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Decreased SMG7 expression associates with lupus-risk variants and elevated antinuclear antibody production
  1. Yun Deng1,
  2. Jian Zhao1,
  3. Daisuke Sakurai1,
  4. Andrea L Sestak2,
  5. Vadim Osadchiy1,
  6. Carl D Langefeld3,
  7. Kenneth M Kaufman4,5,
  8. Jennifer A Kelly6,
  9. Judith A James6,7,8,
  10. Michelle A Petri9,
  11. Sang-Cheol Bae10,
  12. Marta E Alarcón-Riquelme6,11,
  13. Graciela S Alarcón12,
  14. Juan-Manuel Anaya13,
  15. Lindsey A Criswell14,
  16. Barry I Freedman15,
  17. Diane L Kamen16,
  18. Gary S Gilkeson16,
  19. Chaim O Jacob17,
  20. Joan T Merrill18,
  21. Patrick M Gaffney6,
  22. Kathy Moser Sivils6,7,
  23. Timothy B Niewold19,
  24. Rosalind Ramsey-Goldman20,
  25. John D Reveille21,
  26. R Hal Scofield6,8,22,
  27. Anne M Stevens23,24,
  28. Susan A Boackle25,26,
  29. Luis M Vilá27,
  30. I I Woong Sohn10,
  31. Seung Lee10,
  32. Deh-Ming Chang28,
  33. Yeong Wook Song29,
  34. Timothy J Vyse30,
  35. John B Harley4,5,
  36. Elizabeth E Brown12,31,
  37. Jeffrey C Edberg12,
  38. Robert P Kimberly12,
  39. Rita M Cantor32,
  40. Bevra H Hahn1,
  41. Jennifer M Grossman1,
  42. Betty P Tsao1
  1. 1Division of Rheumatology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA
  2. 2Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA
  3. 3Department of Biostatistical Sciences, Center for Public Health Genomics, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA
  4. 4Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
  5. 5US Department of Veterans Affairs Medical Center, Cincinnati, Ohio, USA
  6. 6Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA
  7. 7Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA
  8. 8Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA
  9. 9Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
  10. 10Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, Korea
  11. 11Pfizer-Universidad de Granada-Junta de Andalucía Center for Genomics and Oncological Research, Granada, Spain
  12. 12Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA
  13. 13Center for Autoimmune Diseases Research (CREA), Universidad del Rosario, Bogotá, Colombia
  14. 14Rosalind Russell/Ephraim P. Engleman Rheumatology Research Center, University of California San Francisco, San Francisco, California, USA
  15. 15Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA
  16. 16Division of Rheumatology and Immunology, Medical University of South Carolina, Charleston, South Carolina, USA
  17. 17Department of Medicine, University of Southern California, Los Angeles, California, USA
  18. 18Department of Clinical Pharmacology, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA
  19. 19Division of Rheumatology and Department of Immunology, Mayo Clinic, Rochester, Minnesota, USA
  20. 20Division of Rheumatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
  21. 21Department of Rheumatology and Clinical Immunogenetics, University of Texas Health Science Center at Houston, Houston, Texas, USA
  22. 22US Department of Veterans Affairs Medical Center, Oklahoma City, Oklahoma, USA
  23. 23Division of Rheumatology, Department of Pediatrics, University of Washington, Seattle, Washington, USA
  24. 24Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, Washington, USA
  25. 25Division of Rheumatology, University of Colorado School of Medicine, Aurora, Colorado, USA
  26. 26US Department of Veterans Affairs Medical Center, Denver, Colorado, USA
  27. 27Division of Rheumatology, Department of Medicine, University of Puerto Rico Medical Sciences Campus, San Juan, Puerto Rico
  28. 28Taipei Veterans General Hospital, Taipei City, Taiwan
  29. 29Department 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
  30. 30Division of Genetics and Molecular Medicine and Immunology, King's College London, London, UK
  31. 31Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, USA
  32. 32Department of Human Genetics, University of California Los Angeles, Los Angeles, California, USA
  1. Correspondence to Professor Betty P Tsao, Division of Rheumatology and Immunology, Department of Medicine, Medical University of South Carolina, 96 Jonathan Lucas St, Clinical Science Bldg Suite 936C, Charleston, SC 29425, USA; tsaob{at}musc.edu

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.

  • Systemic Lupus Erythematosus
  • Gene Polymorphism
  • Autoantibodies

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