To identify genomic risk factors for diabetic retinopathy (DR), proliferative diabetic retinopathy (PDR) and diabetic macular edema (DME), in South Indians. Phenotyping, including optical coherence tomography (OCT), of South Indians (n = 2538) with type 2 diabetes (T2D) was obtained. Genome-wide association studies (GWAS) were performed for DR, PDR, and DME with covariate adjustment. The results were replicated in two cohorts. T2D polygenic risk scores (PRS) were examined to determine if DR cases were enriched for T2D loci. A novel locus on chromosome 10 [rs11199996 (OR = 4.10, P = 2.88 × 10–8)] was associated with PDR, replicated in other cohorts, and is located near genes involved in retinal light transduction and growth hormone signaling. Several near genome-wide significant loci were identified, including rs76323047 in the glucokinase gene (GCK, P = 3.89 × 10–7), a glucose sensor; this risk variant displays higher frequency in Asian populations. T2D PRS showed consistent associations with DR, particularly PDR, suggesting that DR cases have a higher genetic load for T2D. This first DR GWAS in South Indians identified a significant association between a chromosome 10 variant and PDR. We also found notable associations of T2D PRS with DR.

Purpose:To identify genetic variants associated with glucocorticoid (GC)-induced intraocular pressure (IOP) change using genome-wide association study (GWAS) and whole exome sequencing (WES) analyses. Design:A pharmacogenetic study within a clinical trial and cohort study. Participants:Five hundred thirty discovery cohort participants were included from the Fluocinolone Acetonide in Diabetic Macular Edema (FAME) trials. Replication was performed in an independent cohort of 588 Mass Eye and Ear/Retina Health Center (MEE/RHC) participants. Participants were exposed to GC, primarily by intravitreal injection. Methods:Intraocular pressure was measured at baseline and serially within the first 6 months after GC exposure. Participants' DNA underwent genome-wide genotyping and WES. Genome-wide association study and WES rare variant gene burden analyses were applied to all ancestries and the European participants separately, adjusting for covariates. Expression and splicing quantitative trait loci colocalization analysis using eCAVIAR, and gene-level and pathway analyses using Multi-marker Analysis of GenoMic Annotation were performed. Main Outcome Measures:Genetic associations with the maximal change in IOP within 6 months after GC exposure. Results:Genetic associations for maximal IOP change within 6 months after GC exposure were evaluated. For the primary outcome across all ancestries in FAME, 1 variant, rs13425173 within the UBE2E3 locus, reached genome-wide significance (P = 2.88 × 10-8). In the FAME and MEE/RHC meta-analysis, variant rs1040227, also in the UBE2E3 locus, was significantly associated at the genome-wide level (P = 1.23 × 10-8). In the colocalization analyses, the significant FAME GWAS UBE2E3 locus was linked to expression regulation of this gene in 6 tissues including artery aorta. In gene-level analysis, UBE2E3 also demonstrated subthreshold significance (P = 6.6 × 10-6). Five hundred thirty-two FAME and 586 MEE/RHC participants were included in the WES gene burden analysis. One gene, MSTO1, passed false discovery rate correction for the primary outcome in FAME. Conclusions:We have identified genome-wide significant common variants associated with GC-IOP change, as well as genes and rare variants that may influence GC-induced IOP change. Financial Disclosures:Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Abstract Background Widespread use of retinal optical coherence tomography angiography (OCT-A) imaging in population-based studies requires methodological and analytical consensus to ensure reproducible and accurate results. Objective Development of a consensus framework for assessment of OCT-A image quality and working with OCT-A-derived variables in population studies. Methods Criteria for image quality were developed for fovea-centered, 3x3-mm OCT-A images acquired with three commercially available devices. Inter- and intragrader agreements for overall image quality, vessel density (VD) and foveal avascular zone (FAZ) area were evaluated among five graders (% agreement). Intergrader agreement was validated on 6x6-mm OCT-A images. Recommendations for grading and use of OCT-A images in epidemiological studies were developed. Results Mean intergrader agreements for overall Unusable, Usable, and Excellent 3x3-mm OCT-A image quality (52 images) were 82.3%, 70.8%, and 87.1%; for Unusable VD and FAZ area agreements were 80.0% and 81.9%, respectively. Mean intragrader agreements for overall Unusable, Usable and Excellent 3x3-mm OCT-A image quality (27 images) were 91.1%, 82.2%, and 81.9%; agreements for Unusable VD and FAZ area were 89.6%; and 92.6%, respectively. Mean intergrader agreements for assessment of overall Unusable, Usable and Excellent 6x6-mm OCT-A images (21 images) were 73.3 %, 57.1% and 83.8%, agreements for Unusable VD and FAZ area were 60.0 % and 84.8 %, respectively. Three analytic scenarios were developed to account for common types of bias related to suboptimal OCT-A image quality and ocular comorbidities. Conclusion These recommendations provide a framework for working with OCT-A imaging in population studies. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement Funding Sources The Maastricht Study This study was supported by the European Regional Development Fund via OP-Zuid, the Province of Limburg, the Dutch Ministry of Economic Affairs (grant 31O.041), Stichting De Weijerhorst (Maastricht, the Netherlands), the Pearl String Initiative Diabetes (Amsterdam, the Netherlands), the Cardiovascular Center (CVC, Maastricht, the Netherlands), CARIM School for Cardiovascular Diseases (Maastricht, the Netherlands), CAPHRI School for Public Health and Primary Care (Maastricht, the Netherlands), NUTRIM School for Nutrition and Translational Research in Metabolism (Maastricht, the Netherlands), Stichting Annadal (Maastricht, the Netherlands), Health Foundation Limburg (Maastricht, the Netherlands), Perimed (Jarfalla, Sweden), and by unrestricted grants from Janssen-Cilag B.V. (Tilburg, the Netherlands), Novo Nordisk Farma B.V. (Alphen aan den Rijn, the Netherlands), and Sanofi-Aventis Netherlands B.V. (Gouda, the Netherlands). Rotterdam Study The Rotterdam Study is supported by the Algemene Nederlandse Vereniging ter Voorkoming van Blindheid, Oogfonds, Stichting voor Ooglijders, Stichting voor Blindenhulp, Henkes stichting, Rotterrdams Stichting voor Blindenbelangen, and Landelijke Stichting voor Blinden en Slechtzienden. Additional support was given by the Erasmus Medical Center, Erasmus University, Netherlands Organization for the Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly, the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. Rhineland Study The Rhineland Study (P.I. Breteler) is primarily supported by DZNE core funding. The DZNE is funded by the Federal Ministry of Education and Research (BMBF) and the Ministry of Culture and Science of the German State of North Rhine-Westphalia. Framingham Heart Study National Institutes of Health R01AG066524 (AHK, SS), FHS contract 75N92019D00031, and P30AG066546. SIGNATR This work was supported by: National Eye Institute under R01 EY027134 and Government of India Department of Biotechnology under Grant BT/PR22701/MED/15/166/2016. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics committee/IRB of all institutions (Maastricht University, Rotterdam University, Framingham Heart Study, Rhineland Study, and Rothschild Hospital) gave ethical approval for this work I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors

This case-control study compared autoimmune retinopathy (AIR) outcomes in patients treated with intravenous immunoglobulin (IVIg) vs. those with no therapy. IVIg was associated with preservation of visual acuity and electroretinography parameters at longer term follow-up.

PurposeTo report two patients with herpetic zoster panuveitis and chorioretinopathy with choroidal hypopigmentation.MethodsRetrospective chart review of two patients.ResultsWe report a series of two patients with a history of HZO with orbital inflammation and panuveitis, who developed patchy choroidal depigmentation consistent with a choroidopathy. The lesions were extensive and involved the posterior pole and mid-periphery in both cases. Both cases demonstrated scattered areas of ellipsoid zone loss, and fluorescein angiography showed corresponding late hyperfluorescence. OCTA in one case demonstrated flow voids at the level of choriocapillaris.ConclusionsOur series suggests that herpetic chorioretinopathy may be a relatively benign process that presents late and may involve large areas of the posterior choroid.

PURPOSE:Intraocular infections are sight-threatening conditions that can lead to vision loss. Rapid identification of the etiologies plays a key role in early initiation of effective therapy to save vision. However, current diagnostic modalities are time consuming and lack sensitivity and inclusiveness. We present here a newly developed comprehensive ocular panel designed to improve diagnostic yields and provide a tool for rapid and sensitive pathogen detection. DESIGN:Experimental laboratory investigation. METHODS:A panel containing 46 pathogens and 2 resistance/virulence markers that are commonly detected in intraocular infections was developed. Genomic targets were scrutinized for stretches predicted to be specific for a particular species while being conserved across different strains. A set of primers for sample enrichment, and two 50mer NanoString compatible probes were then designed for each target. Probe-target hybrids were detected and quantified using the NanoString nCounter SPRINT Profiler. Diagnostic feasibility was assessed in a pilot clinical study testing samples from infectious retinitis (n = 15) and endophthalmitis (n = 12) patients, for which the etiologies were confirmed by polymerase chain reaction (PCR) or culture. RESULTS:Analytical studies demonstrated highly sensitive detection of a broad spectrum of pathogens, including bacteria, viruses, and parasites, with limits of detection being as low as 2.5 femtograms per reaction. We also found excellent target specificity, with minimal cross-reactivity detected. The custom-designed NanoString ocular panel correctly identified the causative agent from all clinical specimens positive for a variety of pathogens. CONCLUSION:This highly multiplexed panel for pathogen detection offers a sensitive, comprehensive, and uniform assay run directly on ocular fluids that could significantly improve diagnostics of sight-threatening intraocular infections.

Choroidal caverns (CCs) have been described in association with age-related macular degeneration and pachychoroid disease. However, it is unknown if caverns are found in patients with chronic non-infectious uveitis (NIU). Herein, we evaluated patients with NIU who had optical coherence tomography and indocyanine green angiography for CCs. Clinical and demographic characteristics were extracted from the chart review. Univariate and multivariate mixed-effects logistical models were used to assess the association between clinical and demographic factors and the presence of CCs. One hundred thirty-five patients (251 eyes) met the inclusion criteria: 1 eye had anterior uveitis, 5 had intermediate uveitis, 194 had posterior uveitis, and 51 had panuveitis. The prevalence of CCs was 10%. CCs were only observed in patients with posterior and panuveitis, with a prevalence of 10.8% and 7.8%, respectively. Multifocal choroiditis (MFC) was the type of uveitis where CCs were most frequently observed, with 40% of eyes with MFC having CCs. In addition, male sex (p = 0.024) was associated with CCs. There was no significant difference in the degree of intraocular inflammation or mean subfoveal choroidal thickness between CC+ and CC− eyes. This is the first study to describe CCs in uveitis. Overall, these findings suggest that caverns may be a sequela of structural and/or vascular perturbations in the choroid from uveitis.

Purpose : To determine if angiotensin converting enzyme-inhibitors (ACE-I) alter the incidence of non-infectious uveitis (NIU). Methods: Patients in a large healthcare claims database who initiated ACE-I (n = 695,557) were compared to patients who initiated angiotensin receptor blockers (ARB, n = 354,295). A second comparison was also made between patients who initiated ACE-I (n = 505,958) and those who initiated beta-blockers (BB, n = 538,109). The primary outcome was incident NIU defined as a first diagnosis code for NIU followed by a second instance of a NIU code within 120 days. For the secondary outcome, a corticosteroid prescription or code for an ocular corticosteroid injection within 120 days of the NIU diagnosis code was used instead of the second NIU diagnosis code. Data were analyzed using Cox regression modeling with inverse probability of treatment weighting (IPTW). Sub-analyses were performed by anatomic subtype. Results: When comparing ACE-I to ARB initiators, the hazard ratio (HR) for incident NIU was not significantly different for the primary outcome [HR = 0.95, 95% Confidence Interval (CI): 0.85-1.07, P = .41] or secondary outcome [HR = 0.96, 95% CI: 0.86-1.07, P = .44]. Similarly, in the ACE-I and BB initiators comparison, the HR for incident NIU was not significantly different comparing ACE-I and BB initiators for either outcome definition or any of the NIU anatomical subtypes. Conclusion: Our results suggest there is no evidence that ACE-I have a protective effect on NIU.

Purpose: The purpose of the South Indian GeNetics of DiAbeTic Retinopathy (SIGNATR) Study is to identify non-genetic and genetic risk factors associated with diabetic retinopathy (DR). This report examines the non-genetic risk factors for DR in South Indian patients. Methods: Participants with South Indian ancestry and type 2 diabetes (T2D) were included from two sources: the Sankara Nethralaya Diabetic Retinopathy and Molecular Genetics Study (SN-DREAMS) and prospective recruitment at Sankara Nethralaya affiliates. Fundus photography and optical coherence tomography (OCT) were obtained on participants. Fundus images were graded for DR severity and OCTs were graded for center-involved diabetic macular edema (ciDME). Multivariate analyses were performed using stepwise logistic regression to assess effects of the demographic and clinical factors on proliferative DR (PDR) and DME. Results: Among the 2941 participants with DR grading, participants with PDR were more likely to be younger [odds ratio (OR)=0.95], men (OR = 1.83), have a longer duration of diabetes (OR = 1.10), have a higher hemoglobin A1c (OR = 1.12), have albuminuria (OR = 5.83), have hypertension (OR = 1.69), have a higher HDL (OR = 1.02) and a lower total cholesterol (OR = 0.99) (all p < 0.05). Among the 483 participants with gradable OCT scans, participants who had ciDME were more likely to be younger (OR = 0.97), men (OR = 2.80), have a longer duration of diabetes (OR = 1.06), have lower triglycerides (OR = 0.99), and have albuminuria (OR = 3.12) (all p < 0.05). Conclusions: Younger age, male sex, longer duration of diabetes, higher HbA1c, and presence of albuminuria were identified as risk factors for PDR and DME in a South Indian population with T2D.

PurposeTo determine the sensitivity and positive predictive value (PPV) of a contiguous, perineural retinal vascular leakage fluorescein angiography (FA) pattern in birdshot chorioretinopathy (BSCR) patients.MethodsPatients with BSCR and other posterior uveitis/retinal vasculitis and a FA were identified. Two graders reviewed the first FA for leakage primarily around the optic nerve and along the larger arcade vessels. We compared the rates of this pattern in BSCR and non-BSCR patients and calculated sensitivity and PPV. We compared clinical characteristics of BSCR patients with and without this pattern.Results64 BSCR and 98 non-BSCR patients were identified. The FA pattern's sensitivity, specificity, and PPV were 57.8%, 91.8%, and 82.2%. This pattern was significantly more common in BSCR patients earlier in their disease (p = .004).ConclusionsA contiguous, perineural retinal vascular leakage FA pattern can help identify potential BSCR patients for further testing. This pattern is more common closer to symptom onset.

PURPOSE:To investigate a causal relationship between Vitamin D levels and non-infectious uveitis and scleritis using Mendelian randomization (MR) techniques. DESIGN:Two-sample Mendelian randomization case-control study. METHODS:The study setting was a biobank of an academic, integrated health care system. The patient population comprised 375 case patients with a non-infectious uveitis and/or scleritis diagnosis and no diagnosis of infectious, trauma-related, or drug-induced uveitis/scleritis. In addition, there were 4167 controls with no uveitis or scleritis diagnosis. Causal effect estimates of low 25-hydroxy Vitamin D (25OHD) on uveitis/scleritis risk were calculated. RESULTS:We found an association of genetically decreased 25OHD with uveitis/scleritis risk (odds ratio [OR] = 2.16, 95% CI = 1.01-4.64, P = .049, per SD decrease in log25OHD). In a first sensitivity MR analysis excluding the genetic variants that are unlikely to have a role in biologically active 25OHD, effect estimates were consistent with those from the primary analysis (OR = 2.38, 95% CI =1.06-5.36, P = 0.035, per SD of log25OHD). Furthermore, in a second sensitivity analysis using only the 6 variants within the CYP2R1 locus (which encodes 25OHD hydroxylase, the liver enzyme responsible for converting Vitamin D to 25OHD), genetically decreased 25OHD was strongly associated with increased uveitis/scleritis risk (OR = 6.42, 95% CI = 3.19-12.89, P = 1.7 × 10-7, per SD of log25OHD). CONCLUSIONS:Our findings suggest a causal relationship between low Vitamin D levels and higher risk of non-infectious uveitis and scleritis. Vitamin D supplementation may be a low-cost, low-risk intervention to mitigate non-infectious uveitis and scleritis risk, and should be explored in a prospective trial.

The publisher regrets that in the January 2022 issue, the title of the above article contained a misspelling due to a data entry error. The word ‘analsyes’ should be spelled ‘analyses.’ The publisher would like to apologise for any inconvenience caused. Gene Set Enrichment Analsyes Identify Pathways Involved in Genetic Risk for Diabetic RetinopathyAmerican Journal of OphthalmologyVol. 233PreviewTo identify functionally related genes associated with diabetic retinopathy (DR) risk using gene set enrichment analyses applied to genome-wide association study meta-analyses. Full-Text PDF

To identify functionally related genes associated with diabetic retinopathy (DR) risk using gene set enrichment analyses applied to genome-wide association study meta-analyses. METHODS:We analyzed DR GWAS meta-analyses performed on 3246 Europeans and 2611 African Americans with type 2 diabetes. Gene sets relevant to 5 key DR pathophysiology processes were investigated: tissue injury, vascular events, metabolic events and glial dysregulation, neuronal dysfunction, and inflammation. Keywords relevant to these processes were queried in 4 pathway and ontology databases. Two GSEA methods, Meta-Analysis Gene set Enrichment of variaNT Associations (MAGENTA) and Multi-marker Analysis of GenoMic Annotation (MAGMA), were used. Gene sets were defined to be enriched for gene associations with DR if the P value corrected for multiple testing (Pcorr) was <.05. RESULTS:Five gene sets were significantly enriched for numerous modest genetic associations with DR in one method (MAGENTA or MAGMA) and also at least nominally significant (uncorrected P < .05) in the other method. These pathways were regulation of the lipid catabolic process (2-fold enrichment, Pcorr = .014); nitric oxide biosynthesis (1.92-fold enrichment, Pcorr = .022); lipid digestion, mobilization, and transport (1.6-fold enrichment, P = .032); apoptosis (1.53-fold enrichment, P = .041); and retinal ganglion cell degeneration (2-fold enrichment, Pcorr = .049). The interferon gamma (IFNG) gene, previously implicated in DR by protein-protein interactions in our GWAS, was among the top ranked genes in the nitric oxide pathway (best variant P = .0001). CONCLUSIONS:These GSEA indicate that variants in genes involved in oxidative stress, lipid transport and catabolism, and cell degeneration are enriched for genes associated with DR risk. NOTE: Publication of this article is sponsored by the American Ophthalmological Society.