We previously reported that the G allele of rs3853839 at 3′untranslated region (UTR) of Toll-like receptor 7 (TLR7) was associated with elevated transcript expression and increased risk for systemic lupus erythematosus (SLE) in 9,274 Eastern Asians [P = 6.5×10−10, odds ratio (OR) (95%CI) = 1.27 (1.17–1.36)]. Here, we conducted trans-ancestral fine-mapping in 13,339 subjects including European Americans, African Americans, and Amerindian/Hispanics and confirmed rs3853839 as the only variant within the TLR7-TLR8 region exhibiting consistent and independent association with SLE (Pmeta = 7.5×10−11, OR = 1.24 [1.18–1.34]). The risk G allele was associated with significantly increased levels of TLR7 mRNA and protein in peripheral blood mononuclear cells (PBMCs) and elevated luciferase activity of reporter gene in transfected cells. TLR7 3′UTR sequence bearing the non-risk C allele of rs3853839 matches a predicted binding site of microRNA-3148 (miR-3148), suggesting that this microRNA may regulate TLR7 expression. Indeed, miR-3148 levels were inversely correlated with TLR7 transcript levels in PBMCs from SLE patients and controls (R2 = 0.255, P = 0.001). Overexpression of miR-3148 in HEK-293 cells led to significant dose-dependent decrease in luciferase activity for construct driven by TLR7 3′UTR segment bearing the C allele (P = 0.0003). Compared with the G-allele construct, the C-allele construct showed greater than two-fold reduction of luciferase activity in the presence of miR-3148. Reduced modulation by miR-3148 conferred slower degradation of the risk G-allele containing TLR7 transcripts, resulting in elevated levels of gene products. These data establish rs3853839 of TLR7 as a shared risk variant of SLE in 22,613 subjects of Asian, EA, AA, and Amerindian/Hispanic ancestries (Pmeta = 2.0×10−19, OR = 1.25 [1.20–1.32]), which confers allelic effect on transcript turnover via differential binding to the epigenetic factor miR-3148.
Vyšlo v časopise: MicroRNA-3148 Modulates Allelic Expression of Toll-Like Receptor 7 Variant Associated with Systemic Lupus Erythematosus. PLoS Genet 9(2): e32767. doi:10.1371/journal.pgen.1003336 Kategorie: Research Article prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1003336
1. KontakiE, BoumpasDT (2010) Innate immunity in systemic lupus erythematosus: sensing endogenous nucleic acids. J Autoimmun 35 : 206–211.
2. LichtmanEI, HelfgottSM, KriegelMA (2012) Emerging therapies for systemic lupus erythematosus–focus on targeting interferon-alpha. Clin Immunol 143 : 210–221.
3. DengY, TsaoBP (2010) Genetic susceptibility to systemic lupus erythematosus in the genomic era. Nat Rev Rheumatol 6 : 683–692.
4. BronsonPG, ChaivorapolC, OrtmannW, BehrensTW, GrahamRR (2012) The genetics of type I interferon in systemic lupus erythematosus. Curr Opin Immunol [Epub ahead of print].
5. ShenN, FuQ, DengY, QianX, ZhaoJ, et al. (2010) Sex-specific association of X-linked Toll-like receptor 7 (TLR7) with male systemic lupus erythematosus. Proc Natl Acad Sci U S A 107 : 15838–15843.
6. BushatiN, CohenSM (2007) microRNA functions. Annu Rev Cell Dev Biol 23 : 175–205.
7. SaundersMA, LiangH, LiWH (2007) Human polymorphism at microRNAs and microRNA target sites. Proc Natl Acad Sci U S A 104 : 3300–3305.
8. ZhangW, EdwardsA, ZhuD, FlemingtonEK, DeiningerP, et al. (2012) miRNA-mediated relationships between Cis-SNP genotypes and transcript intensities in lymphocyte cell lines. PLoS ONE 7: e31429 doi:10.1371/journal.pone.0031429
9. PisitkunP, DeaneJD, DiffilipantonioMJ, TarasenkoT, SatterthwaiteAB, et al. (2006) Autoreactive B cell responses to RNA-related antigens due to TLR7 gene duplication. Science 312 : 1669–1672.
10. SubramanianS, TusK, LiQZ, WangA, TianXH, et al. (2006) A TLR7 translocation accelerates systemic autoimmunity in murine lupus. Proc Natl Acad Sci USA 103 : 9970–9975.
11. FairhurstAM, HwangSH, WangA, TianXH, BoudreauxC, et al. (2008) Yaa autoimmune phenotypes are conferred by overexpression of TLR7. Eur J Immunol 38 : 1971–1978.
12. DeaneJA, PisitkunP, BarrettRS, FeigenbaumL, TownT, et al. (2007) Control of Toll-like Receptor 7 Expression Is Essential to Restrict Autoimmunity and Dendritic Cell Proliferation. Immunity 27 : 801–810.
13. RonnblomL, ElorantaML, AlmGV (2006) The type I interferon system in systemic lupus erythematosus. Arthritis Rheum 54 : 408–420.
14. KomatsudaA, WakuiH, IwamotoK, OzawaM, TogashiM, et al. (2008) Up-regulated expression of Toll-like receptors mRNAs in peripheral blood mononuclear cells from patients with systemic lupus erythematosus. Clin Exp Immunol 152 : 482–487.
15. MidgleyA, ThorbinsonC, BeresfordMW (2012) Expression of Toll-like receptors and their detection of nuclear self-antigen leading to immune activation in JSLE. Rheumatology (Oxford) 51 : 824–832.
16. Garcia-OrtizH, Velazquez-CruzR, Espinosa-RosalesF, Jimenez-MoralesS, BacaV, et al. (2010) Association of TLR7 copy number variation with susceptibility to childhood-onset systemic lupus erythematosus in Mexican population. Ann Rheum Dis 69 : 1861–1865.
17. ConradDF, PintoD, RedonR, FeukL, GokcumenO, et al. (2010) Origins and functional impact of copy number variation in the human genome. Nature 464 : 704–712.
18. ParkH, KimJI, JuYS, GokcumenO, MillsRE, et al. (2010) Discovery of common Asian copy number variants using integrated high-resolution array CGH and massively parallel DNA sequencing. Nat Genet 42 : 400–405.
19. HomG, GrahamRR, ModrekB, TaylorKE, OrtmannW, et al. (2008) Association of systemic lupus erythematosus with C8orf13-BLK and ITGAM-ITGAX. N Engl J Med 358 : 900–909.
20. HarleyJB, Alarcon-RiquelmeME, CriswellLA, JacobCO, KimberlyRP, et al. (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.
21. KozyrevSV, AbelsonAK, WojcikJ, ZaghloolA, Linga ReddyMV, et al. (2008) Functional variants in the B-cell gene BANK1 are associated with systemic lupus erythematosus. Nat Genet 40 : 211–216.
22. GrahamRR, CotsapasC, DaviesL, HackettR, LessardCJ, et al. (2008) Genetic variants near TNFAIP3 on 6q23 are associated with systemic lupus erythematosus. Nat Genet 40 : 1059–1061.
23. HanJW, ZhengHF, CuiY, SunLD, YeDQ, et al. (2009) Genome-wide association study in a Chinese Han population identifies nine new susceptibility loci for systemic lupus erythematosus. Nat Genet 41 : 1234–1237.
24. YangW, ShenN, YeDQ, LiuQ, ZhangY, et al. (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
25. OkadaY, ShimaneK, KochiY, TahiraT, SuzukiA, et al. (2012) A genome-wide association study identified AFF1 as a susceptibility locus for systemic lupus eyrthematosus in Japanese. PLoS Genet 8: e1002455 doi:10.1371/journal.pgen.1002455
26. KawasakiA, FurukawaH, KondoY, ItoS, HayashiT, et al. (2011) TLR7 single-nucleotide polymorphisms in the 3′ untranslated region and intron 2 independently contribute to systemic lupus erythematosus in Japanese women: a case-control association study. Arthritis Res Ther 13: R41.
27. dos SantosBP, ValverdeJV, RohrP, MonticieloOA, BrenolJC, et al. (2012) TLR7/8/9 polymorphisms and their associations in systemic lupus erythematosus patients from southern Brazil. Lupus 21 : 302–309.
28. DavilaS, HibberdML, Hari DassR, WongHE, SahiratmadjaE, et al. (2008) Genetic association and expression studies indicate a role of toll-like receptor 8 in pulmonary tuberculosis. PLoS Genet 4: e1000218 doi:10.1371/journal.pgen.1000218
29. OhDY, TaubeS, HamoudaO, KuchererC, PoggenseeG, et al. (2008) A functional toll-like receptor 8 variant is associated with HIV disease restriction. J Infect Dis 198 : 701–709.
30. CooksonW, LiangL, AbecasisG, MoffattM, LathropM (2009) Mapping complex disease traits with global gene expression. Nat Rev Genet 10 : 184–194.
31. StrangerBE, MontgomerySB, DimasAS, PartsL, StegleO, et al. (2012) Patterns of cis regulatory variation in diverse human populations. PLoS Genet 8: e1002639 doi:10.1371/journal.pgen.1002639
32. O'NeillLA, SheedyFJ, McCoyCE (2011) MicroRNAs: the fine-tuners of Toll-like receptor signalling. Nat Rev Immunol 11 : 163–175.
33. ContrerasJ, RaoDS (2012) MicroRNAs in inflammation and immune responses. Leukemia 26 : 404–413.
34. BenakanakereMR, LiQ, EskanMA, SinghAV, ZhaoJ, et al. (2009) Modulation of TLR2 protein expression by miR-105 in human oral keratinocytes. J Biol Chem 284 : 23107–23115.
35. ChenXM, SplinterPL, O'HaraSP, LaRussoNF (2007) A cellular micro-RNA, let-7i, regulates Toll-like receptor 4 expression and contributes to cholangiocyte immune responses against Cryptosporidium parvum infection. J Biol Chem 282 : 28929–28938.
36. StarkMS, TyagiS, NancarrowDJ, BoyleGM, CookAL, et al. (2010) Characterization of the Melanoma miRNAome by Deep Sequencing. PLoS ONE 5: e9685 doi:10.1371/journal.pone.0009685
37. LehmannSM, KrugerC, ParkB, DerkowK, RosenbergerK, et al. (2012) An unconventional role for miRNA: let-7 activates Toll-like receptor 7 and causes neurodegeneration. Nat Neurosci 15 : 827–835.
38. FabbriM, PaoneA, CaloreF, GalliR, GaudioE, et al. (2012) MicroRNAs bind to Toll-like receptors to induce prometastatic inflammatory response. Proc Natl Acad Sci U S A 109: E2110–2116.
39. HochbergMC (1997) Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 40 : 1725.
40. PriceAL, PattersonNJ, PlengeRM, WeinblattME, ShadickNA, et al. (2006) Principal components analysis corrects for stratification in genome-wide association studies. Nature Genetics 38 : 904–909.
41. HoggartCJ, ParraEJ, ShriverMD, BonillaC, KittlesRA, et al. (2003) Control of confounding of genetic associations in stratified populations. Am J Hum Genet 72 : 1492–1504.
42. LessardCJ, AdriantoI, KellyJA, KaufmanKM, GrundahlKM, et al. (2011) Identification of a systemic lupus erythematosus susceptibility locus at 11p13 between PDHX and CD44 in a multiethnic study. Am J Hum Genet 88 : 83–91.
43. HowieBN, DonnellyP, MarchiniJ (2009) A flexible and accurate genotype imputation method for the next generation of genome-wide association studies. PLoS Genet 5: e1000529 doi:10.1371/journal.pgen.1000529
44. BirnieGD (1988) The HL60 cell line: a model system for studying human myeloid cell differentiation. Br J Cancer Suppl 9 : 41–45.
Zvýšte si kvalifikáciu online z pohodlia domova
Nemáte účet? Registrujte sa
Zadajte e-mailovú adresu, s ktorou ste vytvárali účet. Budú Vám na ňu zasielané informácie k nastaveniu nového hesla.
