title: Decreased SMG7 expression associates with lupus-risk variants and elevated antinuclear antibody production.
abstract: OBJECTIVE
  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=1.1×10-3and 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=2.0×10-5and 2.0×10-4, respectively).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Rheumatology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA.
authors.forename: Yun
authors.initials: Y
authors.lastname: Deng
authors.affiliation: Division of Rheumatology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Division of Rheumatology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA.
authors.forename: Daisuke
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authors.lastname: Sakurai
authors.affiliation: Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Sestak
authors.affiliation: Division of Rheumatology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA.
authors.forename: Vadim
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authors.lastname: Osadchiy
authors.affiliation: Department of Biostatistical Sciences, Center for Public Health Genomics, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.
authors.forename: Carl D
authors.initials: CD
authors.lastname: Langefeld
authors.affiliation: Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA US Department of Veterans Affairs Medical Center, Cincinnati, Ohio, USA.
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Kaufman
authors.affiliation: Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Kelly
authors.affiliation: 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 City, Oklahoma, USA.
authors.forename: Judith A
authors.initials: JA
authors.lastname: James
authors.affiliation: Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Petri
authors.affiliation: Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, Korea.
authors.forename: Sang-Cheol
authors.initials: SC
authors.lastname: Bae
authors.affiliation: 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.
authors.forename: Marta E
authors.initials: ME
authors.lastname: Alarcón-Riquelme
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: Graciela S
authors.initials: GS
authors.lastname: Alarcón
authors.affiliation: Center for Autoimmune Diseases Research (CREA), Universidad del Rosario, Bogotá, Colombia.
authors.forename: Juan-Manuel
authors.initials: JM
authors.lastname: Anaya
authors.affiliation: Rosalind Russell/Ephraim P. Engleman Rheumatology Research Center, University of California San Francisco, San Francisco, California, USA.
authors.forename: Lindsey A
authors.initials: LA
authors.lastname: Criswell
authors.affiliation: Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.
authors.forename: Barry I
authors.initials: BI
authors.lastname: Freedman
authors.affiliation: Division of Rheumatology and Immunology, Medical University of South Carolina, Charleston, South Carolina, USA.
authors.forename: Diane L
authors.initials: DL
authors.lastname: Kamen
authors.affiliation: Division of Rheumatology and Immunology, Medical University of South Carolina, Charleston, South Carolina, USA.
authors.forename: Gary S
authors.initials: GS
authors.lastname: Gilkeson
authors.affiliation: Department of Medicine, University of Southern California, Los Angeles, California, USA.
authors.forename: Chaim O
authors.initials: CO
authors.lastname: Jacob
authors.affiliation: Department of Clinical Pharmacology, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA.
authors.forename: Joan T
authors.initials: JT
authors.lastname: Merrill
authors.affiliation: Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA.
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Gaffney
authors.affiliation: 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.
authors.forename: Kathy Moser
authors.initials: KM
authors.lastname: Sivils
authors.affiliation: Division of Rheumatology and Department of Immunology, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Timothy B
authors.identifier: http://orcid.org/0000-0003-3532-6660
authors.initials: TB
authors.lastname: Niewold
authors.affiliation: Division of Rheumatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
authors.forename: Rosalind
authors.initials: R
authors.lastname: Ramsey-Goldman
authors.affiliation: Department of Rheumatology and Clinical Immunogenetics, University of Texas Health Science Center at Houston, Houston, Texas, USA.
authors.forename: John D
authors.identifier: http://orcid.org/0000-0001-5950-0913
authors.initials: JD
authors.lastname: Reveille
authors.affiliation: 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.
authors.forename: R Hal
authors.initials: RH
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authors.affiliation: 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.
authors.forename: Anne M
authors.initials: AM
authors.lastname: Stevens
authors.affiliation: Division of Rheumatology, University of Colorado School of Medicine, Aurora, Colorado, USA US Department of Veterans Affairs Medical Center, Denver, Colorado, USA.
authors.forename: Susan A
authors.initials: SA
authors.lastname: Boackle
authors.affiliation: Division of Rheumatology, Department of Medicine, University of Puerto Rico Medical Sciences Campus, San Juan, Puerto Rico.
authors.forename: Luis M
authors.initials: LM
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authors.affiliation: Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, Korea.
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authors.initials: II
authors.lastname: Sohn
authors.affiliation: Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, Korea.
authors.forename: Seung
authors.initials: S
authors.lastname: Lee
authors.affiliation: Taipei Veterans General Hospital, Taipei City, Taiwan.
authors.forename: Deh-Ming
authors.initials: DM
authors.lastname: Chang
authors.affiliation: 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.
authors.forename: Yeong Wook
authors.initials: YW
authors.lastname: Song
authors.affiliation: Division of Genetics and Molecular Medicine and Immunology, King's College London, London, UK.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Vyse
authors.affiliation: Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA US Department of Veterans Affairs Medical Center, Cincinnati, Ohio, USA.
authors.forename: John B
authors.initials: JB
authors.lastname: Harley
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: Elizabeth E
authors.initials: EE
authors.lastname: Brown
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Edberg
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: Robert P
authors.initials: RP
authors.lastname: Kimberly
authors.affiliation: Department of Human Genetics, University of California Los Angeles, Los Angeles, California, USA.
authors.forename: Rita M
authors.initials: RM
authors.lastname: Cantor
authors.affiliation: Division of Rheumatology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA.
authors.forename: Bevra H
authors.initials: BH
authors.lastname: Hahn
authors.affiliation: Division of Rheumatology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Grossman
authors.affiliation: Division of Rheumatology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA.
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mesh_terms: D000483:Alleles; D044467:American Indian or Alaska Native / Q000235:genetics; D000974:Antibodies, Antinuclear / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D060005:Genotyping Techniques; D057809:HEK293 Cells; D006630:Hispanic or Latino / Q000235:genetics; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000276:immunology*; D015810:Linkage Disequilibrium; D008180:Lupus Erythematosus, Systemic / Q000235:genetics* / Q000276:immunology; D008297:Male; D009612:Nicotinamide-Nucleotide Adenylyltransferase / Q000235:genetics*; D010375:Pedigree; D012333:RNA, Messenger / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D012307:Risk Factors; D044465:White People / Q000235:genetics
chemical_list: D000974:Antibodies, Antinuclear; D002352:Carrier Proteins; D012333:RNA, Messenger; C494578:SMG7 protein, human; C484008:NMNAT2 protein, human; D009612:Nicotinamide-Nucleotide Adenylyltransferase
keywords: Autoantibodies; Gene Polymorphism; Systemic Lupus Erythematosus