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Decreased SMG7 expression associates with lupus-risk variants and elevated antinuclear antibody production.
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; Alarcón-Riquelme, Marta E; Alarcón, Graciela S; Anaya, Juan-Manuel; Criswell, Lindsey A; Freedman, Barry I; Kamen, Diane L; Gilkeson, Gary S; Jacob, Chaim O; Merrill, Joan T; Gaffney, Patrick M; Sivils, Kathy Moser; Niewold, Timothy B; Ramsey-Goldman, Rosalind; Reveille, John D; Scofield, R Hal; Stevens, Anne M; Boackle, Susan A; Vilá, Luis M; Sohn, I I Woong; Lee, Seung; Chang, Deh-Ming; Song, Yeong Wook; Vyse, Timothy J; Harley, John B; Brown, Elizabeth E; Edberg, Jeffrey C; Kimberly, Robert P; Cantor, Rita M; Hahn, Bevra H; Grossman, Jennifer M; Tsao, Betty P.
Afiliação
  • Deng Y; Division of Rheumatology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA.
  • Zhao J; Division of Rheumatology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA.
  • Sakurai D; Division of Rheumatology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA.
  • Sestak AL; Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
  • Osadchiy V; Division of Rheumatology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA.
  • Langefeld CD; Department of Biostatistical Sciences, Center for Public Health Genomics, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.
  • Kaufman KM; Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA US Department of Veterans Affairs Medical Center, Cincinnati, Ohio, USA.
  • Kelly JA; Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA.
  • James JA; Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma
  • Petri MA; Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
  • Bae SC; Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, Korea.
  • Alarcón-Riquelme ME; Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA Pfizer-Universidad de Granada-Junta de Andalucía Center for Genomics and Oncological Research, Granada, Spain.
  • Alarcón GS; Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.
  • Anaya JM; Center for Autoimmune Diseases Research (CREA), Universidad del Rosario, Bogotá, Colombia.
  • Criswell LA; Rosalind Russell/Ephraim P. Engleman Rheumatology Research Center, University of California San Francisco, San Francisco, California, USA.
  • Freedman BI; Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.
  • Kamen DL; Division of Rheumatology and Immunology, Medical University of South Carolina, Charleston, South Carolina, USA.
  • Gilkeson GS; Division of Rheumatology and Immunology, Medical University of South Carolina, Charleston, South Carolina, USA.
  • Jacob CO; Department of Medicine, University of Southern California, Los Angeles, California, USA.
  • Merrill JT; Department of Clinical Pharmacology, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA.
  • Gaffney PM; Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA.
  • Sivils KM; Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
  • Niewold TB; Division of Rheumatology and Department of Immunology, Mayo Clinic, Rochester, Minnesota, USA.
  • Ramsey-Goldman R; Division of Rheumatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
  • Reveille JD; Department of Rheumatology and Clinical Immunogenetics, University of Texas Health Science Center at Houston, Houston, Texas, USA.
  • Scofield RH; Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA US Department of Veterans Affairs Medical Center, Oklahoma City, Oklahoma, USA.
  • Stevens AM; Division of Rheumatology, Department of Pediatrics, University of Washington, Seattle, Washington, USA Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, Washington, USA.
  • Boackle SA; Division of Rheumatology, University of Colorado School of Medicine, Aurora, Colorado, USA US Department of Veterans Affairs Medical Center, Denver, Colorado, USA.
  • Vilá LM; Division of Rheumatology, Department of Medicine, University of Puerto Rico Medical Sciences Campus, San Juan, Puerto Rico.
  • Sohn II; Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, Korea.
  • Lee S; Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, Korea.
  • Chang DM; Taipei Veterans General Hospital, Taipei City, Taiwan.
  • Song YW; Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, and College of Medicine, Medical Research Center, Seoul National University, Seoul, Korea.
  • Vyse TJ; Division of Genetics and Molecular Medicine and Immunology, King's College London, London, UK.
  • Harley JB; Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA US Department of Veterans Affairs Medical Center, Cincinnati, Ohio, USA.
  • Brown EE; Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, USA.
  • Edberg JC; Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.
  • Kimberly RP; Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.
  • Cantor RM; Department of Human Genetics, University of California Los Angeles, Los Angeles, California, USA.
  • Hahn BH; Division of Rheumatology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA.
  • Grossman JM; Division of Rheumatology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA.
  • Tsao BP; Division of Rheumatology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA.
Ann Rheum Dis ; 75(11): 2007-2013, 2016 Nov.
Article em En | MEDLINE | ID: mdl-26783109
OBJECTIVES: Following up the systemic lupus erythematosus (SLE) genome-wide association studies (GWAS) identification of NMNAT2 at rs2022013, we fine-mapped its 150 kb flanking regions containing NMNAT2 and SMG7 in a 15 292 case-control multi-ancestry population and tested functions of identified variants. METHODS: 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. RESULTS: We confirmed association at NMNAT2 in European American (EA) and Amerindian/Hispanic ancestries, and identified independent signal at SMG7 tagged by rs2702178 in EA only (p=2.4×10-8, OR=1.23 (95% CI 1.14 to 1.32)). In complete linkage disequilibrium with rs2702178, rs2275675 in the promoter region robustly associated with SMG7 mRNA levels in multiple expression quantitative trait locus (eQTL) datasets. Its risk allele was dose-dependently associated with decreased SMG7 mRNA levels in PBMCs of 86 patients with SLE and 119 controls (p=1.1×10-3 and 6.8×10-8, 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 SMG7 mRNA levels in PBMCs correlated inversely with ANA titres of patients with SLE (r=-0.31, p=0.01), and SMG7 knockdown increased levels of ANA IgG and chemokine (C-C motif) ligand 19 in SLE PBMCs (p=2.0×10-5 and 2.0×10-4, respectively). CONCLUSION: We confirmed NMNAT2 and identified independent SMG7 association with SLE. The inverse relationship between levels of the risk allele-associated SMG7 mRNAs and ANA suggested the novel contribution of mRNA surveillance pathway to SLE pathogenesis.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Leucócitos Mononucleares / Proteínas de Transporte / Anticorpos Antinucleares / Lúpus Eritematoso Sistêmico / Nicotinamida-Nucleotídeo Adenililtransferase Tipo de estudo: Etiology_studies / Prognostic_studies / Risk_factors_studies Limite: Female / Humans / Male Idioma: En Ano de publicação: 2016 Tipo de documento: Article
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Leucócitos Mononucleares / Proteínas de Transporte / Anticorpos Antinucleares / Lúpus Eritematoso Sistêmico / Nicotinamida-Nucleotídeo Adenililtransferase Tipo de estudo: Etiology_studies / Prognostic_studies / Risk_factors_studies Limite: Female / Humans / Male Idioma: En Ano de publicação: 2016 Tipo de documento: Article