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Amino acid signatures of HLA Class-I and II molecules are strongly associated with SLE susceptibility and autoantibody production in Eastern Asians

Molineros JE 1 , Looger LL 2 , Kim K 3 , Okada Y 4 , Terao C 5 , Sun C 1 Show all authors , Zhou XJ 6 , Raj P 7 , Kochi Y 8 , Suzuki A 8 , Akizuki S 9 , Nakabo S 9 , Bang SY 10 , Lee HS 10 , Kang YM 11 , Suh CH 12 , Chung WT 13 , Park YB 14 , Choe JY 15 , Shim SC 16 , Lee SS 17 , Zuo X 18 , Yamamoto K 8 , Li QZ 19 , Shen N 20 , Porter LL 2 , Harley JB 21 , Chua KH 22 , Zhang H 6 , Wakeland EK 7 , Tsao BP 23 , Bae SC 10 , Nath SK 1

Affiliations 

  • 1 Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, United States of America
  • 2 Howard Hughes Medical Institute, Janelia Research Campus, Ashburn, Virginia, United States of America
  • 3 Department of Biology, Kyung Hee University, Seoul, Republic of Korea
  • 4 Department of Statistical Genetics, Osaka University Graduate School of Medicine, Osaka, Japan
  • 5 Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan
  • 6 Renal Division, Peking University First Hospital, Peking University Institute of Nephrology, Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China
  • 7 Department of Immunology, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America
  • 8 Laboratory for Autoimmune Diseases, Center for Integrative Medical Sciences, RIKEN, Yokohama, Japan
  • 9 Department of Rheumatology and Clinical Immunology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
  • 10 Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, Korea
  • 11 School of Medicine, Kyungpook National University Hospital, Daegu, Korea
  • 12 Department of Rheumatology, Ajou University Hospital, Suwon, Korea
  • 13 Dong-A University Hospital, Department of Internal Medicine, Busan, Korea
  • 14 Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
  • 15 Department of Rheumatology, Catholic University of Daegu School of Medicine, Daegu, Korea
  • 16 Daejeon Rheumatoid & Degenerative Arthritis Center, Chungnam National University Hospital, Daejeon, Korea
  • 17 Department of Rheumatology, Chonnam National University Medical School and Hospital, Gwangju, Korea
  • 18 Department of Rheumatology and Immunology, Xiangya Hospital, Central South University, Changsha, China
  • 19 Department of Immunology and Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America
  • 20 Department of Rheumatology and Shanghai Institute of Rheumatology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
  • 21 Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America
  • 22 Department of Biomedical Science, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
  • 23 Division of Rheumatology and Immunology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, United States of America
PLoS Genet, 2019 04;15(4):e1008092.
PMID: 31022184 DOI: 10.1371/journal.pgen.1008092

Abstract

Human leukocyte antigen (HLA) is a key genetic factor conferring risk of systemic lupus erythematosus (SLE), but precise independent localization of HLA effects is extremely challenging. As a result, the contribution of specific HLA alleles and amino-acid residues to the overall risk of SLE and to risk of specific autoantibodies are far from completely understood. Here, we dissected (a) overall SLE association signals across HLA, (b) HLA-peptide interaction, and (c) residue-autoantibody association. Classical alleles, SNPs, and amino-acid residues of eight HLA genes were imputed across 4,915 SLE cases and 13,513 controls from Eastern Asia. We performed association followed by conditional analysis across HLA, assessing both overall SLE risk and risk of autoantibody production. DR15 alleles HLA-DRB1*15:01 (P = 1.4x10-27, odds ratio (OR) = 1.57) and HLA-DQB1*06:02 (P = 7.4x10-23, OR = 1.55) formed the most significant haplotype (OR = 2.33). Conditioned protein-residue signals were stronger than allele signals and mapped predominantly to HLA-DRB1 residue 13 (P = 2.2x10-75) and its proxy position 11 (P = 1.1x10-67), followed by HLA-DRB1-37 (P = 4.5x10-24). After conditioning on HLA-DRB1, novel associations at HLA-A-70 (P = 1.4x10-8), HLA-DPB1-35 (P = 9.0x10-16), HLA-DQB1-37 (P = 2.7x10-14), and HLA-B-9 (P = 6.5x10-15) emerged. Together, these seven residues increased the proportion of explained heritability due to HLA to 2.6%. Risk residues for both overall disease and hallmark autoantibodies (i.e., nRNP: DRB1-11, P = 2.0x10-14; DRB1-13, P = 2.9x10-13; DRB1-30, P = 3.9x10-14) localized to the peptide-binding groove of HLA-DRB1. Enrichment for specific amino-acid characteristics in the peptide-binding groove correlated with overall SLE risk and with autoantibody presence. Risk residues were in primarily negatively charged side-chains, in contrast with rheumatoid arthritis. We identified novel SLE signals in HLA Class I loci (HLA-A, HLA-B), and localized primary Class II signals to five residues in HLA-DRB1, HLA-DPB1, and HLA-DQB1. These findings provide insights about the mechanisms by which the risk residues interact with each other to produce autoantibodies and are involved in SLE pathophysiology.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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