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- 저자 : Petri Michelle (검색결과 1 건)
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Deng, Yun,Zhao, Jian,Sakurai, Daisuke,Sestak, Andrea L,Osadchiy, Vadim,Langefeld, Carl D,Kaufman, Kenneth M,Kelly, Jennifer A,James, Judith A,Petri, Michelle A,Bae, Sang-Cheol,Alarcó,n-Riquelme, H. K. Lewis 2016 Annals of the rheumatic diseases Vol.75 No.11
<B>Objectives</B><P>Following up the systemic lupus erythematosus (SLE) genome-wide association studies (GWAS) identification of <I>NMNAT2</I> at rs2022013, we fine-mapped its 150 kb flanking regions containing <I>NMNAT2</I> and <I>SMG7</I> in a 15 292 case-control multi-ancestry population and tested functions of identified variants.</P><B>Methods</B><P>We performed genotyping using custom array, imputation by IMPUTE 2.1.2 and allele specific functions using quantitative real-time PCR and luciferase reporter transfections. SLE peripheral blood mononuclear cells (PBMCs) were cultured with small interfering RNAs to measure antinuclear antibody (ANA) and cyto/chemokine levels in supernatants using ELISA.</P><B>Results</B><P>We confirmed association at <I>NMNAT2</I> in European American (EA) and Amerindian/Hispanic ancestries, and identified independent signal at <I>SMG7</I> tagged by rs2702178 in EA only (p=2.4×10<SUP>−8</SUP>, OR=1.23 (95% CI 1.14 to 1.32)). In complete linkage disequilibrium with rs2702178, rs2275675 in the promoter region robustly associated with <I>SMG7</I> mRNA levels in multiple expression quantitative trait locus (eQTL) datasets. Its risk allele was dose-dependently associated with decreased <I>SMG7</I> mRNA levels in PBMCs of 86 patients with SLE and 119 controls (p=1.1×10<SUP>−3</SUP> and 6.8×10<SUP>−8</SUP>, respectively) and conferred reduced transcription activity in transfected HEK-293 (human embryonic kidney cell line) and Raji cells (p=0.0035 and 0.0037, respectively). As a critical component in the nonsense-mediated mRNA decay pathway, SMG7 could regulate autoantigens including ribonucleoprotein (RNP) and Smith (Sm). We showed <I>SMG7</I> mRNA levels in PBMCs correlated inversely with ANA titres of patients with SLE (r=−0.31, p=0.01), and <I>SMG7</I> knockdown increased levels of ANA IgG and chemokine (C-C motif) ligand 19 in SLE PBMCs (p=2.0×10<SUP>−5</SUP> and 2.0×10<SUP>−4</SUP>, respectively).</P><B>Conclusion</B><P>We confirmed <I>NMNAT2</I> and identified independent <I>SMG7</I> association with SLE. The inverse relationship between levels of the risk allele-associated <I>SMG7</I> mRNAs and ANA suggested the novel contribution of mRNA surveillance pathway to SLE pathogenesis.</P>
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