corrected visual acuity at 12 months ending below the baseline level (-1.00 letters) compared with a gain of 9.39 letters in the control group at 12 months. Comparison of the mean CRT in the VMT group between baseline and 12 months showed no significant difference (P = 0.67), whereas the PrONTO study and control groups showed a highly significant difference at 12 months compared with baseline (P &lt; 0.001). Mean CRT values at 6 months and 12 months were essentially at baseline levels (0.26 µm, -0.62 µm, respectively).Conclusion: Vitreomacular traction at baseline, existing concurrently with newly diagnosed exudative AMD treated with intravitreal anti-VEGF therapy on a variable-dosing regime, was associated with poorer visual outcomes and a decreased response to reduction in CRT, compared with a control group of wet AMD without VMT and compared with major variable-dosing studies for intravitreal anti-VEGF in exudative AMD

Pachychoroid spectrum disease

Recent improvements in ophthalmic imaging have led to the identification of a thickened choroid or pachychoroid to be associated with a number of retinal diseases. The number of conditions linked to this phenotype has continued to widen with specific endophenotypes found within the pachychoroid spectrum. The spectrum includes choroidal features such as focal or diffuse choroidal thickening and thinning of the overlying inner choroid, and choroidal hyperpermeability as demonstrated by indocyanine green angiography. In addition, these diseases are associated with overlying retinal pigmentary changes and retinal pigment epithelial dysfunction and may also be associated with choroidal neovascularization. This article provides a comprehensive review of the literature looking at diseases currently described within the pachychoroid spectrum including central serous chorioretinopathy, pachychoroid pigment epitheliopathy, pachychoroid neovasculopathy, polypoidal choroidal vasculopathy/aneurysmal type 1 neovascularization, peripapillary pachychoroid disease and focal choroidal excavation. We particularly focus on clinical imaging, genetics and pathological findings in these conditions with the aim of updating evidence suggesting a common aetiology between diseases within the pachychoroid spectrum

Genetic study of diabetic retinopathy: recruitment methodology and analysis of baseline characteristics

Background: Diabetic retinopathy (DR) is a blinding disease of increasing prevalence that is caused by a complex interplay of genetic and environmental factors. Here we describe the patient recruitment methodology, case and control definitions, and clinical characteristics of a study sample to be used for genome-wide association analysis to detect genetic risk variants of DR. Methods: One thousand six hundred sixty-nine participants with either type 1 (T1) or type 2 (T2) diabetes mellitus (DM) aged 18 to 95 years were recruited in Australian hospital clinics. Individuals with T2DM had disease duration of at least 5 years and were taking oral hypoglycaemic medication, and/or insulin therapy. Participants underwent ophthalmic examination. Medical history and biochemistry results were collected. Venous blood was obtained for genetic analysis. Results: Six hundred eighty-three diabetic cases (178 T1DM and 505 T2DM participants) with sight-threatening DR, defined as severe non-proliferative DR, proliferative DR or diabetic macular oedema were included in this analysis. Eight hundred twelve individuals with DM but no DR or minimal non-proliferative DR were recruited as controls (191 with T1DM and 621 with T2DM). The presence of sight-threatening DR was significantly correlated with DM duration, hypertension, nephropathy, neuropathy, HbA1C and body mass index. Diabetic macular oedema was associated with T2DM (P<0.001), whereas proliferative DR was associated with T1DM (P<0.001). Conclusions: Adoption of a case-control study design involving extremes of the DR phenotype makes this a suitable cohort, for a well-powered genome-wide association study to detect genetic risk variants for DR

Individualizing Therapy for Neovascular Age-Related Macular Degeneration with Aflibercept (VITAL): A Two-Year Prospective, Interventional Single-Centre Trial

Abstract Aims To report the mean change in Early Treatment Diabetic Retinopathy Study (ETDRS) best-corrected visual acuity (BCVA) and reading performance (reading acuity and maximum reading speed (MRS) using the MNREAD test) between baseline and 24 months in treatment-naïve patients with neovascular age-related macular degeneration (nAMD) treated with intravitreal aflibercept injections. Methods A prospective, open-label, interventional non-randomised case series with 24 months’ duration. Patients were recruited to the study from medical retina clinics at Moorfields Eye Hospital. Intravitreal injections of 2.0 mg aflibercept in the study eye were administered using a fixed dosing regimen during the first year and a treat-and-extend treatment regimen during the second year of treatment. Results Fifty patients were enrolled with a mean age (SD) of 78.7 (7.6) years; a mean BCVA of 62.8 ETDRS letters; mean reading acuity of 0.52 logMAR; mean maximum reading speed (MRS) of 141.3 words per minute and a central macular thickness of 322.6 µm at baseline. The mean improvement in BCVA was 6.4 letters for the 44 patients (88%) for whom data was available at 2 years. The mean improvement in reading acuity was 0.13 logMAR with an improvement in MRS of 2.9 words per minute. The mean reduction in CRT from baseline was 104.8 µm. Conclusions Aflibercept treatment of nAMD using fixed dosing in year 1 and treat and extend in year 2 leads to improvements in reading ability, visual acuity and retinal morphology which were maintained to 2 years of treatment. Trial Registration ClinicalTrials.gov Identifier NCT02441816, the VITAL study