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Publication Information
Affiliation
1University of California, San Francisco, Department of Physiological Nursing, San Francisco, CA, USA
2New York University Bluestone Center for Clinical Research, New York, NY, USA, 10010
3New York University Department of Oral and Maxillofacial Surgery, New York, NY, USA, 10010
5University of California, San Francisco, Department of Epidemiology and Biostatistics, San Francisco, CA, USA
6University of California, San Francisco, Department of Medicine, Division of Hematology and Oncology, San Francisco, CA
7University of California, San Francisco, Department of Medicine, Division of General Internal Medicine, San Francisco, CA, USA
8Center for Genomic Medicine and Diabetes Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA
9Programs in Metabolism and Medical &Population Genetics, Broad Institute, Cambridge, MA
10Department of Medicine, Harvard Medical School, Boston, MA
11University of California, San Francisco, Institute for Human Genetics, San Francisco, CA, USA
Authors
Aouizerat BE, Asam K, Florez J, Flowers E, Kanaya AM, Kariuki D, Zhang L
Studies
Abstract
Aims/Hypothesis:
Our prior secondary analysis of the Diabetes Prevention Program study identified a subset of five microRNAs (miRs) that predict incident T2D. 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 downloaded experimentally validated data from miRTarBase version 8.0 and used R (2021) to identify mRNAs with strong evidence to be regulated by the five previously identified miRs. Overrepresentation of the mRNA targets was assessed in pathways from the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway annotation database.
Results:
The five miRs targeted a total of 122 mRNAs and 167 pathways. Among the identified pathways, nine have known associations with T2D: Insulin signaling, Insulin resistance, Diabetic cardiomyopathy, Type II diabetes, AGE-RAGE signaling in diabetic complications, HIF-1 signaling, TGF-beta signaling, PI3K/Akt signaling, and Adipocytokine signaling pathways. Of these, AGE-RAGE signaling was targeted by all five miRs, HIF-1 signaling was targeted by all except miR-144, and PI3K/Akt signaling by all except miR-186. 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), phosphatase and tensin homolog (PTEN), and VEGFA have prior genetic associations with risk for T2D.
Conclusions/Interpretation:
These findings show 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 inform the mechanisms underlying risk reduction interventions, allowing for more precise treatments for individuals.