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A functional variant in microRNA-146a promoter modulates its expression and confers disease risk for systemic lupus erythematosus.

ABSTRACT: Systemic lupus erythematosus (SLE) is a complex autoimmune disease with a strong genetic predisposition, characterized by an upregulated type I interferon pathway. MicroRNAs are important regulators of immune homeostasis, and aberrant microRNA expression has been demonstrated in patients with autoimmune diseases. We recently identified miR-146a as a negative regulator of the interferon pathway and linked the abnormal activation of this pathway to the underexpression of miR-146a in SLE patients. To explore why the expression of miR-146a is reduced in SLE patients, we conducted short parallel sequencing of potentially regulatory regions of miR-146a and identified a novel genetic variant (rs57095329) in the promoter region exhibiting evidence for association with SLE that was replicated independently in 7,182 Asians (P(meta)?=?2.74×10(-8), odds ratio?=?1.29 [1.18-1.40]). The risk-associated G allele was linked to reduced expression of miR-146a in the peripheral blood leukocytes of the controls. Combined functional assays showed that the risk-associated G allele reduced the protein-binding affinity and activity of the promoter compared with those of the promoter containing the protective A allele. Transcription factor Ets-1, encoded by the lupus-susceptibility gene ETS1, identified in recent genome-wide association studies, binds near this variant. The manipulation of Ets-1 levels strongly affected miR-146a promoter activity in vitro; and the knockdown of Ets-1, mimicking its reduced expression in SLE, directly impaired the induction of miR-146a. We also observed additive effects of the risk alleles of miR-146a and ETS1. Our data identified and confirmed an association between a functional promoter variant of miR-146a and SLE. This risk allele had decreased binding to transcription factor Ets-1, contributing to reduced levels of miR-146a in SLE patients.

SUBMITTER: Luo X

PROVIDER: S-EPMC3128113 | biostudies-literature | 2011 Jun

REPOSITORIES: biostudies-literature

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A functional variant in microRNA-146a promoter modulates its expression and confers disease risk for systemic lupus erythematosus.

Luo Xiaobing X Yang Wanling W Ye Dong-Qing DQ Cui Huijuan H Zhang Yan Y Hirankarn Nattiya N Qian Xiaoxia X Tang Yuanjia Y Lau Yu Lung YL de Vries Niek N Tak Paul Peter PP Tsao Betty P BP Shen Nan N

PLoS genetics 20110630 6

Systemic lupus erythematosus (SLE) is a complex autoimmune disease with a strong genetic predisposition, characterized by an upregulated type I interferon pathway. MicroRNAs are important regulators of immune homeostasis, and aberrant microRNA expression has been demonstrated in patients with autoimmune diseases. We recently identified miR-146a as a negative regulator of the interferon pathway and linked the abnormal activation of this pathway to the underexpression of miR-146a in SLE patients. ...[more]

PMID: 21738483

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Project description:Background and objectivemiRNA-146a is a microRNA that plays an important role in systemic lupus erythematosus (SLE). Several studies have examined the role of miRNA-146a in SLE, but have demonstrated equivocal or even contradictory conclusions. Therefore, this meta-analysis aimed to assess the role of miRNA-146a in SLE by examining data from previous studies.MethodsA meta-analysis of relevant papers published before August 31, 2019, in the WanFang, Chinese Biomedical Literature Database (CBM), Chinese National Knowledge Infrastructure (CNKI), PubMed, EMBASE, and Web of Science databases was performed to verify the relationship of miRNA-146a expression level to SLE. Two investigators independently extracted the data and conducted a quality assessment of the studies. All statistical analyses were performed using Stata 14.0. Trial sequence analysis (TSA) was conducted to assess the quality and strength of the studies using the TSA software.ResultsSix publications, involving 151 SEL patients and 132 healthy individuals as controls were included in this meta-analysis. The results showed that the expression of miRNA-146a was associated with SLE risk [standard mean difference (SMD) = -1.21, 95% confidence interval (95% CI) (-2.18, -0.23), P = .015]. The stratified analysis revealed that the expression of miRNA-146a was highly related to higher SLE risk among Asian (SMD = -1.30, 95% CI (-2.52, -0.07), P = .038) and Caucasian (SMD = -0.72, 95% CI (-1.20, -0.24), P = .003) populations. Besides, the serum levels of miRNA146a were significantly different (SMD = -1.73, 95% CI (-3.11, -0.36), P = .014). The TSA revealed that the cumulative Z-curve crossed the typical boundary value, and reached the TSA monitoring boundary, but did not reach the required information size. This indicates that even if the cumulative sample size did not meet required information size, no more trials were needed and a reliable conclusion was reached in advance. Sensitivity analyses indicated the instability of the meta-analysis.ConclusionsOverall, the expression of miRNA-146a is associated with SLE risk. Therefore, miRNA-146a is a promising candidate for the effective diagnosis of SLE. But, due to the limitations of this study, it is necessary to cautiously explain the results of this study.Systematic review registrationPROSPERO CRD42019151381.

Project description:ObjectiveTo evaluate the specificity of expression patterns of cell-free circulating microRNAs (miRNAs) in systemic lupus erythematosus (SLE).MethodsTotal RNA was purified from plasma, and 45 different specific, mature miRNAs were determined using quantitative reverse transcription-polymerase chain reaction assays. A total of 409 plasma samples were obtained from 364 different patients with SLE, healthy control subjects, and control subjects with other autoimmune diseases. The results in the primary cohort of 62 patients with SLE and 29 healthy control subjects were validated in 2 independent cohorts: a validation cohort comprising 68 patients with SLE and 68 healthy control subjects, and a disease control cohort comprising 20 patients with SLE (19 of whom were from the other validation cohort), 46 healthy control subjects, 38 patients with vasculitis, 18 patients with rheumatoid arthritis, and 20 immunosuppressed patients.ResultsSeven miRNAs were statistically significantly differentially expressed in plasma from patients with SLE. The expression of miRNA-142-3p (miR-142-3p) and miR-181a was increased, and the expression of miR-106a, miR-17, miR-20a, miR-203, and miR-92a was decreased. In addition, the expression of miR-342-3p, miR-223, and miR-20a was significantly decreased in SLE patients with active nephritis. A predictive model for SLE based on 2 or 4 miRNAs differentiated patients with SLE from control subjects (76% accuracy) when validated independently (P < 2 × 10(-9) ). Use of the 4-miRNA model provided highly significant differentiation between the SLE group and disease controls, except for those with vasculitis.ConclusionCirculating miRNAs are systematically altered in SLE. A 4-miRNA signature was diagnostic of SLE, and a specific subset of miRNA profiles was associated with nephritis. All of the signature miRNAs target genes in the transforming growth factor β signaling pathways. Other targets include regulation of apoptosis, cytokine-cytokine receptors, T cell development, and cytoskeletal organization. These findings highlight possible dysregulated pathways in SLE and suggest that circulating miRNA patterns distinguish SLE from other immunoinflammatory phenotypes.

Dataset Information

A functional variant in microRNA-146a promoter modulates its expression and confers disease risk for systemic lupus erythematosus.

Publications

A functional variant in microRNA-146a promoter modulates its expression and confers disease risk for systemic lupus erythematosus.

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