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HLA class I and II alleles in susceptibility to ankylosing spondylitis
  1. John D Reveille1,
  2. Xiaodong Zhou1,
  3. MinJae Lee2,
  4. Michael H Weisman3,
  5. Lin Yi4,
  6. Lianne S Gensler5,
  7. Hejian Zou6,
  8. Michael M Ward7,
  9. Mariko L Ishimori3,
  10. Thomas J Learch3,
  11. Dongyi He8,
  12. Mohammad H Rahbar2,
  13. Jiucun Wang6,
  14. Matthew A Brown9
  1. 1 Division of Rheumatology and Clinical Immunogenetics, McGovern Medical School at The University of Texas Health Science Center, Houston, Texas, USA
  2. 2 Division of Clinical and Translational Sciences, McGovern Medical School at The University of Texas Health Science Center, Houston, Texas, USA
  3. 3 Department of Radiology, Cedars-Sinai Medical Center, Los Angeles, California, USA
  4. 4 Division of Rheumatology, Gansu College of Traditional Chinese Medicine, Gansu, China
  5. 5 Division of Rheumatology, The University of California, San Francisco, California, USA
  6. 6 Huashan Hospital, Fudan University, Shanghai, China
  7. 7 Division of Rheumatology, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, Maryland, USA
  8. 8 Division of Rheumatology, Shanghai Guanghua Hospital, Shanghai, China
  9. 9 Institute of Health and Biomedical Innovation, Queensland University of Technology, Translational Research Institute, Princess Alexandra Hospital, Brisbane, Queensland, Australia
  1. Correspondence to Dr John D Reveille, Division of Rheumatology and Clinical Immunogenetics, The University of Texas-Houston Health Science Center, Houston, TX 77030, USA; john.d.reveille{at}uth.tmc.edu

Abstract

Objective To examine associations of HLA class I and class II alleles with ankylosing spondylitis (AS) in three cohorts of patients of European, Asian and African ancestry.

Methods HLA-A, HLA-B, HLA-C, HLA-DRB1, HLA-DQB1 and HLA-DPB1 alleles were genotyped in 1948 unrelated white and 67 African-American patients with AS from the Prospective Study of Outcomes in Ankylosing Spondylitis cohort, the North American Spondylitis Consortium and Australo-Anglo-American Spondyloarthritis Consortium, 990 white and 245 African-American Controls and HLA-B alleles in 442 Han Chinese patients with AS and 346 controls from Shanghai and Gansu, China. In addition to the case:control analyses, HLA-B*27-negative patients with AS were analysed separately, and logistic regression and ‘relative predispositional effects’ (RPE) analyses were carried out to control for the major effect of HLA-B*27 on disease susceptibility.

Results Although numerous associations were seen between HLA alleles and AS in whites, among HLA-B*27-negative patients with AS , positive associations were seen with HLA-A*29, B*38, B*49, B*52, DRB1*11 and DPB1*03:01 and negative associations with HLA-B*07, HLA-B*57, HLA-DRB1*15:01, HLA-DQB1*02:01 and HLA -DQB1*06:02. Additional associations with HLA-B*14 and B*40 (B60) were observed via RPE analysis, which excludes the HLA-B*27 alleles. The increased frequency of HLA-B*40:01 and decreased frequency of HLA-B*07 was also seen in Han Chinese and African-Americans with AS. HLA-B*08 was decreased in whites with acute anterior uveitis.

Conclusions These data, analysing the largest number of patients with AS examined to date in three ethnic groups, confirm that other HLA class I and II alleles other than HLA-B*27 to be operative in AS predisposition.

  • spondylitis
  • HLA
  • Chinese
  • African-American
  • ethnicity
  • uveitis
  • disease susceptibility
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Footnotes

  • Handling editor Josef S Smolen

  • Contributors JDR contributed many of the patients, carried out the HLA typing, entered the data, interpreted the results, did many of the statistical analyses, wrote the manuscript and provided the funding for the study. XZ established the Chinese collaboration and oversaw its completion, reviewed the manuscript and provided some of the funding for this study. ML carried out the multivariable and regression statistical analyses and participated in the writing and drafting of the manuscript. MHW contributed a large amount of the patients for this study as well as some of the controls. He also reviewed the manuscript. LY contributed a large amount of the Chinese patients for this study as well as some of the controls and also qc'd the Chinese HLA genotyping and reviewed the manuscript. LSG contributed number of the US patients for this study. She also reviewed the manuscript. Hejian Zou contributed a large amount of the Chinese patients for this study as well as some of the controls. He also reviewed the manuscript. MMW contributed a number of US patients for this study. He also reviewed the manuscript and obtained funding from the NIH Clinical Center to carry on the project there. MLI contributed a number of US patients for this study as well as some of the controls. She also reviewed the manuscript. TJL read all the X-rays for the study to determine who qualified for inclusion. He also reviewed the manuscript. DH contributed a large amount of the Chinese patients for this study as well as some of the controls. He also reviewed the manuscript. MHR oversaw the qc process of the datasets and worked with ML in the statistical analyses. JW oversaw the Chinese segment of this study, carrying out the HLA typing and coordinating the participating centers as well as providing funding for the Chinese portion of this project MAB provided the Australian patients in this study. He also qc'd the HLA typing with the imputed data from our GWAS, confirmed the statistical analyses and assisted JDR in manuscript preparation.

  • Funding This study was supported by the National Institutes of Health-National Institute of Allergy and Infectious Diseases (NIH-NIAIS) grant UO1 AI09090 (Drs Zhou, Reveille), National Institute of Arthritis, Musculoskeletal and Skin Diseases (NIH-NIAMS) grants R01 AR-46208 and 2P01AR052915-06A1 (Dr Reveille) and by University Clinical Research Grants M01-RR-02558 (The University of Texas Health Science Center at Houston) and M01-RR-000425 (Cedars-Sinai Medical Center) and by a grant from the Spondylitis Association of America. MAB was funded by a National Health and Medical Research Council (Australia) Senior Principal Research Fellowship. LSG is supported by the Rosalind Engelman Research Center at the University of California, San Francisco. MMW is funded by the Intramural Research Program, NIAMS/NIH.

  • Competing interests None declared.

  • Patient consent Not required.

  • Ethics approval The Internal Review Boards at The University of Texas-Health McGovern Medical School, The University of California-San Francisco, Cedars-Sinai Medical Center, The NIH-NIAMS Clinical Center, The Princess Alexandra Hospital (Brisbane), Fudan University reviewed and approved this study.

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

  • Data sharing statement We would be happy to share the data published in this manuscript. There are no unpublished data referable to the work included here.

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