A Functional Variant in Promoter Modulates Its Expression and Confers Disease Risk for Systemic Lupus Erythematosus
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 (Pmeta = 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.
Vyšlo v časopise:
A Functional Variant in Promoter Modulates Its Expression and Confers Disease Risk for Systemic Lupus Erythematosus. PLoS Genet 7(6): e32767. doi:10.1371/journal.pgen.1002128
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.pgen.1002128
Souhrn
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 (Pmeta = 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.
Zdroje
1. D'CruzDPKhamashtaMAHughesGR 2007 Systemic lupus erythematosus. Lancet 369 587 596
2. RahmanAIsenbergDA 2008 Systemic lupus erythematosus. N Engl J Med 358 929 939
3. HarleyJBAlarcon-RiquelmeMECriswellLAJacobCOKimberlyRP 2008 Genome-wide association scan in women with systemic lupus erythematosus identifies susceptibility variants in ITGAM, PXK, KIAA1542 and other loci. Nat Genet 40 204 210
4. HomGGrahamRRModrekBTaylorKEOrtmannW 2008 Association of systemic lupus erythematosus with C8orf13-BLK and ITGAM-ITGAX. N Engl J Med 358 900 909
5. GrahamRRCotsapasCDaviesLHackettRLessardCJ 2008 Genetic variants near TNFAIP3 on 6q23 are associated with systemic lupus erythematosus. Nat Genet 40 1059 1061
6. KozyrevSVAbelsonAKWojcikJZaghloolALinga ReddyMV 2008 Functional variants in the B-cell gene BANK1 are associated with systemic lupus erythematosus. Nat Genet 40 211 216
7. GatevaVSandlingJKHomGTaylorKEChungSA 2009 A large-scale replication study identifies TNIP1, PRDM1, JAZF1, UHRF1BP1 and IL10 as risk loci for systemic lupus erythematosus. Nat Genet 41 1228 1233
8. HanJWZhengHFCuiYSunLDYeDQ 2009 Genome-wide association study in a Chinese Han population identifies nine new susceptibility loci for systemic lupus erythematosus. Nat Genet 41 1234 1237
9. YangWShenNYeDQLiuQZhangY 2010 Genome-wide association study in Asian populations identifies variants in ETS1 and WDFY4 associated with systemic lupus erythematosus. PLoS Genet 6 e1000841 doi:10.1371/journal.pgen.1000841
10. CrowMK 2008 Collaboration, genetic associations, and lupus erythematosus. N Engl J Med 358 956 961
11. FlesherDLSunXBehrensTWGrahamRRCriswellLA 2010 Recent advances in the genetics of systemic lupus erythematosus. Expert Rev Clin Immunol 6 461 479
12. BennettLPaluckaAKArceECantrellVBorvakJ 2003 Interferon and granulopoiesis signatures in systemic lupus erythematosus blood. J Exp Med 197 711 723
13. HanGMChenSLShenNYeSBaoCD 2003 Analysis of gene expression profiles in human systemic lupus erythematosus using oligonucleotide microarray. Genes Immun 4 177 186
14. BaechlerECBatliwallaFMKarypisGGaffneyPMOrtmannWA 2003 Interferon-inducible gene expression signature in peripheral blood cells of patients with severe lupus. Proc Natl Acad Sci U S A 100 2610 2615
15. PascualVFarkasLBanchereauJ 2006 Systemic lupus erythematosus: all roads lead to type I interferons. Curr Opin Immunol 18 676 682
16. RonnblomLElorantaMLAlmGV 2006 The type I interferon system in systemic lupus erythematosus. Arthritis Rheum 54 408 420
17. CrowMK 2007 Type I interferon in systemic lupus erythematosus. Curr Top Microbiol Immunol 316 359 386
18. RonnblomLAlmGVElorantaML 2009 Type I interferon and lupus. Curr Opin Rheumatol 21 471 477
19. BartelDP 2004 MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116 281 297
20. BaltimoreDBoldinMPO'ConnellRMRaoDSTaganovKD 2008 MicroRNAs: new regulators of immune cell development and function. Nat Immunol 9 839 845
21. LodishHFZhouBLiuGChenCZ 2008 Micromanagement of the immune system by microRNAs. Nat Rev Immunol 8 120 130
22. XiaoCRajewskyK 2009 MicroRNA control in the immune system: basic principles. Cell 136 26 36
23. TangYLuoXCuiHNiXYuanM 2009 MicroRNA-146A contributes to abnormal activation of the type I interferon pathway in human lupus by targeting the key signaling proteins. Arthritis Rheum 60 1065 1075
24. DuanRPakCJinP 2007 Single nucleotide polymorphism associated with mature miR-125a alters the processing of pri-miRNA. Hum Mol Genet 16 1124 1131
25. MenciaAModamio-HoybjorSRedshawNMorinMMayo-MerinoF 2009 Mutations in the seed region of human miR-96 are responsible for nonsyndromic progressive hearing loss. Nat Genet 41 609 613
26. JazdzewskiKMurrayELFranssilaKJarzabBSchoenbergDR 2008 Common SNP in pre-miR-146a decreases mature miR expression and predisposes to papillary thyroid carcinoma. Proc Natl Acad Sci U S A 105 7269 7274
27. TaganovKDBoldinMPChangKJBaltimoreD 2006 NF-kappaB-dependent induction of microRNA miR-146, an inhibitor targeted to signaling proteins of innate immune responses. Proc Natl Acad Sci U S A 103 12481 12486
28. PurcellSNealeBTodd-BrownKThomasLFerreiraMA 2007 PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81 559 575
29. CurtaleGCitarellaFCarissimiCGoldoniMCarucciN 2010 An emerging player in the adaptive immune response: microRNA-146a is a modulator of IL-2 expression and activation-induced cell death in T lymphocytes. Blood 115 265 273
30. LuoXTsaiLMShenNYuD 2010 Evidence for microRNA-mediated regulation in rheumatic diseases. Ann Rheum Dis 69 Suppl 1 i30 36
31. XuTZhuYWeiQKYuanYZhouF 2008 A functional polymorphism in the miR-146a gene is associated with the risk for hepatocellular carcinoma. Carcinogenesis 29 2126 2131
32. XuBFengNHLiPCTaoJWuD 2010 A functional polymorphism in Pre-miR-146a gene is associated with prostate cancer risk and mature miR-146a expression in vivo. Prostate 70 467 472
33. Delgado-VegaAMAlarcon-RiquelmeMEKozyrevSV 2010 Genetic associations in type I interferon related pathways with autoimmunity. Arthritis Res Ther 12 Suppl 1 S2
34. SigurdssonSNordmarkGGoringHHLindroosKWimanAC 2005 Polymorphisms in the tyrosine kinase 2 and interferon regulatory factor 5 genes are associated with systemic lupus erythematosus. Am J Hum Genet 76 528 537
35. GrahamRRKozyrevSVBaechlerECReddyMVPlengeRM 2006 A common haplotype of interferon regulatory factor 5 (IRF5) regulates splicing and expression and is associated with increased risk of systemic lupus erythematosus. Nat Genet 38 550 555
36. GrahamRRKyogokuCSigurdssonSVlasovaIADaviesLR 2007 Three functional variants of IFN regulatory factor 5 (IRF5) define risk and protective haplotypes for human lupus. Proc Natl Acad Sci U S A 104 6758 6763
37. RemmersEFPlengeRMLeeATGrahamRRHomG 2007 STAT4 and the risk of rheumatoid arthritis and systemic lupus erythematosus. N Engl J Med 357 977 986
38. KariukiSNKirouKAMacDermottEJBarillas-AriasLCrowMK 2009 Cutting edge: autoimmune disease risk variant of STAT4 confers increased sensitivity to IFN-alpha in lupus patients in vivo. J Immunol 182 34 38
39. RulloOJWooJMWuHHoftmanADMaranianP 2010 Association of IRF5 polymorphisms with activation of the interferon alpha pathway. Ann Rheum Dis 69 611 617
40. WuKK 2006 Analysis of protein-DNA binding by streptavidin-agarose pulldown. Methods Mol Biol 338 281 290
41. BarrettJCFryBMallerJDalyMJ 2005 Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21 263 265
Štítky
Genetika Reprodukčná medicínaČlánok vyšiel v časopise
PLOS Genetics
2011 Číslo 6
- Je „freeze-all“ pro všechny? Odborníci na fertilitu diskutovali na virtuálním summitu
- Gynekologové a odborníci na reprodukční medicínu se sejdou na prvním virtuálním summitu
Najčítanejšie v tomto čísle
- Statistical Inference on the Mechanisms of Genome Evolution
- Recurrent Chromosome 16p13.1 Duplications Are a Risk Factor for Aortic Dissections
- Chromosomal Macrodomains and Associated Proteins: Implications for DNA Organization and Replication in Gram Negative Bacteria
- Maps of Open Chromatin Guide the Functional Follow-Up of Genome-Wide Association Signals: Application to Hematological Traits