Abstract 12818: Microrna Biomarkers Target Genes and Pathways Associated With Type 2 Diabetes

Abstract

Introduction: Type 2 diabetes (T2D) is a major risk factor for cardiovascular disease (CVD), and CVD remains a leading cause of death among those living with T2D. MicroRNAs (miRs) target messenger RNAs (mRNAs) to alter gene expression, and circulating miRs, which are readily measured from blood, have been studied as potential biomarkers for T2D risk. Our prior analysis of the Diabetes Prevention Program identified a subset of five miRs that were optimal predictors of incident T2D with interactions by trial arm. The purpose of this study was to identify the mRNA and biological pathways targeted by these five miRs to elucidate potential mechanisms of risk and responses to the tested interventions. Methods: We obtained experimentally validated human data from miRTarBase (version 8.0), filtered and subsetted the data using R (version 4.1.1) to identify mRNAs with strong evidence of being regulated by the five miRs. Pathway analysis was employed to assess for overrepresentation of the mRNA targets of miRs using the Kyoto Encyclopedia of Genes and Genomes (KEGG) annotation database and clusterProfiler (version 4.2.2) package. Results: The five miRs targeted a total of 167 pathways and 122 genes. Among the identified pathways, nine have known T2D associations: Insulin signaling, Insulin resistance, Diabetic cardiomyopathy, T2D, AGE-RAGE signaling in diabetic complications, HIF-1 signaling, TGF-beta signaling, Fatty acid biosynthesis, and Endocrine resistance. Of these, AGE-RAGE signaling was targeted by all five miRs and HIF-1 signaling was targeted by all except miR-144. A total of 36 genes were targeted in the two pathways. Vascular endothelial growth factor A (VEGFA) was targeted by miR-186, miR-203a, miR-205, and miR-206 in both AGE-RAGE and HIF-1 signaling pathways. Among genes that were targeted by two or more miRs, BCL2 apoptosis regulator (BCL2) and VEGFA have prior genetic associations with risk for T2D. Conclusions: These findings suggest that miR predictors of incident T2D target mRNAs and pathways known to underlie risk for T2D. Future studies can evaluate miRs as potential therapeutic targets for preventing and treating T2D and for informing mechanisms underlying risk reduction interventions, allowing for more precise treatments for individuals.