MicroRNAs Within the Continuum of Postgenomics Biomarker Discovery

Mayr, Manuel; Zampetaki, Anna; Willeit, Peter; Willeit, Johann; Kiechl, Stefan

doi:10.1161/atvbaha.112.300141

Cited by 90 publications

(67 citation statements)

References 65 publications

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“…It has been suggested that extracellular miRNAs have specific physiological functions, depending on their cellular origin and regulating immune function, cell migration and differentiation, and other aspects of cell-to-cell communication (7,11). This has sparked the concept that extracellular miRNAs contained in body fluids could be useful as biomarkers for the detection and classification of diseases (12). Indeed, their presence in plasma and the possibility of detecting and analyzing small interindividual variations make circulating miRNAs excellent potential biomarkers for complex systemic diseases such as T2D (8,13,14).…”

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confidence: 99%

Profiling of Circulating MicroRNAs Reveals Common MicroRNAs Linked to Type 2 Diabetes That Change With Insulin Sensitization

et al. 2014

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OBJECTIVEThis study sought to identify the profile of circulating microRNAs (miRNAs) in type 2 diabetes (T2D) and its response to changes in insulin sensitivity. RESEARCH DESIGN AND METHODSThe circulating miRNA profile was assessed in a pilot study of 12 men: 6 with normal glucose tolerance (NGT) and 6 T2D patients. The association of 10 circulating miRNAs with T2D was cross-sectionally validated in an extended sample of 45 NGT vs. 48 T2D subjects (65 nonobese and 28 obese men) and longitudinally in 35 T2D patients who were recruited in a randomized, double-blinded, and placebo-controlled 3-month trial of metformin treatment. Circulating miRNAs were also measured in seven healthy volunteers before and after a 6-h hyperinsulinemiceuglycemic clamp and insulin plus intralipid/heparin infusion. RESULTSCross-sectional studies disclosed a marked increase of miR-140-5p, miR-142-3p, and miR-222 and decreased miR- 423-5p, miR-125b, miR-192, miR-195, miR-130b, miR-532-5p, and miR-126 in T2D patients. Multiple linear regression analyses revealed that miR-140-5p and miR-423-5p contributed independently to explain 49.5% (P < 0.0001) of fasting glucose variance after controlling for confounders. A discriminant function of four miRNAs (miR-140-5p, miR-423-5p, miR-195, and miR-126) was specific for T2D with an accuracy of 89.2% (P < 0.0001). Metformin (but not placebo) led to significant changes in circulating miR-192 (49.5%; P = 0.022), miR-140-5p (215.8%; P = 0.004), and miR-222 (247.2%; P = 0.03), in parallel to decreased fasting glucose and HbA 1c . Furthermore, while insulin infusion during clamp decreased miR-222 (262%; P = 0.002), the intralipid/heparin mixture increased circulating miR-222 (163%; P = 0.015) and miR-140-5p (67.5%; P = 0.05). CONCLUSIONSThis study depicts the close association between variations in circulating miRNAs and T2D and their potential relevance in insulin sensitivity.

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Profiling of Circulating MicroRNAs Reveals Common MicroRNAs Linked to Type 2 Diabetes That Change With Insulin Sensitization

et al. 2014

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“…We have also highlighted their platelet origin (6) and applied concepts of network topology to explore their biomarker potential (7). Exciting opportunities exist to pursue miRNAs as novel biomarkers for risk estimation and patient stratification (8).…”

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Angiogenic microRNAs Linked to Incidence and Progression of Diabetic Retinopathy in Type 1 Diabetes

et al. 2015

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Circulating microRNAs (miRNAs) have emerged as novel biomarkers of diabetes. The current study focuses on the role of circulating miRNAs in patients with type 1 diabetes and their association with diabetic retinopathy. A total of 29 miRNAs were quantified in serum samples (n = 300) using a nested case-control study design in two prospective cohorts of the DIabetic REtinopathy Candesartan Trial (DIRECT): PROTECT-1 and PREVENT-1. The PREVENT-1 trial included patients without retinopathy at baseline; the PROTECT-1 trial included patients with nonproliferative retinopathy at baseline. Two miRNAs previously implicated in angiogenesis, miR-27b and miR-320a, were associated with incidence and with progression of retinopathy: the odds ratio per SD higher miR-27b was 0.57 (95% CI 0.40, 0.82; P = 0.002) in PREVENT-1, 0.78 (0.57, 1.07; P = 0.124) in PROTECT-1, and 0.67 (0.50, 0.92; P = 0.012) combined. The respective odds ratios for higher miR-320a were 1.57 (1.07, 2.31; P = 0.020), 1.43 (1.05, 1.94; P = 0.021), and 1.48 (1.17, 1.88; P = 0.001). Proteomics analyses in endothelial cells returned the antiangiogenic protein thrombospondin-1 as a common target of both miRNAs. Our study identifies two angiogenic miRNAs, miR-320a and miR-27b, as potential biomarkers for diabetic retinopathy.Recent studies have begun to unveil a powerful and unexpected role of microRNAs (miRNAs) in numerous forms of diseases, providing a unique opportunity to translate this knowledge into the clinical setting in the form of miRNA-based therapeutics and diagnostics (1,2). miRNAs are small noncoding RNAs with cell-type specific expression patterns that orchestrate biological networks by modulating gene expression. miRNAs form base pairs with their target messenger RNAs and mediate gene silencing, often regulating multiple proteins within the same biological pathways. Given their importance in angiogenesis, along with the technical feasibility in manipulating their function in vivo, vascular miRNAs have become central targets for therapeutic manipulation, including diabetes (3).Additionally, miRNAs circulate in blood. We have previously performed the first systematic analysis of circulating miRNAs in a population-based study (the Bruneck Study) and identified distinct miRNA signatures associated with type 2 diabetes (4) and risk of myocardial infarction (5). We have also highlighted their platelet origin (6) and applied concepts of network topology to explore their biomarker potential (7). Exciting opportunities exist to pursue miRNAs as novel biomarkers for risk estimation and patient stratification (8).The current study addresses the role of circulating miRNAs in patients with type 1 diabetes (T1D) and their association with microvascular complications, in particular, diabetic retinopathy. Our aims were threefold: first, to evaluate whether miRNA profiles are independently associated with retinopathy development and progression in diabetes; second, to quantify the incremental discriminatory power of miRNAs over and above traditional risk markers; ...

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“…[3][4][5][6] In this issue of Circulation Research, Elgheznawy et al 7 add mechanistic insights to the loss of platelet-derived miRNAs in diabetes mellitus. They hypothesized that changes in Dicer expression and activity could account for the observed alterations in the miRNA profile of diabetic patients.…”

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confidence: 99%