Decreased SMG7 expression associates with lupus-risk variants and elevated antinuclear antibody production

Yun Deng; Jian Zhao; Daisuke Sakurai; Andrea L Sestak; Vadim Osadchiy; Carl D Langefeld; Kenneth M Kaufman; Jennifer A Kelly; Judith A James; Michelle A Petri; Sang-Cheol Bae; Marta E Alarcón-Riquelme; Graciela S Alarcón; Juan-Manuel Anaya; Lindsey A Criswell; Barry I Freedman; Diane L Kamen; Gary S Gilkeson; Chaim O Jacob; Joan T Merrill; Patrick M Gaffney; Kathy Moser Sivils; Timothy B Niewold; Rosalind Ramsey-Goldman; John D Reveille; R Hal Scofield; Anne M Stevens; Susan A Boackle; Luis M Vilá; I I Woong Sohn; Seung Lee; Deh-Ming Chang; Yeong Wook Song; Timothy J Vyse; John B Harley; Elizabeth E Brown; Jeffrey C Edberg; Robert P Kimberly; Rita M Cantor; Bevra H Hahn; Jennifer M Grossman; Betty P Tsao

doi:10.1136/annrheumdis-2015-208441

Decreased SMG7 expression associates with lupus-risk variants and elevated antinuclear antibody production

Ann Rheum Dis. 2016 Nov;75(11):2007-2013. doi: 10.1136/annrheumdis-2015-208441. Epub 2016 Jan 18.

Authors

Yun Deng¹, Jian Zhao¹, Daisuke Sakurai¹, Andrea L Sestak², Vadim Osadchiy¹, Carl D Langefeld³, Kenneth M Kaufman⁴, Jennifer A Kelly⁵, Judith A James⁶, Michelle A Petri⁷, Sang-Cheol Bae⁸, Marta E Alarcón-Riquelme⁹, Graciela S Alarcón¹⁰, Juan-Manuel Anaya¹¹, Lindsey A Criswell¹², Barry I Freedman¹³, Diane L Kamen¹⁴, Gary S Gilkeson¹⁴, Chaim O Jacob¹⁵, Joan T Merrill¹⁶, Patrick M Gaffney⁵, Kathy Moser Sivils¹⁷, Timothy B Niewold¹⁸, Rosalind Ramsey-Goldman¹⁹, John D Reveille²⁰, R Hal Scofield²¹, Anne M Stevens²², Susan A Boackle²³, Luis M Vilá²⁴, I I Woong Sohn⁸, Seung Lee⁸, Deh-Ming Chang²⁵, Yeong Wook Song²⁶, Timothy J Vyse²⁷, John B Harley⁴, Elizabeth E Brown²⁸, Jeffrey C Edberg¹⁰, Robert P Kimberly¹⁰, Rita M Cantor²⁹, Bevra H Hahn¹, Jennifer M Grossman¹, Betty P Tsao¹

Affiliations

¹ Division of Rheumatology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA.
² Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
³ Department of Biostatistical Sciences, Center for Public Health Genomics, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.
⁴ Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA US Department of Veterans Affairs Medical Center, Cincinnati, Ohio, USA.
⁵ Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA.
⁶ 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.
⁷ Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
⁸ Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, Korea.
⁹ 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.
¹⁰ Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.
¹¹ Center for Autoimmune Diseases Research (CREA), Universidad del Rosario, Bogotá, Colombia.
¹² Rosalind Russell/Ephraim P. Engleman Rheumatology Research Center, University of California San Francisco, San Francisco, California, USA.
¹³ Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.
¹⁴ Division of Rheumatology and Immunology, Medical University of South Carolina, Charleston, South Carolina, USA.
¹⁵ Department of Medicine, University of Southern California, Los Angeles, California, USA.
¹⁶ Department of Clinical Pharmacology, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA.
¹⁷ 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.
¹⁸ Division of Rheumatology and Department of Immunology, Mayo Clinic, Rochester, Minnesota, USA.
¹⁹ Division of Rheumatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
²⁰ Department of Rheumatology and Clinical Immunogenetics, University of Texas Health Science Center at Houston, Houston, Texas, USA.
²¹ 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.
²² 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.
²³ Division of Rheumatology, University of Colorado School of Medicine, Aurora, Colorado, USA US Department of Veterans Affairs Medical Center, Denver, Colorado, USA.
²⁴ Division of Rheumatology, Department of Medicine, University of Puerto Rico Medical Sciences Campus, San Juan, Puerto Rico.
²⁵ Taipei Veterans General Hospital, Taipei City, Taiwan.
²⁶ 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.
²⁷ Division of Genetics and Molecular Medicine and Immunology, King's College London, London, UK.
²⁸ Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, USA.
²⁹ Department of Human Genetics, University of California Los Angeles, Los Angeles, California, USA.

Abstract

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.

Keywords: Autoantibodies; Gene Polymorphism; Systemic Lupus Erythematosus.

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MeSH terms

Alleles
American Indian or Alaska Native / genetics
Antibodies, Antinuclear / metabolism*
Carrier Proteins / genetics*
Female
Genetic Predisposition to Disease
Genome-Wide Association Study
Genotyping Techniques
HEK293 Cells
Hispanic or Latino / genetics
Humans
Leukocytes, Mononuclear / immunology*
Linkage Disequilibrium
Lupus Erythematosus, Systemic / genetics*
Lupus Erythematosus, Systemic / immunology
Male
Nicotinamide-Nucleotide Adenylyltransferase / genetics*
Pedigree
RNA, Messenger / metabolism
Real-Time Polymerase Chain Reaction
Risk Factors
White People / genetics

Substances

Antibodies, Antinuclear
Carrier Proteins
RNA, Messenger
SMG7 protein, human
NMNAT2 protein, human
Nicotinamide-Nucleotide Adenylyltransferase

Abstract

MeSH terms

Substances

Grants and funding