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Fine mapping of Xq28: both MECP2 and IRAK1 contribute to risk for systemic lupus erythematosus in multiple ancestral groups
  1. Kenneth M Kaufman1,2,
  2. Jian Zhao3,
  3. Jennifer A Kelly4,
  4. Travis Hughes4,
  5. Adam Adler4,
  6. Elena Sanchez4,
  7. Joshua O Ojwang5,
  8. Carl D Langefeld6,
  9. Julie T Ziegler6,
  10. Adrienne H Williams6,
  11. Mary E Comeau6,
  12. Miranda C Marion6,
  13. Stuart B Glenn4,
  14. Rita M Cantor7,
  15. Jennifer M Grossman3,
  16. Bevra H Hahn3,
  17. Yeong Wook Song8,
  18. Chack-Yung Yu9,
  19. Judith A James4,10,
  20. Joel M Guthridge4,
  21. Elizabeth E Brown11,12,
  22. Graciela S Alarcón12,
  23. Robert P Kimberly12,
  24. Jeffrey C Edberg12,
  25. Rosalind Ramsey-Goldman13,
  26. Michelle A Petri14,
  27. John D Reveille15,
  28. Luis M Vilá16,
  29. Juan-Manuel Anaya17,
  30. Susan A Boackle18,
  31. Anne M Stevens19,
  32. Barry I Freedman20,
  33. Lindsey A Criswell21,
  34. Bernardo A Pons-Estel on behalf of the Argentine Collaborative Group22,*,
  35. Joo-Hyun Lee23,
  36. Ji-Seon Lee24,
  37. Deh-Ming Chang25,
  38. R Hal A Scofield4,10,26,
  39. Gary S Gilkeson27,
  40. Joan T Merrill2,28,
  41. Timothy B Niewold29,
  42. Timothy James Vyse30,
  43. Sang-Cheol Bae24,
  44. Marta E Alarcón-Riquelme on behalf of the BIOLUPUS network4,31,*,
  45. Chaim O Jacob32,
  46. Kathy Moser Sivils4,
  47. Patrick M Gaffney4,
  48. John B Harley1,2,
  49. Amr H Sawalha4,
  50. Betty P Tsao3
  1. 1Division of Rheumatology and The Center for Autoimmune Genomics & Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
  2. 2US Department of Veterans Affairs Medical Center, Cincinnati, Ohio, USA
  3. 3Division of Rheumatology, University of California Los Angeles, Los Angeles, California, USA
  4. 4Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA
  5. 5Department of Chemistry, Brevard College, Palm Bay, Florida, USA
  6. 6Department of Biostatistical Sciences, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA
  7. 7Department of Human Genetics, University of California Los Angeles, Los Angeles, California, USA
  8. 8Division of Rheumatology, Seoul National University, Seoul, Korea
  9. 9Department of Pediatrics, The Ohio State University, Columbus, Ohio, USA
  10. 10Department of Medicine, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma, USA
  11. 11Department of Epidemiology, University of Alabama at Birmingham, Birmingham, Alabama, USA
  12. 12Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA
  13. 13Division of Rheumatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
  14. 14Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
  15. 15Department of Internal Medicine, University of Texas-Houston Health Science Center, Houston, Texas, USA
  16. 16Department of Medicine, University of Puerto Rico Medical Sciences Campus, San Juan, Puerto Rico
  17. 17Center for Autoimmune Disease Research, Universidad del Rosario, Bogota, Colombia
  18. 18Division of Rheumatology, University of Colorado Denver, Aurora, Colorado, USA
  19. 19Division of Rheumatology, Department of Pediatrics, University of Washington, and Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, Washington, USA
  20. 20Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA
  21. 21Rosalind Russell Medical Research Center for Arthritis, Department of Medicine, University of California at San Francisco, San Francisco, California, USA
  22. 22Department of Medicine, Sanatorio Parque, Rosario, Argentina
  23. 23Department of Rheumatology, Inje University College of Medicine, IIsan Paik Hospital, Korea
  24. 24Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, Korea
  25. 25National Defense Medical Center, Taipei, Taiwan
  26. 26US Department of Veterans Affairs Medical Center, Oklahoma City, Oklahoma, USA
  27. 27Department of Medicine, Division of Rheumatology, Medical University of South Carolina, Charleston, South Carolina, USA
  28. 28Clinical Pharmacology Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA
  29. 29Section of Rheumatology and Gwen Knapp Center for Lupus and Immunology Research, University of Chicago, Chicago, Illinois, USA
  30. 30Divisions of Genetics and Molecular Medicine and Immunology, King's College London, London, UK
  31. 31Centro de Genómica e Investigación Oncológica (GENYO), Pfizer-Universidad de Granada-Junta de Andalucia, Granada, Spain
  32. 32Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
  1. Correspondence to Dr Kenneth Kaufman, MLC 15012, 3333 Burnet Ave, Cincinnati, Ohio, 45229 USA; kaufman.kenneth{at}cchmc.org; Professor Betty Tsao, Division of Rheumatology, University of California Los Angeles, Warren Hall Rm 14-224, 900 Veteran Avenue, Los Angeles, California 90095, USA; BTsao{at}mednet.ucla.edu

Abstract

Objectives The Xq28 region containing IRAK1 and MECP2 has been identified as a risk locus for systemic lupus erythematosus (SLE) in previous genetic association studies. However, due to the strong linkage disequilibrium between IRAK1 and MECP2, it remains unclear which gene is affected by the underlying causal variant(s) conferring risk of SLE.

Methods We fine-mapped ≥136 SNPs in a ∼227 kb region on Xq28, containing IRAK1, MECP2 and seven adjacent genes (L1CAM, AVPR2, ARHGAP4, NAA10, RENBP, HCFC1 and TMEM187), for association with SLE in 15 783 case-control subjects derived from four different ancestral groups.

Results Multiple SNPs showed strong association with SLE in European Americans, Asians and Hispanics at p<5×10−8 with consistent association in subjects with African ancestry. Of these, six SNPs located in the TMEM187-IRAK1-MECP2 region captured the underlying causal variant(s) residing in a common risk haplotype shared by all four ancestral groups. Among them, rs1059702 best explained the Xq28 association signals in conditional testings and exhibited the strongest p value in transancestral meta-analysis (pmeta = 1.3×10−27, OR=1.43), and thus was considered to be the most likely causal variant. The risk allele of rs1059702 results in the amino acid substitution S196F in IRAK1 and had previously been shown to increase NF-κB activity in vitro. We also found that the homozygous risk genotype of rs1059702 was associated with lower mRNA levels of MECP2, but not IRAK1, in SLE patients (p=0.0012) and healthy controls (p=0.0064).

Conclusions These data suggest contributions of both IRAK1 and MECP2 to SLE susceptibility.

  • Systemic Lupus Erythematosus
  • Gene Polymorphism
  • Epidemiology

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