Human pancreatic islet microRNAs implicated in diabetes and related traits by large-scale genetic analysis

Abstract

Genetic studies have identified ≥240 loci associated with the risk of type 2 diabetes (T2D), yet most of these loci lie in non-coding regions, masking the underlying molecular mechanisms. Recent studies investigating mRNA expression in human pancreatic islets have yielded important insights into the molecular drivers of normal islet function and T2D pathophysiology. However, similar studies investigating microRNA (miRNA) expression remain limited. Here, we present data from 63 individuals, the largest sequencing-based analysis of miRNA expression in human islets to date. We characterized the genetic regulation of miRNA expression by decomposing the expression of highly heritable miRNAs into cis- and trans- acting genetic components and mapping cis -acting loci associated with miRNA expression [miRNA-expression quantitative trait loci (eQTLs)]. We found i) 84 heritable miRNAs, primarily regulated by trans -acting genetic effects, and ii) 5 miRNA-eQTLs. We also used several different strategies to identify T2D-associated miRNAs. First, we colocalized miRNA-eQTLs with genetic loci associated with T2D and multiple glycemic traits, identifying one miRNA, miR-1908, that shares genetic signals for blood glucose and glycated hemoglobin (HbA1c). Next, we intersected miRNA seed regions and predicted target sites with credible set SNPs associated with T2D and glycemic traits and found 32 miRNAs that may have altered binding and function due to disrupted seed regions. Finally, we performed differential expression analysis and identified 14 miRNAs associated with T2D status—including miR-187-3p, miR-21-5p, miR-668, and miR-199b-5p—and 4 miRNAs associated with a polygenic score for HbA1c levels—miR-216a, miR-25, miR-30a-3p, and miR-30a-5p.

Emerging roles of microRNAs as diagnostics and potential therapeutic interest in type 2 diabetes mellitus

“…This suppression of miR-let-7g-5p contributes to reduced fat metabolism and increases inflammation, promoting myopathy[ 37 ]. Taylor et al [ 38 ] identified 84 heritable miRNAs and 5 miRNA-expression (miR-216a, miR-25, miR-30a-3p, and miR-30a-5p) quantitative trait loci associated with blood glucose and glycated HbA1c levels. miRNA-152-3p expression, despite initial consideration ineffectiveness as a prognostic indicator for the progression to end-stage renal disease, unlike serum CX3CL1 levels and urinary IgG, which showed promising efficacy in early prediction of nephropathy[ 39 ].…”

Lessons and Applications of Omics Research in Diabetes Epidemiology

“…Eighty-four miRNAs were found to be highly heritable, and mainly regulated by trans-acting genetic effects. In addition, the study identified 14 T2D-related miRNAs including miR-21-5p and miR-187-3p [ 82 ]. High-throughput quantitative real-time PCR (qPCR) is another commonly used approach in miRNA profiling.…”

Comparison of glimepiride and linagliptin in the treatment of non-alcoholic hepatic disease with Type 2 diabetes mellitus

“…MicroRNAs (miRNAs) are a kind of small noncoding RNA molecules (21)(22)(23)(24)(25) nucleotides in length) that regulate gene expression at the post-transcriptional level and participate in various critical biological processes [17][18][19]. miRNA regulates human genes that are involved in almost all cellular processes [20,21] and is linked to the diagnosis or prognosis of numerous diseases, including T2DM [22][23][24]. Studies have revealed that miR-210 is related to hepatic function and dysregulation in T2DM [25,26].…”