Association of serum microRNAs with islet autoimmunity, disease progression and metabolic impairment in relatives at risk of type 1 diabetes

Abstract

Aims/hypothesis MicroRNAs (miRNAs) are key regulators of gene expression and novel biomarkers for many diseases. We investigated the hypothesis that serum levels of some miRNAs would be associated with islet autoimmunity and/or progression to type 1 diabetes. Methods We measured levels of 93 miRNAs most commonly detected in serum. This retrospective cohort study included 150 autoantibody-positive and 150 autoantibody-negative family-matched siblings enrolled in the TrialNet Pathway to Prevention Study. This was a young cohort (mean age = 11 years), and most autoantibody-positive relatives were at high risk because they had multiple autoantibodies, with 39/150 (26%, progressors) developing type 1 diabetes within an average 8.7 months of follow-up. We analysed miRNA levels in relation to autoantibody status, future development of diabetes and OGTT C-peptide and glucose indices of disease progression. Results Fifteen miRNAs were differentially expressed when comparing autoantibody-positive/negative siblings (range −2.5 to 1.3-fold). but receiver operating characteristic (ROC) analysis indicated low specificity and sensitivity. Seven additional miRNAs were differentially expressed among autoantibody-positive relatives according to disease progression; ROC returned significant AUC values and identified miRNA cut-off levels associated with an increased risk of disease in both cross-sectional and survival analyses. Levels of several miRNAs showed significant correlations (r 0.22-0.55) with OGTT outcomes. miR-21-3p, miR-29a-3p and miR-424-5p had the most robust associations. Conclusions/interpretation Serum levels of selected miRNAs are associated with disease progression and confer additional risk of the development of type 1 diabetes in young autoantibody-positive relatives. Further studies, including longitudinal assessments, are warranted to further define miRNA biomarkers for prediction of disease risk and progression.

MicroRNA Signatures as Future Biomarkers for Diagnosis of Diabetes States

“…In non-diabetic children (autoantibody positive) who participated in the T1D TrialNet Pathway to Prevention study, children with multiple autoantibodies and elevated miR-29a-3p, miR-21-3p, and miR-424-5p were more likely to progress to T1D within 2 years of follow-up [16]. In another cohort of non-diabetic children with islet autoantibodies, circulating miR-339-3p was elevated while miR-497-5p was decreased [17].…”

A composite immune signature parallels disease progression across T1D subjects

“…Higher-dimension (genome-scale) assays were also included to identify data-driven features of disease progression. These included RNA-Seq of whole blood (30) and sorted B cell, CD4 + and CD8 + T cell, and monocyte subsets (32); immunophenotyping by flow cytometry (33); transcriptional response to T1D serum (22) assessed using Affymetrix microarrays; and serum miRNAs measured by quantitative PCR (qPCR) (24).…”

“…The transcriptional response to T1D serum assay was conducted as described previously (13). The miRNA assay was conducted using the Exiqon qPCR platform as described previously (24). The Treg transcript assay was performed using the NanoString platform as described previously (14,17), with samples for the Treg assay sorted concomitantly with the cell subset RNA-Seq sample set.…”

“…These included genome-scale technologies, included here for broad screening and hypothesis generation: whole-blood and cell subset RNA-Seq (15,20) and an assay measuring the transcriptional response to T1D serum (13,21,22) were used. Assays also included screening assessments that were smaller scale, including immunophenotyping by flow cytometry (23) and measurements of serum miRNA (24). Using these assays, we conducted a proof-of-concept study in a cohort of recent-onset T1D subjects with variable rates of C-peptide decline, who were followed meticulously for both metabolic outcomes and ancillary sample collection over a 2-year period within the context of clinical trial monitoring.…”

The Genetic Architecture of Type 1 Diabetes

“…Of the many areas of potential interest and value, the study of microRNAs (miRNAs) has attracted attention, as they can be detected in serum. A recent study was reported of 93 such miRNAs in the serum of 150 children who were at high disease risk, as they had multiple DAA, and a similar number of low disease risk children without DAA [ 82 ]. It was found that 15 of these 93 miRNAs were higher or lower in the disease risk children, but that the disease’s sensitivity and specificity as a predictor was limited.…”