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IRF5 haplotypes demonstrate diverse serological associations which predict serum interferon alpha activity and explain the majority of the genetic association with systemic lupus erythematosus
  1. Timothy B Niewold1,
  2. Jennifer A Kelly2,
  3. Silvia N Kariuki1,
  4. Beverly S Franek1,
  5. Akaash A Kumar1,
  6. Kenneth M Kaufman2,
  7. Kenaz Thomas2,
  8. Daniel Walker2,
  9. Stan Kamp2,
  10. Jacqueline M Frost3,
  11. Andrew K Wong4,
  12. Joan T Merrill2,5,
  13. Marta E Alarcón-Riquelme2,6,
  14. Mohammed Tikly3,
  15. Rosalind Ramsey-Goldman7,8,
  16. John D Reveille7,9,
  17. Michelle A Petri7,10,
  18. Jeffrey C Edberg7,11,
  19. Robert P Kimberly7,11,
  20. Graciela S Alarcón7,11,
  21. Diane L Kamen12,
  22. Gary S Gilkeson12,
  23. Timothy J Vyse13,
  24. Judith A James2,5,
  25. Patrick M Gaffney2,
  26. Kathy L Moser2,
  27. Mary K Crow14,
  28. John B Harley15
  1. 1Section of Rheumatology and Gwen Knapp Center for Lupus and Immunology Research, University of Chicago, Chicago, Illinois, USA
  2. 2Arthritis and Clinical Immunology, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA
  3. 3Division of Rheumatology, University of the Witwatersrand, Johannesburg, South Africa
  4. 4MRC Unit for Lifelong Health & Ageing, London, UK
  5. 5Department of Medicine, University of Oklahoma, Oklahoma City, Oklahoma, USA
  6. 6Pfizer-University of Granada-Junta de Andalucía Center for Genomics and Oncological Research, Granada, Spain
  7. 7PROFILE Study Group
  8. 8Division of Rheumatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
  9. 9Division of Rheumatology, University of Texas Health Science Center at Houston, Houston, Texas, USA
  10. 10Division of Rheumatology, Johns Hopkins University, Baltimore, Maryland, USA
  11. 11University of Alabama at Birmingham, Birmingham, Alabama, USA
  12. 12Medical University of South Carolina, Charleston, South Carolina, USA
  13. 13Divisions of Genetics and Molecular Medicine and Immunology, Infection and Inflammatory Disease, King's College London, Guy's Hospital, London, UK
  14. 14Mary Kirkland Center for Lupus Research, Hospital for Special Surgery, New York, New York, USA
  15. 15Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital, Cincinnati, Ohio, USA
  1. Correspondence to Timothy B. Niewold, University of Chicago, Section of Rheumatology, Gwen Knapp Center for Lupus and Immunology Research, 924 E. 57th St. R420, Chicago, IL 60637, USA; tniewold{at}


Objective High serum interferon α (IFNα) activity is a heritable risk factor for systemic lupus erythematosus (SLE). Auto-antibodies found in SLE form immune complexes which can stimulate IFNα production by activating endosomal Toll-like receptors and interferon regulatory factors (IRFs), including IRF5. Genetic variation in IRF5 is associated with SLE susceptibility; however, it is unclear how IRF5 functional genetic elements contribute to human disease.

Methods 1034 patients with SLE and 989 controls of European ancestry, 555 patients with SLE and 679 controls of African–American ancestry, and 73 patients with SLE of South African ancestry were genotyped at IRF5 polymorphisms, which define major haplotypes. Serum IFNα activity was measured using a functional assay.

Results In European ancestry subjects, anti-double-stranded DNA (dsDNA) and anti-Ro antibodies were each associated with different haplotypes characterised by a different combination of functional genetic elements (OR>2.56, p<1.9×10−14 for both). These IRF5 haplotype-auto-antibody associations strongly predicted higher serum IFNα in patients with SLE and explained >70% of the genetic risk of SLE due to IRF5. In African–American patients with SLE a similar relationship between serology and IFNα was observed, although the previously described European ancestry-risk haplotype was present at admixture proportions in African–American subjects and absent in African patients with SLE.

Conclusions The authors define a novel risk haplotype of IRF5 that is associated with anti-dsDNA antibodies and show that risk of SLE due to IRF5 genotype is largely dependent upon particular auto-antibodies. This suggests that auto-antibodies are directly pathogenic in human SLE, resulting in increased IFNα in cooperation with particular combinations of IRF5 functional genetic elements.

SLE is a systemic autoimmune disorder affecting multiple organ systems including the skin, musculoskeletal, renal and haematopoietic systems. Humoral autoimmunity is a hallmark of SLE, and patients frequently have circulating auto-antibodies directed against dsDNA, as well as RNA binding proteins (RBP). Anti-RBP autoantibodies include antibodies which recognize Ro, La, Smith (anti-Sm), and ribonucleoprotein (anti-nRNP), collectively referred to as anti-retinol-binding protein). Anti-retinol-binding protein and anti-dsDNA auto-antibodies are rare in the healthy population.1 These auto-antibodies can be present in sera for years preceding the onset of clinical SLE illness2 and are likely pathogenic in SLE.3 4

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  • Funding Funding was obtained from research grants from the National Institutes of Health (AR060861, AI083790, DK42086, AI071651 and RR024999 to TBN; AR62277, AR42460 and AI24717 to JAK and JBH; CA141700 and AR058621 to MEAR; AR002138, RR025741, AR30692 and Mo1-RR0048 to RRG; AR49084 to RRG, JCE and JBH; AR33062, AR42476 and MO1-RR00052 to JCE; RR-01070 to DLK; UL1RR029882 to DLK and GSG; AR049459 to GSG; AI065687 to TJV; RR15577, AR48940, AR045084 and AR053483 to JAJ; AR052125 and AI063274 to PMG; AI059893 to MKC; AI53747, AI31584, DE15223, RR20143, AI62629 and AR48940 to JBH) and from the Lupus Research Institute to TBN and MKC; the Alliance for Lupus Research to TBN, JBH, and MKC; the Arthritis National Research Foundation to TBN; the HHMI Gilliam Fellowship to SNK; the Connective Tissue Diseases Research Fund to JMF and MT; the Swedish Research Council and Gustaf Vth-80th-year Jubilee to MEAR; the US Department of Veterans Affairs to GSG and JBH; the Wellcome Trust and National Institute for Health and Research to TJV; the Mary Kirkland Center for Lupus Research to JAJ and MKC; and the Lou Kerr Chair in Biomedical Research to JAJ.

  • Competing interests None.

  • Patient consent All subjects signed informed consent to participate in the study, and no personal identifying information is presented for any of the patients.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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