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Interferon-gamma gene polymorphisms associated with susceptibility to systemic lupus erythematosus.
Kim, Kwangwoo,Cho, Soo-Kyung,Sestak, Andrea,Namjou, Bahram,Kang, Changwon,Bae, Sang-Cheol British Medical Association 2010 Annals of the Rheumatic Diseases Vol.69 No.6
<P>Interferon-gamma (IFNG) is a type II interferon playing diverse roles in innate and adaptive immune systems. Elevated expression of IFNG has been associated with systemic lupus erythematosus (SLE). This study examined the association of IFNG polymorphisms with SLE susceptibility.</P>
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>