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

TitleA functional variant in microRNA-146a promoter modulates its expression and confers disease risk for systemic lupus erythematosus
Authors
Issue Date2011
PublisherPublic Library of Science. The Journal's web site is located at http://www.plosgenetics.org/
Citation
Plos Genetics, 2011, v. 7 n. 6 How to Cite?
AbstractSystemic 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. © 2011 Luo et al.
Persistent Identifierhttp://hdl.handle.net/10722/139587
ISSN
2014 Impact Factor: 7.528
2015 SCImago Journal Rankings: 6.308
PubMed Central ID
ISI Accession Number ID
Funding AgencyGrant Number
National Natural Science Foundation of China30971632
81025016
30830089
National High Technology Research and Development Program of China (863 Program)2007AA02Z123
Program of the Shanghai Commission of Science and Technology08JC1414700
10JC1409300
National Basic Research Program of China (973 Program)2007CB947900
Shanghai Commission of Science and Technology10ZR1434900
Research Grant Council of Hong KongGRF HKU781709M
US National Institutes of HealthRO1AR043814
Higher Education Research Promotion
National Research University Project of Thailand
Office of the Higher Education CommissionHR1163A
Funding Information:

This work was partially supported by the National Natural Science Foundation of China 30971632, 81025016; the National High Technology Research and Development Program of China (863 Program) 2007AA02Z123; the Program of the Shanghai Commission of Science and Technology 08JC1414700, 10JC1409300; the National Basic Research Program of China (973 Program) 2007CB947900 (to NS); the Program of the Shanghai Commission of Science and Technology 10ZR1434900 (to HC); the Research Grant Council of Hong Kong GRF HKU781709M (to WY); the National Natural Science Foundation of China 30830089 (to D-QY); and the US National Institutes of Health grant RO1AR043814 (to BPT). YLL thanks the generous donations from Shun Tak District Min Yuen Tong of Hong Kong. NH thanks the Higher Education Research Promotion and National Research University Project of Thailand, Office of the Higher Education Commission (HR1163A). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

References

 

DC FieldValueLanguage
dc.contributor.authorLuo, Xen_HK
dc.contributor.authorYang, Wen_HK
dc.contributor.authorYe, DQen_HK
dc.contributor.authorCui, Hen_HK
dc.contributor.authorZhang, Yen_HK
dc.contributor.authorHirankarn, Nen_HK
dc.contributor.authorQian, Xen_HK
dc.contributor.authorTang, Yen_HK
dc.contributor.authorLau, YLen_HK
dc.contributor.authorde Vries, Nen_HK
dc.contributor.authorTak, PPen_HK
dc.contributor.authorTsao, BPen_HK
dc.contributor.authorShen, Nen_HK
dc.date.accessioned2011-09-23T05:52:08Z-
dc.date.available2011-09-23T05:52:08Z-
dc.date.issued2011en_HK
dc.identifier.citationPlos Genetics, 2011, v. 7 n. 6en_HK
dc.identifier.issn1553-7390en_HK
dc.identifier.urihttp://hdl.handle.net/10722/139587-
dc.description.abstractSystemic 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. © 2011 Luo et al.en_HK
dc.languageengen_US
dc.publisherPublic Library of Science. The Journal's web site is located at http://www.plosgenetics.org/en_HK
dc.relation.ispartofPLoS Geneticsen_HK
dc.rightsCreative Commons: Attribution 3.0 Hong Kong License-
dc.subject.meshGene Expression Regulation - genetics-
dc.subject.meshGenetic Predisposition to Disease - genetics-
dc.subject.meshLupus Erythematosus, Systemic - genetics - metabolism-
dc.subject.meshMicroRNAs - genetics - metabolism-
dc.subject.meshPromoter Regions, Genetic - genetics-
dc.titleA functional variant in microRNA-146a promoter modulates its expression and confers disease risk for systemic lupus erythematosusen_HK
dc.typeArticleen_HK
dc.identifier.emailYang, W:yangwl@hkucc.hku.hken_HK
dc.identifier.emailLau, YL:lauylung@hkucc.hku.hken_HK
dc.identifier.authorityYang, W=rp00524en_HK
dc.identifier.authorityLau, YL=rp00361en_HK
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1371/journal.pgen.1002128en_HK
dc.identifier.pmid21738483-
dc.identifier.pmcidPMC3128113-
dc.identifier.scopuseid_2-s2.0-79959836816en_HK
dc.identifier.hkuros196003en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-79959836816&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume7en_HK
dc.identifier.issue6en_HK
dc.identifier.spagee1002128en_US
dc.identifier.epagee1002128en_US
dc.identifier.isiWOS:000292386300044-
dc.publisher.placeUnited Statesen_HK
dc.identifier.scopusauthoridLuo, X=26531455400en_HK
dc.identifier.scopusauthoridYang, W=23101349500en_HK
dc.identifier.scopusauthoridYe, DQ=24588340700en_HK
dc.identifier.scopusauthoridCui, H=36155185400en_HK
dc.identifier.scopusauthoridZhang, Y=35789432400en_HK
dc.identifier.scopusauthoridHirankarn, N=12783320200en_HK
dc.identifier.scopusauthoridQian, X=36572441800en_HK
dc.identifier.scopusauthoridTang, Y=13407838200en_HK
dc.identifier.scopusauthoridLau, YL=7201403380en_HK
dc.identifier.scopusauthoridde Vries, N=7006108303en_HK
dc.identifier.scopusauthoridTak, PP=39362346900en_HK
dc.identifier.scopusauthoridTsao, BP=7005956550en_HK
dc.identifier.scopusauthoridShen, N=7102785475en_HK
dc.identifier.citeulike9516925-

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