Retinal transcriptome and cellular landscape in relation to the progression of diabetic retinopathy

Abstract

AbstractImportancePrevious studies identify putative genes associated with diabetic retinopathy only focusing on specific clinical stage, thus resulting genes are not necessarily reflective of disease progression.ObjectiveTo identify genes associated with the severity level of diabetic retinopathy using likelihood-ration test (LRT) and ordinal logistic regression (OLR) model, as well as to profile immune and retinal cell landscape in progressive diabetic retinopathy using a machine learning deconvolution approach.Design, Setting, and ParticipantsThis study used published transcriptomic dataset (GSE160306) from macular regions of donors with different degrees of diabetic retinopathy (10 healthy controls, 10 cases of diabetes, 9 cases of nonproliferative diabetic retinopathy and 10 cases of proliferative diabetic retinopathy or combined with diabetic macular edema). Transcriptomic dataset was released on April 19, 2021; data were analyzed on 28th March 2022.Main Outcomes and MeasuresIdentification of severity-associated genes with LRT and OLR model and proportional changes of immune and retinal cells in progressive diabetic retinopathy.ResultsBy controlling for gender and age using LRT and OLR, 50 genes were identified to be significantly increased in expression with the severity of diabetic retinopathy. Functional enrichment analyses suggested these severity-associated genes are related to inflammation and immune responses. CCND1 and FCGR2B are further identified as key regulators to interact with many other severity-associated genes and are crucial to inflammation. Deconvolution analyses demonstrated that the proportions of memory B cells, M2 macrophages and Müller glia were significantly increased with the progression of diabetic retinopathy.Conclusions and RelevanceThese findings demonstrate the deep analyses of transcriptomic data can advance our understanding of progressive ocular diseases, such as DR, by applying LRT and OLR model as well as bulk gene expression deconvolution.Key PointsQuestionDo genes change in expression or immune cells and retinal cells change in proportions in the human retina with the severity of diabetic retinopathy?FindingsIn this in-depth retinal transcriptomic analysis of 39 participants, consisting of 10 heathy controls, 29 cases of diabetic retinopathy at different clinical stages, severity-associated genes were identified, and the estimated proportions of immune cell and retinal cells were profiled, respectively.MeaningThese findings demonstrate that a group of genes are significantly increased in expression, and the proportions of memory B cells, M2 macrophages and Müller glia were significantly increased with the severity of diabetic retinopathy.