Amino acid signatures of HLA Class-I and II molecules are strongly associated with SLE susceptibility and autoantibody production in Eastern Asians
DC Field | Value | Language |
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dc.contributor.author | Molineros, Julio E. | - |
dc.contributor.author | Looger, Loren L. | - |
dc.contributor.author | Kim, Kwangwoo | - |
dc.contributor.author | Okada, Yukinori | - |
dc.contributor.author | Terao, Chikashi | - |
dc.contributor.author | Sun, Celi | - |
dc.contributor.author | Zhou, Xu-jie | - |
dc.contributor.author | Raj, Prithvi | - |
dc.contributor.author | Kochi, Yuta | - |
dc.contributor.author | Suzuki, Akari | - |
dc.contributor.author | Akizuki, Shuji | - |
dc.contributor.author | Nakabo, Shuichiro | - |
dc.contributor.author | Bang, So-Young | - |
dc.contributor.author | Lee, Hye-Soon | - |
dc.contributor.author | Kang, Young Mo | - |
dc.contributor.author | Suh, Chang-Hee | - |
dc.contributor.author | Chung, Won Tae | - |
dc.contributor.author | Park, Yong-Beom | - |
dc.contributor.author | Choe, Jung-Yoon | - |
dc.contributor.author | Shim, Seung-Cheol | - |
dc.contributor.author | Lee, Shin-Seok | - |
dc.contributor.author | Zuo, Xiaoxia | - |
dc.contributor.author | Yamamoto, Kazuhiko | - |
dc.contributor.author | Li, Quan-Zhen | - |
dc.contributor.author | Shen, Nan | - |
dc.contributor.author | Porter, Lauren L. | - |
dc.contributor.author | Harley, John B. | - |
dc.contributor.author | Chua, Kek Heng | - |
dc.contributor.author | Zhang, Hong | - |
dc.contributor.author | Wakeland, Edward K. | - |
dc.contributor.author | Tsao, Betty P. | - |
dc.contributor.author | Bae, Sang-Cheol | - |
dc.contributor.author | Nath, Swapan K. | - |
dc.date.accessioned | 2021-08-02T11:54:01Z | - |
dc.date.available | 2021-08-02T11:54:01Z | - |
dc.date.created | 2021-05-11 | - |
dc.date.issued | 2019-04 | - |
dc.identifier.issn | 1553-7390 | - |
dc.identifier.uri | https://scholarworks.bwise.kr/hanyang/handle/2021.sw.hanyang/14290 | - |
dc.description.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. Author summary The Human leukocyte antigen (HLA) region is a key genetic factor conferring risk of systemic lupus erythematosus (SLE). In spite of multiple SLE association signals identified in the HLA region, only amino-acid residues within HLA-DRB1 have been specifically described previously. In this study, we performed an imputation-based analysis on individuals with East Asian ancestry, and characterized SLE risk within the HLA region for all involved independent genes (HLA-DRB1, HLA-DPB1, HLA-DQB1, HLA-A, and HLA-B). Furthermore, we identified a characteristic SLE risk residue signature as well as a pattern of specific nRNP and Ro/La autoantibody residues located in the peptide-binding grooves, suggesting their key involvement in autoantibody production. | - |
dc.language | 영어 | - |
dc.language.iso | en | - |
dc.publisher | PUBLIC LIBRARY SCIENCE | - |
dc.title | Amino acid signatures of HLA Class-I and II molecules are strongly associated with SLE susceptibility and autoantibody production in Eastern Asians | - |
dc.type | Article | - |
dc.contributor.affiliatedAuthor | Bang, So-Young | - |
dc.contributor.affiliatedAuthor | Lee, Hye-Soon | - |
dc.contributor.affiliatedAuthor | Bae, Sang-Cheol | - |
dc.identifier.doi | 10.1371/journal.pgen.1008092 | - |
dc.identifier.scopusid | 2-s2.0-85065810063 | - |
dc.identifier.wosid | 000466866000033 | - |
dc.identifier.bibliographicCitation | PLOS GENETICS, v.15, no.4 | - |
dc.relation.isPartOf | PLOS GENETICS | - |
dc.citation.title | PLOS GENETICS | - |
dc.citation.volume | 15 | - |
dc.citation.number | 4 | - |
dc.type.rims | ART | - |
dc.type.docType | Article | - |
dc.description.journalClass | 1 | - |
dc.description.isOpenAccess | Y | - |
dc.description.journalRegisteredClass | scie | - |
dc.description.journalRegisteredClass | scopus | - |
dc.relation.journalResearchArea | Genetics & Heredity | - |
dc.relation.journalWebOfScienceCategory | Genetics & Heredity | - |
dc.subject.keywordPlus | SYSTEMIC-LUPUS-ERYTHEMATOSUS | - |
dc.subject.keywordPlus | GENOME-WIDE ASSOCIATION | - |
dc.subject.keywordPlus | PEPTIDE-BINDING POCKET | - |
dc.subject.keywordPlus | RHEUMATOID-ARTHRITIS | - |
dc.subject.keywordPlus | GENETIC ASSOCIATION | - |
dc.subject.keywordPlus | REVISED CRITERIA | - |
dc.subject.keywordPlus | SELF-PEPTIDES | - |
dc.subject.keywordPlus | DPB1 ALLELES | - |
dc.subject.keywordPlus | MHC REGION | - |
dc.subject.keywordPlus | LOCI | - |
dc.identifier.url | https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1008092 | - |
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