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Extended report
Variation in the ICAM1–ICAM4–ICAM5 locus is associated with systemic lupus erythematosus susceptibility in multiple ancestries
  1. Kwangwoo Kim1,
  2. Elizabeth E Brown2,
  3. Chan-Bum Choi3,
  4. Marta E Alarcón-Riquelme on behalf of BIOLUPUS4,5,
  5. Jennifer A Kelly4,
  6. Stuart B Glenn4,
  7. Joshua O Ojwang4,
  8. Adam Adler4,
  9. Hye-Soon Lee3,
  10. Susan A Boackle6,
  11. Lindsey A Criswell7,
  12. Graciela S Alarcón2,
  13. Jeffrey C Edberg2,
  14. Anne M Stevens8,
  15. Chaim O Jacob9,
  16. Gary S Gilkeson10,
  17. Diane L Kamen10,
  18. Betty P Tsao11,
  19. Juan-Manuel Anaya12,
  20. Joel M Guthridge4,
  21. Swapan K Nath4,
  22. Bruce Richardson13,
  23. Amr H Sawalha4,14,15,
  24. Young Mo Kang16,
  25. Seung Cheol Shim17,
  26. Chang-Hee Suh18,
  27. Soo-Kon Lee19,
  28. Chang-sik Kim20,
  29. Joan T Merrill4,
  30. Michelle Petri21,
  31. Rosalind Ramsey-Goldman22,
  32. Luis M Vilá23,
  33. Timothy B Niewold24,
  34. Javier Martin25,
  35. Bernardo A Pons-Estel on behalf of GENLES26,
  36. Timothy J Vyse27,
  37. Barry I Freedman28,
  38. Kathy L Moser4,
  39. Patrick M Gaffney4,
  40. Adrienne Williams28,
  41. Mary Comeau28,
  42. John D Reveille29,
  43. Judith A James14,
  44. R Hal Scofield14,
  45. Carl D Langefeld28,
  46. Kenneth M Kaufman4,15,
  47. John B Harley30,
  48. Changwon Kang1,
  49. Robert P Kimberly2,
  50. Sang-Cheol Bae3
  1. 1Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Korea
  2. 2Departments of Medicine and Epidemiology, Schools of Medicine and Public Health, The University of Alabama at Birmingham, Birmingham, Alabama, USA
  3. 3Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, Korea
  4. 4Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA
  5. 5Area of Human DNA Variability, Centro de Genómica e Investigación Oncológica (GENYO), Pfizer-Universidad de Granada-Junta de Andalucía, Granada, Spain
  6. 6Division of Rheumatology, University of Colorado Denver School of Medicine, Aurora, Colorado, USA
  7. 7Rosalind Russell Medical Research Center for Arthritis, University of California, San Francisco, California, USA
  8. 8University of Washington, Seattle Children's Hospital, Seattle, Washington, USA
  9. 9The Lupus Genetic Group, University of Southern California, Los Angeles, California, USA
  10. 10Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, USA
  11. 11David Geffen School of Medicine, University of California, Los Angeles, California, USA
  12. 12Center for Autoimmune Diseases Research, Universidad del Rosario, Bogota, Colombia
  13. 13Division of Rheumatology, University of Michigan and US Department of Veterans Affairs Medical Center, Ann Arbor, Michigan, USA
  14. 14Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA
  15. 15Department of Medicine, US Department of Veterans Affairs Medical Center, Oklahoma City, Oklahoma, USA
  16. 16Department of Internal Medicine (Rheumatology), Kyungpook National University School of Medicine, Daegu, Korea
  17. 17Division of Rheumatology, Department of Medicine, Eulji Medi-Bio Research Institute, Eulji University, Daejeon, Korea
  18. 18Department of Rheumatology, Ajou University School of Medicine, Suwon, Korea
  19. 19Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
  20. 20Department of Ophthalmology, Chungnam National University School of Medicine, Daejeon, Korea
  21. 21Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
  22. 22Northwestern University, Feinberg School of Medicine, Chicago, Illinois, USA
  23. 23Department of Medicine University of Puerto Rico Medical Sciences Campus, San Juan, Puerto Rico
  24. 24Gwen Knapp Center for Lupus and Immunology Research, University of Chicago, Chicago, Illinois, USA
  25. 25Department of Immunology, Instituto de Biomedicina y Parasitología López-Neyra, CSIC, Granada, Spain
  26. 26Department of Medicine, Sanatorio Parque, Rosario, Argentina
  27. 27King's College London, Divisions of Genetics and Molecular Medicine and Immunology, Infection and Inflammatory Disease, Guy's Hospital, London, UK
  28. 28Departments of Biostatistical Sciences and Internal Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA
  29. 29Division of Rheumatology, The University of Texas Health Science Center at Houston, Houston, Texas, USA
  30. 30 Pediatrics and US Department of Veterans Affairs Medical Center, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
  1. Correspondence to Changwon Kang, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Republic of Korea; ckang{at}kaist.ac.kr or Robert P Kimberly, The University of Alabama at Birmingham, Birmingham, Alabama 35294, USA; Robert.Kimberly{at}ccc.uab.edu, or Sang-Cheol Bae, Hanyang University Hospital for Rheumatic Diseases, Seoul 133-792, Republic of Korea; scbae{at}hanyang.ac.kr

Abstract

Objective Systemic lupus erythematosus (SLE; OMIM 152700) is a chronic autoimmune disease for which the aetiology includes genetic and environmental factors. ITGAM, integrin αM (complement component 3 receptor 3 subunit) encoding a ligand for intracellular adhesion molecule (ICAM) proteins, is an established SLE susceptibility locus. This study aimed to evaluate the independent and joint effects of genetic variations in the genes that encode ITGAM and ICAM.

Methods The authors examined several markers in the ICAM1–ICAM4–ICAM5 locus on chromosome 19p13 and the single ITGAM polymorphism (rs1143679) using a large-scale case–control study of 17 481 unrelated participants from four ancestry populations. The single-marker association and gene–gene interaction were analysed for each ancestry, and a meta-analysis across the four ancestries was performed.

Results The A-allele of ICAM1–ICAM4–ICAM5 rs3093030, associated with elevated plasma levels of soluble ICAM1, and the A-allele of ITGAM rs1143679 showed the strongest association with increased SLE susceptibility in each of the ancestry populations and the trans-ancestry meta-analysis (ORmeta=1.16, 95% CI 1.11 to 1.22; p=4.88×10−10 and ORmeta=1.67, 95% CI 1.55 to 1.79; p=3.32×10−46, respectively). The effect of the ICAM single-nucleotide polymorphisms (SNPs) was independent of the effect of the ITGAM SNP rs1143679, and carriers of both ICAM rs3093030-AA and ITGAM rs1143679-AA had an OR of 4.08 compared with those with no risk allele in either SNP (95% CI 2.09 to 7.98; p=3.91×10−5).

Conclusion These findings are the first to suggest that an ICAM–integrin-mediated pathway contributes to susceptibility to SLE.

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Footnotes

  • KK and EEB contributed equally to this work and are joint first authors. CK, RPK and SCB contributed equally to this work and are joint corresponding authors.

  • Funding The work was supported by grants from US NIH (AI063622, AI071651, AI082714, AI083194, AI094377, AI24717, AR042460, AR043274, AR043814, AR044804, AR048940, AR052300, AR053483, AR058554, AR060366, AR43727, AR62277, CA141700-01, GM063483, HD07463, K08-AI083790, K24-AR002138, M01-RR00079, N01-AR-6-227, P01-AR49084, P30-DK42086, P30-AR055385, P60-AR049459 P60-AR053308, P60-2-AR30692, PO1-AR49084, PR094002, R01-AR33062, R21-AI070304, RR015577, RR020143, UL1RR024999, UL1RR025005, UL1RR025741, UL1RR029882 and 5UL1RR025777), the Lupus Foundation of America, the Alliance for Lupus Research, a Kirkland Scholar Award, the US Department of Veterans Affairs, the Korean Healthcare Technology Research and Development Project (A111218-11-GM01), the Korea Research Program for New Drug Target Discovery (20090083335), the National Research Foundation of Korea (2010-0014162), the Lupus Research Institute Novel Research Grant, the Alliance for Lupus Research Target Identification in Lupus Grant, the Arthritis National Research Foundation Eng Tan Scholar Award, the ESF in the framework of the Research Networking Programme European Science Foundation—The Identification of Novel Genes and Biomarkers for Systemic Lupus Erythematosus (BIOLUPUS) 07-RNP-083, the Swedish Research Council, the Swedish Association against Rheumatism, the Swedish International Development Agency, the Gustaf Vth 80th-Jubilee Foundation, the Instituto de Salud Carlos III (PS09/00129) partly financed by the FEDER funds of the European Union, and a grant from the Consejería de Salud de la Junta de Andalucía.

  • Competing interests None.

  • Patient consent Obtained.

  • Ethics approval The study was approved by the Institutional Review Board of all participating institutions.

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

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