1] Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul 133-792, Republic of Korea [2] Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA [3] Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA [4] Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts 02142, USA.
Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul 133-792, Republic of Korea.
Nat Commun. 2014 Dec 23;5:5902. doi: 10.1038/ncomms6902.
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.
主要组织相容性复合体（MHC）位点的遗传关联在系统性红斑狼疮（SLE）中得到了很好的证实，但该区域的因果功能变异尚未被发现。在这里，我们进行了首次精细映射研究，该研究在 5342 名无关韩国病例对照受试者中，利用新构建的亚洲 HLA 参考面板进行 HLA 推断，彻底研究了 SLE-MHC 关联，直至主要 HLA 基因的氨基酸水平。最显著的关联映射到 HLA-DRβ1 的氨基酸位置 13（P=2.48×10(-17)）及其代理位置 11（P=4.15×10(-17)），其次是逐步条件分析中的位置 26（P=2.42×10(-9)）。由氨基酸位置 11-13-26 定义的单倍型支持亚洲和欧洲人群中大多数经典 HLA-DRB1 等位基因报道的效应。总之，我们的研究确定了 HLA-DRβ1 表位结合槽中的三个氨基酸位置，这些位置负责 SLE 与 MHC 之间的大部分关联。
