Identification of a Multi-Long Noncoding RNA Signature for the Diagnosis of Type 1 Diabetes Mellitus.

Guannan Geng,Zicheng Zhang,Liang Cheng

doi:10.3389/fbioe.2020.00553

Abstract

Due to the increasing prevalence of type 1 diabetes mellitus (T1DM) and its complications, there is an urgent need to identify novel methods for predicting the occurrence and understanding the pathogenetic mechanisms of the disease. Accumulated data have demonstrated the potential of long noncoding RNAs (lncRNAs), as biomarkers in establishing diagnosis and predicting prognosis of numerous diseases. Yet, little is known about the expression patterns and regulatory roles of lncRNAs in the pathogenesis of T1DM and whether they can be used as diagnostic biomarkers for the disease. To further explore these questions, in the present study, we conducted a comparative analysis of the expression patterns of lncRNAs between 20 T1DM patients and 42 health controls by retrospectively analyzing a published microarray data set. Our results indicate that, compared with healthy controls, diabetic patients had altered levels of lncRNAs. Then, we used three time cross-validation strategy and support vector machine to propose a specific 26-lncRNA signature (termed 26LncSigT1DM). This 26LncSigT1DM signature can be used to effectively distinguish between healthy and diabetic individuals (area under the curve = 0.825) of a validation cohort. After the 26LncSigT1DM was prospectively validated, we used Pearson correlation to identify 915 mRNAs, whose expression levels were positively correlated with those of the 26 lncRNAs. According to their Gene Ontology annotations, these mRNAs participate in processes including cellular response to stimulus, cell communication, multicellular organismal process, and cell motility. Kyoto Encyclopedia of Genes and Genomes analysis demonstrated that the genes encoding the 915 mRNAs may be associated with the NOD-like receptor signaling pathway, transforming growth factor β signaling pathway, and mineral absorption, suggesting that the deregulation of these lncRNAs may mediate inflammatory abnormalities and immune dysfunctions, which jointly promote the pathogenesis of T1DM. Thus, our study identifies a novel diagnostic tool and may shed more light on the molecular mechanisms underlying the pathogenesis of T1DM.

Highlights

As one of the most notorious autoimmune disorders, type 1 diabetes mellitus (T1DM) is a chronic childhood-onset disease caused by selective destruction of pancreatic islet beta cells (Petersmann et al, 2018)
To provide more insights into the expression patterns of long noncoding RNAs (lncRNAs) in T1DM patients and evaluate their potential as T1DM biomarkers, in this study, we comparatively analyzed lncRNA expression levels in 42 healthy individuals and 20 T1DM patients based on a published microarray data set and identified a group of differentially expressed lncRNAs. We demonstrated that these lncRNAs may represent a multi–long noncoding RNA signature that can be used to effectively distinguish between healthy and diabetic individuals and identify T1DM susceptible individuals
After abandoning lncRNAs with a false discovery rate (FDR)– adjusted p < 0.01, we totally identified 1,326 differentially expressed lncRNAs (DELs)

Summary

INTRODUCTION

As one of the most notorious autoimmune disorders, type 1 diabetes mellitus (T1DM) is a chronic childhood-onset disease caused by selective destruction of pancreatic islet beta cells (Petersmann et al, 2018). All the aforementioned studies suggest that lncRNAs can regulate both the activation of the innate immune system and islet β cell function, the defects of which contribute significantly to the pathogenesis of T1DM. After the 26LncSigT1DM signature was prospectively validated, we identified 915 mRNAs whose expression levels are positively correlated with those of the 26LncSigT1DM lncRNAs. After the 26LncSigT1DM signature was prospectively validated, we identified 915 mRNAs whose expression levels are positively correlated with those of the 26LncSigT1DM lncRNAs Functional analysis of these mRNAs indicates that they are involved in a variety of biological processes, including cellular function and communication, and that the genes encoding these mRNAs are associated with pathways that can potentially mediate inflammatory abnormalities and immune dysfunctions. Our study provides a platform for developing 26LncSigT1DM into a diagnostic tool for T1DM and for future research into the molecular mechanisms underlying the pathogenesis of T1DM

MATERIALS AND METHODS

RESULTS

DISCUSSION