title: 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.
authors: Joint Molecular Rheumatology Laboratory of the Institute of Health Sciences and Shanghai Renji Hospital, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors: Xiaobing
authors: X
authors: Luo
authors: Wanling
authors: W
authors: Yang
authors: Dong-Qing
authors: DQ
authors: Ye
authors: Huijuan
authors: H
authors: Cui
authors: Yan
authors: Y
authors: Zhang
authors: Nattiya
authors: N
authors: Hirankarn
authors: Xiaoxia
authors: X
authors: Qian
authors: Yuanjia
authors: Y
authors: Tang
authors: Yu Lung
authors: YL
authors: Lau
authors: Niek
authors: N
authors: de Vries
authors: Paul Peter
authors: PP
authors: Tak
authors: Betty P
authors: BP
authors: Tsao
authors: Nan
authors: N
authors: Shen
mesh_terms: D000483:Alleles; D045744:Cell Line, Tumor; D005786:Gene Expression Regulation / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006367:HeLa Cells; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000235:genetics* / Q000378:metabolism*; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism*; D008954:Models, Biological; D009687:Nuclear Proteins / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011485:Protein Binding / Q000502:physiology; D050784:Proto-Oncogene Protein c-ets-1 / Q000235:genetics / Q000378:metabolism; D012307:Risk Factors
chemical_list: C494041:ETS1 protein, human; C542542:MIRN146 microRNA, human; D035683:MicroRNAs; D009687:Nuclear Proteins; D050784:Proto-Oncogene Protein c-ets-1