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Phenotypic associations of genetic susceptibility loci in systemic lupus erythematosus
  1. Elena Sanchez1,
  2. Ajay Nadig1,
  3. Bruce C Richardson2,3,
  4. Barry I Freedman4,
  5. Kenneth M Kaufman1,5,6,
  6. Jennifer A Kelly1,
  7. Timothy B Niewold7,
  8. Diane L Kamen8,
  9. Gary S Gilkeson8,
  10. Julie T Ziegler9,
  11. Carl D Langefeld9,
  12. Graciela S Alarcón10,
  13. Jeffrey C Edberg10,
  14. Rosalind Ramsey-Goldman11,
  15. Michelle Petri12,
  16. Elizabeth E Brown10,
  17. Robert P Kimberly10,
  18. John D Reveille13,
  19. Luis M Vilá14,
  20. Joan T Merrill5,15,
  21. Juan-Manuel Anaya16,
  22. Judith A James1,5,
  23. Bernardo A Pons-Estel17,
  24. Javier Martin18,
  25. So-Yeon Park19,
  26. So-Young Bang19,
  27. Sang-Cheol Bae19,
  28. Kathy L Moser1,
  29. Timothy J Vyse20,
  30. Lindsey A Criswell21,
  31. Patrick M Gaffney1,
  32. Betty P Tsao22,
  33. Chaim O Jacob23,
  34. John B Harley24,25,
  35. Marta E Alarcón-Riquelme on behalf of BIOLUPUS and GENLES1,26,
  36. Amr H Sawalha1,5,6
  1. 1Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA
  2. 2Division of Rheumatology, University of Michigan, Ann Arbor, Michigan, USA
  3. 3US Department of Veterans Affairs Medical Center, Ann Arbor, Michigan, USA
  4. 4Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA
  5. 5Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA
  6. 6Department of Veterans Affairs Medical Center, Oklahoma City, Oklahoma, USA
  7. 7Section of Rheumatology and Gwen Knapp Center for Lupus and Immunology Research, University of Chicago, Chicago, Illinois, USA
  8. 8Department of Medicine, Division of Rheumatology, Medical University of South Carolina, Charleston, South Carolina, USA
  9. 9Department of Biostatistical Sciences, Wake Forest University Health Sciences, Winston-Salem, North Carolina, USA
  10. 10Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA
  11. 11Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
  12. 12Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
  13. 13Department of Medicine, University of Texas-Houston Health Science Center, Houston, Texas, USA
  14. 14Department of Medicine, University of Puerto Rico Medical Sciences Campus, San Juan, Puerto Rico
  15. 15Clinical Pharmacology Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA
  16. 16Center for Autoimmune Diseases Research (CREA), Universidad del Rosario, Bogota, Colombia
  17. 17Sanatorio Parque, Rosario, Argentina
  18. 18Instituto de Parasitologia y Biomedicina Lopez-Neyra (CSIC), Granada, Spain
  19. 19Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, Korea
  20. 20Divisions of Genetics and Molecular Medicine and Immunology, Infection and Inflammatory Disease, King's College London, Guy's Hospital, London, UK
  21. 21Rosalind Russell Medical Research Center for Arthritis, University of California, San Francisco, San Francisco, California, USA
  22. 22Department of Medicine, Division of Rheumatology, University of California, Los Angeles, Los Angeles, California, USA
  23. 23Department of Medicine, University of Southern California, Los Angeles, California, USA
  24. 24Rheumatology Division and Autoimmune Genomics Center, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
  25. 25US Department of Veterans Affairs Medical Center, Cincinnati, Ohio, USA
  26. 26Center for Genomics and Oncological Research, Pfizer-University of Granada-Junta de Andalucía, Granada, Spain
  1. Correspondence to Dr Amr H Sawalha, 825 NE 13th Street, MS 24, Oklahoma City, OK 73104, USA; amr-sawalha{at}


Objective Systemic lupus erythematosus is a clinically heterogeneous autoimmune disease. A number of genetic loci that increase lupus susceptibility have been established. This study examines if these genetic loci also contribute to the clinical heterogeneity in lupus.

Materials and methods 4001 European-derived, 1547 Hispanic, 1590 African-American and 1191 Asian lupus patients were genotyped for 16 confirmed lupus susceptibility loci. Ancestry informative markers were genotyped to calculate and adjust for admixture. The association between the risk allele in each locus was determined and compared in patients with and without the various clinical manifestations included in the ACR criteria.

Results Renal disorder was significantly correlated with the lupus risk allele in ITGAM (p=5.0×10−6, OR 1.25, 95% CI 1.12 to 1.35) and in TNFSF4 (p=0.0013, OR 1.14, 95% CI 1.07 to 1.25). Other significant findings include the association between risk alleles in FCGR2A and malar rash (p=0.0031, OR 1.11, 95% CI 1.17 to 1.33), ITGAM and discoid rash (p=0.0020, OR 1.20, 95% CI 1.06 to 1.33), STAT4 and protection from oral ulcers (p=0.0027, OR 0.89, 95% CI 0.83 to 0.96) and IL21 and haematological disorder (p=0.0027, OR 1.13, 95% CI 1.04 to 1.22). All these associations are significant with a false discovery rate of <0.05 and pass the significance threshold using Bonferroni correction for multiple testing.

Conclusion Signifi cant associations were found between clinical manifestations and the FCGR2A, ITGAM, STAT4, TNSF4 and IL21 genes. The findings suggest that genetic profiling might be a useful tool to predict disease manifestations in lupus patients in the future.

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  • Funding This work was made possible by the National Institutes of Health R03AI076729, P20RR020143, P20RR015577, P30AR053483, R01AR042460, R37AI024717, R01AI031584, N01AR62277, P50AR048940, P01AI083194, RC1AR058621, U19AI082714, HHSN266200500026C, P30RR031152, P01AR049084, R01AR043274, R01AI063274, K08AI083790, P30DK42086, L30AI071651, UL1RR024999, K24AR002138, P602AR30692, UL1RR025741, R01DE018209, R01AR043727, UL1RR025005, UL1RR029882, P60AR049459, AR043814, P60AR053308, R01AR044804, R01AR052300, M01RR-000079, the Lupus Research Institute, the Arthritis National Research Foundation, American College of Rheumatology/Research and Education Foundation, University of Oklahoma College of Medicine, Kirkland Scholar award, Alliance for Lupus Research, US Department of Veterans Affairs, US Department of Defense PR094002, Federico Wihelm Agricola Foundation, Instituto de Salud Carlos III (PS09/00129), cofinanced partly through FEDER funds of the European Union, grant PI0012 from the Consejeria de Salud de Andalucia, the Swedish Research Council, and Korea Healthcare technology R&D project, Ministry for Health and Welfare, Republic of Korea (A080588).

  • Competing interests None.

  • Patient consent Obtained.

  • Ethics approval This study was conducted with the approval of each institution involved in the study.

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

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