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The HLA-DRβ1 amino acid positions 11–13–26 explain the majority of SLE–MHC associations

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  • Kwangwoo Kim

    (Hanyang University Hospital for Rheumatic Diseases
    Immunology and Allergy, Brigham and Women’s Hospital, Harvard Medical School
    Brigham and Women’s Hospital, Harvard Medical School
    Program in Medical and Population Genetics, Broad Institute)

  • So-Young Bang

    (Hanyang University Hospital for Rheumatic Diseases)

  • Hye-Soon Lee

    (Hanyang University Hospital for Rheumatic Diseases)

  • Yukinori Okada

    (Immunology and Allergy, Brigham and Women’s Hospital, Harvard Medical School
    Brigham and Women’s Hospital, Harvard Medical School
    Program in Medical and Population Genetics, Broad Institute
    Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University)

  • Buhm Han

    (Brigham and Women’s Hospital, Harvard Medical School
    Program in Medical and Population Genetics, Broad Institute
    Asan Institute for Life Sciences, University of Ulsan College of Medicine, Asan Medical Center)

  • Woei-Yuh Saw

    (Life Sciences Institute, National University of Singapore)

  • Yik-Ying Teo

    (Life Sciences Institute, National University of Singapore
    Saw Swee Hock School of Public Health, National University of Singapore
    National University of Singapore
    NUS Graduate School for Integrative Science and Engineering, National University of Singapore)

  • Sang-Cheol Bae

    (Hanyang University Hospital for Rheumatic Diseases)

Abstract

Genetic association of the major histocompatibility complex (MHC) locus is well established in systemic lupus erythematosus (SLE), but the causal functional variants in this region have not yet been discovered. Here we conduct the first fine-mapping study, which thoroughly investigates the SLE–MHC associations down to the amino acid level of major HLA genes in 5,342 unrelated Korean case–control subjects, taking advantages of HLA imputation with a newly constructed Asian HLA reference panel. The most significant association is mapped to amino acid position 13 of HLA-DRβ1 (P=2.48 × 10−17) and its proxy position 11 (P=4.15 × 10−17), followed by position 26 in a stepwise conditional analysis (P=2.42 × 10−9). Haplotypes defined by amino acid positions 11–13–26 support the reported effects of most classical HLA-DRB1 alleles in Asian and European populations. In conclusion, our study identifies the three amino acid positions at the epitope-binding groove of HLA-DRβ1 that are responsible for most of the association between SLE and MHC.

Suggested Citation

  • Kwangwoo Kim & So-Young Bang & Hye-Soon Lee & Yukinori Okada & Buhm Han & Woei-Yuh Saw & Yik-Ying Teo & Sang-Cheol Bae, 2014. "The HLA-DRβ1 amino acid positions 11–13–26 explain the majority of SLE–MHC associations," Nature Communications, Nature, vol. 5(1), pages 1-7, December.
    • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms6902
    DOI: 10.1038/ncomms6902
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