Association of Peroxisome Proliferator-Activated Receptors (PPARs) with Diabetic Retinopathy in Human and Animal Models: Analysis of the Literature and Genome Browsers

Abstract

Diabetic retinopathy (DR) is a condition that develops after long-lasting and poorly handled diabetes and is presently the main reason for blindness among elderly and youth. Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that are involved in carbohydrate and fatty-acid metabolism and have also been associated with DR. Three PPAR isoforms are known: PPARG, PPARA, and PPARD. In the present study, we retrieved articles reporting associations between PPARs and DR from PubMed database and compiled the data in two catalogues, for human and animal models. Extracted data was then complemented with additional relevant genomic information. Seven retrieved articles reported testing an association between PPARs with DR in human. Four of them concluded association of PPARG and PPARA with DR in European and Asian populations, having a protective role on DR development. One study reported pathogenic role of PPARG, while two articles reported no association between PPARG and DR among Indian and Chinese populations. Six retrieved articles reported testing of involvement of PPARG and PPARA in DR in animal models, including mouse and rat. The review includes case-control studies, meta-analysis, expression studies, animal models, and cell line studies. Despite a large number of documented sequence variants of the PPAR genes available in genome browsers, researchers usually focus on a small set of previously reported variants. Data extraction from Ensembl genome browser revealed several sequence variants with predicted deleterious effect on protein function which present candidates for further experimental validation. Results of the present analysis will enable more holistic approach for understanding of PPARs in DR development. Additionally, developed catalogues present a baseline for standardized reporting of PPAR-phenotype association in upcoming studies.

Figure 1

Workflow of the study.

Figure 2

Overview of the results. The number of retrieved articles associating PPARs with DR/PDR is marked in grey color. Yellow color represents the number of articles reporting gene-DR/PDR association including protective effect or decreased DR risk. Green color represents the number of articles reporting no association between the gene and DR/PDR, and red color represents the number of articles reporting a pathogenic effect on DR/PDR.

Figure 3

Print screen of the Ensembl genome browser presenting a part of the variant table of the PPARG gene. The table includes seven selected sequence variants and results of bioinformatics prediction of their effect on protein function. Ensembl browser includes six tools for predicting effects of substitutions on protein function: SIFT, PolyPhen, CADD. REVEL, MetaLR, and Mutation Assessor. Predicted effect on protein function is shown in different colors: benign: green; tolerated/neutral: blue; possibly damaging: orange; damaging: red. Clin. Sig.: clinical significance; a classification of a variant's impact on disease, according to the ClinVar database: pathogenic: red triangle; likely pathogenic: orange triangle; likely benign: blue cross.