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Basic and translational research
Extended report
Preferential association of a functional variant in complement receptor 2 with antibodies to double-stranded DNA
  1. Jian Zhao1,
  2. Brendan M Giles2,
  3. Rhonda L Taylor3,
  4. Gabriel A Yette2,
  5. Kara M Lough2,
  6. Han Leng Ng3,
  7. Lawrence J Abraham3,
  8. Hui Wu1,
  9. Jennifer A Kelly4,
  10. Stuart B Glenn4,
  11. Adam J Adler4,
  12. Adrienne H Williams5,
  13. Mary E Comeau5,
  14. Julie T Ziegler5,
  15. Miranda Marion5,
  16. Marta E Alarcón-Riquelme4,6,
  17. for the BIOLUPUS and GENLES Networks,
  18. Graciela S Alarcón7,
  19. Juan-Manuel Anaya8,
  20. Sang-Cheol Bae9,
  21. Dam Kim9,
  22. Hye-Soon Lee9,
  23. Lindsey A Criswell10,
  24. Barry I Freedman11,
  25. Gary S Gilkeson12,
  26. Joel M Guthridge4,
  27. Chaim O Jacob13,
  28. Judith A James4,14,15,
  29. Diane L Kamen12,
  30. Joan T Merrill16,
  31. Kathy Moser Sivils4,14,
  32. Timothy B Niewold17,
  33. Michelle A Petri18,
  34. Rosalind Ramsey-Goldman19,
  35. John D Reveille20,
  36. R Hal Scofield4,15,21,
  37. Anne M Stevens22,23,
  38. Luis M Vilá24,
  39. Timothy J Vyse25,
  40. Kenneth M Kaufman26,27,
  41. John B Harley26,27,
  42. Carl D Langefeld5,
  43. Patrick M Gaffney4,
  44. Elizabeth E Brown7,28,
  45. Jeffrey C Edberg7,
  46. Robert P Kimberly7,
  47. Daniela Ulgiati3,
  48. Betty P Tsao1,
  49. Susan A Boackle2,29
  1. 1Division of Rheumatology, Department of Medicine, University of California at Los Angeles, Los Angeles, California, USA
  2. 2Division of Rheumatology, University of Colorado School of Medicine, Aurora, Colorado, USA
  3. 3School of Pathology and Laboratory Medicine, Centre for Genetic Origins of Health and Disease, The University of Western Australia, Crawley, Western Australia, Australia
  4. 4Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA
  5. 5Department of Biostatistical Sciences and Center for Public Health Genomics, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA
  6. 6Pfizer-Universidad de Granada-Junta de Andalucía Center for Genomics and Oncological Research, Granada, Spain
  7. 7Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA
  8. 8Center for Autoimmune Diseases Research (CREA), Universidad del Rosario, Bogotá, Colombia
  9. 9Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, South Korea
  10. 10Rosalind Russell/Ephraim P. Engleman Rheumatology Research Center, University of California San Francisco, San Francisco, California, USA
  11. 11Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA
  12. 12Division of Rheumatology, Medical University of South Carolina, Charleston, South Carolina, USA
  13. 13Department of Medicine, University of Southern California, Los Angeles, California, USA
  14. 14Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA
  15. 15Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA
  16. 16Department of Clinical Pharmacology, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA
  17. 17Division of Rheumatology and Department of Immunology, Mayo Clinic, Rochester, Minnesota, USA
  18. 18Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
  19. 19Division of Rheumatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
  20. 20Department of Rheumatology and Clinical Immunogenetics, University of Texas Health Science Center at Houston, Houston, Texas, USA
  21. 21US Department of Veterans Affairs Medical Center, Oklahoma City, Oklahoma, USA
  22. 22Division of Rheumatology, Department of Pediatrics, University of Washington, Seattle, Washington, USA
  23. 23Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, Washington, USA
  24. 24Division of Rheumatology, Department of Medicine, University of Puerto Rico Medical Sciences Campus, San Juan, Puerto Rico
  25. 25Division of Genetics and Molecular Medicine and Immunology, King's College London, London, UK
  26. 26Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
  27. 27US Department of Veterans Affairs Medical Center, Cincinnati, Ohio, USA
  28. 28Department of Epidemiology, University of Alabama at Birmingham, Birmingham, Alabama, USA
  29. 29Denver Veterans Affairs Medical Center, Denver, Colorado, USA
  1. Correspondence to Dr Susan A Boackle, University of Colorado School of Medicine, 1775 Aurora Court, Room 3102 B, Mail Stop B115, Aurora, CO 80045, USA; susan.boackle{at}ucdenver.edu

Abstract

Objectives Systemic lupus erythematosus (SLE; OMIM 152700) is characterised by the production of antibodies to nuclear antigens. We previously identified variants in complement receptor 2 (CR2/CD21) that were associated with decreased risk of SLE. This study aimed to identify the causal variant for this association.

Methods Genotyped and imputed genetic variants spanning CR2 were assessed for association with SLE in 15 750 case-control subjects from four ancestral groups. Allele-specific functional effects of associated variants were determined using quantitative real-time PCR, quantitative flow cytometry, electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP)-PCR.

Results The strongest association signal was detected at rs1876453 in intron 1 of CR2 (pmeta=4.2×10−4, OR 0.85), specifically when subjects were stratified based on the presence of dsDNA autoantibodies (case-control pmeta=7.6×10−7, OR 0.71; case-only pmeta=1.9×10−4, OR 0.75). Although allele-specific effects on B cell CR2 mRNA or protein levels were not identified, levels of complement receptor 1 (CR1/CD35) mRNA and protein were significantly higher on B cells of subjects harbouring the minor allele (p=0.0248 and p=0.0006, respectively). The minor allele altered the formation of several DNA protein complexes by EMSA, including one containing CCCTC-binding factor (CTCF), an effect that was confirmed by ChIP-PCR.

Conclusions These data suggest that rs1876453 in CR2 has long-range effects on gene regulation that decrease susceptibility to lupus. Since the minor allele at rs1876453 is preferentially associated with reduced risk of the highly specific dsDNA autoantibodies that are present in preclinical, active and severe lupus, understanding its mechanisms will have important therapeutic implications.

  • Systemic Lupus Erythematosus
  • Autoantibodies
  • Gene Polymorphism
  • B cells

This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/

https://doi.org/10.1136/annrheumdis-2014-205584

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