PMID- 31022184
OWN - NLM
STAT- MEDLINE
DCOM- 20190930
LR  - 20221207
IS  - 1553-7404 (Electronic)
IS  - 1553-7390 (Print)
IS  - 1553-7390 (Linking)
VI  - 15
IP  - 4
DP  - 2019 Apr
TI  - Amino acid signatures of HLA Class-I and II molecules are strongly associated 
      with SLE susceptibility and autoantibody production in Eastern Asians.
PG  - e1008092
LID - 10.1371/journal.pgen.1008092 [doi]
LID - e1008092
AB  - 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.
FAU - Molineros, Julio E
AU  - Molineros JE
AD  - Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research 
      Foundation, Oklahoma City, Oklahoma, United States of America.
FAU - Looger, Loren L
AU  - Looger LL
AD  - Howard Hughes Medical Institute, Janelia Research Campus, Ashburn, Virginia, 
      United States of America.
FAU - Kim, Kwangwoo
AU  - Kim K
AUID- ORCID: 0000-0001-8926-6216
AD  - Department of Biology, Kyung Hee University, Seoul, Republic of Korea.
FAU - Okada, Yukinori
AU  - Okada Y
AD  - Department of Statistical Genetics, Osaka University Graduate School of Medicine, 
      Osaka, Japan.
AD  - Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical 
      Sciences, Yokohama, Japan.
AD  - Laboratory of Statistical Immunology, Immunology Frontier Research Center 
      (WPI-IFReC), Osaka University, Suita, Japan.
FAU - Terao, Chikashi
AU  - Terao C
AUID- ORCID: 0000-0002-6452-4095
AD  - Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, 
      Japan.
AD  - Center for the Promotion of Interdisciplinary Education and Research, Kyoto 
      University, Kyoto, Japan.
AD  - Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, 
      Boston, Massachusetts, United States of America.
AD  - Program in Medical and Population Genetics, Broad Institute, Cambridge, 
      Massachusetts, United States of America.
FAU - Sun, Celi
AU  - Sun C
AD  - Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research 
      Foundation, Oklahoma City, Oklahoma, United States of America.
FAU - Zhou, Xu-Jie
AU  - Zhou XJ
AD  - Renal Division, Peking University First Hospital, Peking University Institute of 
      Nephrology, Key Laboratory of Renal Disease, Ministry of Health of China, 
      Beijing, China.
AD  - Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking 
      University), Ministry of Education, Beijing, China.
FAU - Raj, Prithvi
AU  - Raj P
AD  - Department of Immunology, University of Texas Southwestern Medical Center, 
      Dallas, Texas, United States of America.
FAU - Kochi, Yuta
AU  - Kochi Y
AD  - Laboratory for Autoimmune Diseases, Center for Integrative Medical Sciences, 
      RIKEN, Yokohama, Japan.
FAU - Suzuki, Akari
AU  - Suzuki A
AD  - Laboratory for Autoimmune Diseases, Center for Integrative Medical Sciences, 
      RIKEN, Yokohama, Japan.
FAU - Akizuki, Shuji
AU  - Akizuki S
AD  - Department of Rheumatology and Clinical Immunology, Graduate School of Medicine, 
      Kyoto University, Kyoto, Japan.
FAU - Nakabo, Shuichiro
AU  - Nakabo S
AUID- ORCID: 0000-0002-9250-1851
AD  - Department of Rheumatology and Clinical Immunology, Graduate School of Medicine, 
      Kyoto University, Kyoto, Japan.
FAU - Bang, So-Young
AU  - Bang SY
AD  - Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, 
      Seoul, Korea.
FAU - Lee, Hye-Soon
AU  - Lee HS
AUID- ORCID: 0000-0002-8535-0442
AD  - Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, 
      Seoul, Korea.
FAU - Kang, Young Mo
AU  - Kang YM
AD  - School of Medicine, Kyungpook National University Hospital, Daegu, Korea.
FAU - Suh, Chang-Hee
AU  - Suh CH
AUID- ORCID: 0000-0001-6156-393X
AD  - Department of Rheumatology, Ajou University Hospital, Suwon, Korea.
FAU - Chung, Won Tae
AU  - Chung WT
AUID- ORCID: 0000-0002-1585-1022
AD  - Dong-A University Hospital, Department of Internal Medicine, Busan, Korea.
FAU - Park, Yong-Beom
AU  - Park YB
AD  - Department of Internal Medicine, Yonsei University College of Medicine, Seoul, 
      Korea.
FAU - Choe, Jung-Yoon
AU  - Choe JY
AD  - Department of Rheumatology, Catholic University of Daegu School of Medicine, 
      Daegu, Korea.
FAU - Shim, Seung-Cheol
AU  - Shim SC
AD  - Daejeon Rheumatoid & Degenerative Arthritis Center, Chungnam National University 
      Hospital, Daejeon, Korea.
FAU - Lee, Shin-Seok
AU  - Lee SS
AUID- ORCID: 0000-0001-6810-7355
AD  - Department of Rheumatology, Chonnam National University Medical School and 
      Hospital, Gwangju, Korea.
FAU - Zuo, Xiaoxia
AU  - Zuo X
AD  - Department of Rheumatology and Immunology, Xiangya Hospital, Central South 
      University, Changsha, China.
FAU - Yamamoto, Kazuhiko
AU  - Yamamoto K
AD  - Laboratory for Autoimmune Diseases, Center for Integrative Medical Sciences, 
      RIKEN, Yokohama, Japan.
FAU - Li, Quan-Zhen
AU  - Li QZ
AD  - Department of Immunology and Internal Medicine, University of Texas Southwestern 
      Medical Center, Dallas, Texas, United States of America.
FAU - Shen, Nan
AU  - Shen N
AD  - Department of Rheumatology and Shanghai Institute of Rheumatology, Renji 
      Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
AD  - Institute of Health Sciences, Shanghai Institutes for Biological Sciences, 
      Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine, 
      Shanghai, China.
AD  - Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital 
      Medical Center, Cincinnati, Ohio, United States of America.
AD  - Department of Pediatrics, University of Cincinnati College of Medicine, 
      Cincinnati, Ohio, United States of America.
FAU - Porter, Lauren L
AU  - Porter LL
AUID- ORCID: 0000-0003-2031-8326
AD  - Howard Hughes Medical Institute, Janelia Research Campus, Ashburn, Virginia, 
      United States of America.
FAU - Harley, John B
AU  - Harley JB
AD  - Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital 
      Medical Center, Cincinnati, Ohio, United States of America.
AD  - Department of Pediatrics, University of Cincinnati College of Medicine, 
      Cincinnati, Ohio, United States of America.
AD  - US Department of Veterans Affairs Medical Center, Cincinnati, Ohio, United States 
      of America.
FAU - Chua, Kek Heng
AU  - Chua KH
AD  - Department of Biomedical Science, Faculty of Medicine, University of Malaya, 
      Kuala Lumpur, Malaysia.
FAU - Zhang, Hong
AU  - Zhang H
AD  - Renal Division, Peking University First Hospital, Peking University Institute of 
      Nephrology, Key Laboratory of Renal Disease, Ministry of Health of China, 
      Beijing, China.
AD  - Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking 
      University), Ministry of Education, Beijing, China.
FAU - Wakeland, Edward K
AU  - Wakeland EK
AD  - Department of Immunology, University of Texas Southwestern Medical Center, 
      Dallas, Texas, United States of America.
FAU - Tsao, Betty P
AU  - Tsao BP
AUID- ORCID: 0000-0001-7938-5975
AD  - Division of Rheumatology and Immunology, Department of Medicine, Medical 
      University of South Carolina, Charleston, South Carolina, United States of 
      America.
FAU - Bae, Sang-Cheol
AU  - Bae SC
AUID- ORCID: 0000-0003-4658-1093
AD  - Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, 
      Seoul, Korea.
FAU - Nath, Swapan K
AU  - Nath SK
AUID- ORCID: 0000-0001-6013-9328
AD  - Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research 
      Foundation, Oklahoma City, Oklahoma, United States of America.
LA  - eng
GR  - U01 AI130830/AI/NIAID NIH HHS/United States
GR  - R01 MD007909/MD/NIMHD NIH HHS/United States
GR  - R21 AR073941/AR/NIAMS NIH HHS/United States
GR  - R01 AR060366/AR/NIAMS NIH HHS/United States
GR  - P30 AR070549/AR/NIAMS NIH HHS/United States
GR  - R01 AI024717/AI/NIAID NIH HHS/United States
GR  - U01 HG008666/HG/NHGRI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20190425
PL  - United States
TA  - PLoS Genet
JT  - PLoS genetics
JID - 101239074
RN  - 0 (Autoantibodies)
RN  - 0 (Histocompatibility Antigens Class I)
RN  - 0 (Histocompatibility Antigens Class II)
SB  - IM
MH  - Alleles
MH  - *Amino Acid Sequence
MH  - Amino Acid Substitution
MH  - Asian People
MH  - Autoantibodies/*immunology
MH  - *Disease Susceptibility
MH  - Female
MH  - Genetic Predisposition to Disease
MH  - Genetic Variation
MH  - Histocompatibility Antigens Class I/*chemistry/genetics/*immunology
MH  - Histocompatibility Antigens Class II/*chemistry/genetics/*immunology
MH  - Humans
MH  - Lupus Erythematosus, Systemic/*etiology
MH  - Male
MH  - Odds Ratio
MH  - Polymorphism, Single Nucleotide
PMC - PMC6504188
COIS- The authors have declared that no competing interests exist.
EDAT- 2019/04/26 06:00
MHDA- 2019/10/01 06:00
PMCR- 2019/04/25
CRDT- 2019/04/26 06:00
PHST- 2018/12/26 00:00 [received]
PHST- 2019/03/13 00:00 [accepted]
PHST- 2019/05/07 00:00 [revised]
PHST- 2019/04/26 06:00 [pubmed]
PHST- 2019/10/01 06:00 [medline]
PHST- 2019/04/26 06:00 [entrez]
PHST- 2019/04/25 00:00 [pmc-release]
AID - PGENETICS-D-18-02419 [pii]
AID - 10.1371/journal.pgen.1008092 [doi]
PST - epublish
SO  - PLoS Genet. 2019 Apr 25;15(4):e1008092. doi: 10.1371/journal.pgen.1008092. 
      eCollection 2019 Apr.