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MicroRNA-3148 Modulates Allelic Expression of Toll-Like Receptor 7 Variant Associated with Systemic Lupus Erythematosus
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نویسنده
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deng y. ,zhao j. ,sakurai d. ,kaufman k.m. ,edberg j.c. ,kimberly r.p. ,kamen d.l. ,gilkeson g.s. ,jacob c.o. ,scofield r.h. ,langefeld c.d. ,kelly j.a. ,ramsey-goldman r. ,petri m.a. ,reveille j.d. ,vilá l.m. ,alarcón g.s. ,vyse t.j. ,pons-estel b.a. ,freedman b.i. ,gaffney p.m. ,sivils k.m. ,james j.a. ,gregersen p.k. ,anaya j.-m. ,niewold t.b. ,merrill j.t. ,criswell l.a. ,stevens a.m. ,boackle s.a. ,cantor r.m. ,chen w. ,grossman j.m. ,hahn b.h. ,harley j.b. ,alarcn-riquelme m.e. ,brown e.e. ,tsao b.p.
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منبع
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plos genetics - 2013 - دوره : 9 - شماره : 2
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چکیده
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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. © 2013 deng et al.
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آدرس
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division of rheumatology,university of california los angeles,los angeles,ca, United States, division of rheumatology,university of california los angeles,los angeles,ca, United States, division of rheumatology,university of california los angeles,los angeles,ca, United States, division of rheumatology and the center for autoimmune genomics and etiology,cincinnati children's hospital medical center,cincinnati,oh,united states,u.s. department of veterans affairs medical center,cincinnati,oh, United States, department of medicine,university of alabama at birmingham,birmingham,al, United States, department of medicine,university of alabama at birmingham,birmingham,al, United States, department of medicine,division of rheumatology,medical university of south carolina,charleston,sc, United States, department of medicine,division of rheumatology,medical university of south carolina,charleston,sc, United States, department of medicine,keck school of medicine,university of southern california,los angeles,ca, United States, arthritis and clinical immunology program,oklahoma medical research foundation,oklahoma city,ok,united states,department of medicine,university of oklahoma health sciences center,oklahoma city,ok,united states,u.s. department of veterans affairs medical center,oklahoma city,ok, United States, department of biostatistical sciences,wake forest university health sciences,wake forest,nc, United States, arthritis and clinical immunology program,oklahoma medical research foundation,oklahoma city,ok, United States, division of rheumatology,northwestern university feinberg school of medicine,chicago,il, United States, department of medicine,johns hopkins university school of medicine,baltimore,md, United States, department of internal medicine,university of texas health science center at houston,houston,tx, United States, department of medicine,university of puerto rico medical sciences campus,san juan, Puerto Rico, department of medicine,university of alabama at birmingham,birmingham,al, United States, divisions of genetics and molecular medicine and immunology,king's college london,london, United Kingdom, department of medicine,sanatorio parque,rosario, Argentina, department of internal medicine,wake forest school of medicine,winston-salem,nc, United States, arthritis and clinical immunology program,oklahoma medical research foundation,oklahoma city,ok, United States, arthritis and clinical immunology program,oklahoma medical research foundation,oklahoma city,ok, United States, arthritis and clinical immunology program,oklahoma medical research foundation,oklahoma city,ok,united states,department of medicine,university of oklahoma health sciences center,oklahoma city,ok, United States, robert s. boas center for genomics and human genetics,feinstein institute for medical research,north shore lij health system,manhasset,ny, United States, center for autoimmune diseases research,universidad del rosario,bogota,col, United States, division of rheumatology and department of immunology,mayo clinic,rochester,mn, United States, clinical pharmacology program,oklahoma medical research foundation,oklahoma city,ok, United States, rosalind russell medical research center for arthritis,department of medicine,university of california san francisco,san francisco,ca, United States, division of rheumatology,department of pediatrics,university of washington,seattle,wa,united states,center for immunity and immunotherapies,seattle children's research institute,seattle,wa, United States, division of rheumatology,school of medicine,university of colorado denver,aurora,co, United States, department of human genetics,university of california los angeles,los angeles,ca, United States, division of rheumatology,university of california los angeles,los angeles,ca, United States, division of rheumatology,university of california los angeles,los angeles,ca, United States, division of rheumatology,university of california los angeles,los angeles,ca, United States, division of rheumatology and the center for autoimmune genomics and etiology,cincinnati children's hospital medical center,cincinnati,oh,united states,u.s. department of veterans affairs medical center,cincinnati,oh, United States, arthritis and clinical immunology program,oklahoma medical research foundation,oklahoma city,ok,united states,centro de genómica e investigación oncológica (genyo),pfizer-universidad de granada-junta de andalucia,granada, Spain, department of medicine,university of alabama at birmingham,birmingham,al,united states,department of epidemiology,university of alabama at birmingham,birmingham,al, United States, division of rheumatology,university of california los angeles,los angeles,ca, United States
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Authors
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