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

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

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 r...

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Main Authors:	Absher, Devin M, Molineros, Julio E., Looger, Loren L., Kim, Kwangwoo, Okada, Yukinori, Terao, Chikashi, Sun, Celi, Zhou, Xu-jie, Raj, Prithvi, Kochi, Yuta, Suzuki, Akari, Akizuki, Shuji, Nakabo, Shuichiro, Bang, So Young, Lee, Hye Soon, Kang, Young Mo, Suh, Chang Hee, Chung, Won Tae, Park, Yong Beom, Choe, Jung Yoon, Shim, Seung Cheol, Lee, Shin Seok, Zuo, Xiaoxia, Yamamoto, Kazuhiko, Li, Quan Zhen, Shen, Nan, Porter, Lauren L., Harley, John B., Chua, Kek Heng, Zhang, Hong, Wakeland, Edward K., Tsao, Betty P., Bae, Sang Cheol, Nath, Swapan K.
Format:	Article
Published:	Public Library of Science 2019
Subjects:	R Medicine
Online Access:	http://eprints.um.edu.my/23970/ https://doi.org/10.1371/journal.pgen.1008092
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id	my.um.eprints.23970
record_format	eprints
institution	Universiti Malaya
building	UM Library
collection	Institutional Repository
continent	Asia
country	Malaysia
content_provider	Universiti Malaya
content_source	UM Research Repository
url_provider	http://eprints.um.edu.my/
topic	R Medicine
spellingShingle	R Medicine Absher, Devin M Molineros, Julio E. Looger, Loren L. Kim, Kwangwoo Okada, Yukinori Terao, Chikashi Sun, Celi Zhou, Xu-jie Raj, Prithvi Kochi, Yuta Suzuki, Akari Akizuki, Shuji Nakabo, Shuichiro Bang, So Young Lee, Hye Soon Kang, Young Mo Suh, Chang Hee Chung, Won Tae Park, Yong Beom Choe, Jung Yoon Shim, Seung Cheol Lee, Shin Seok Zuo, Xiaoxia Yamamoto, Kazuhiko Li, Quan Zhen Shen, Nan Porter, Lauren L. Harley, John B. Chua, Kek Heng Zhang, Hong Wakeland, Edward K. Tsao, Betty P. Bae, Sang Cheol Nath, Swapan K. Amino acid signatures of HLA Class-I and II molecules are strongly associated with SLE susceptibility and autoantibody production in Eastern Asians
description	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 HLADRB115:01 (P = 1.4x10-27, odds ratio (OR) = 1.57) and HLA-DQB106:02 (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 HLADQB1. 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. © 2019 Molineros et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
format	Article
author	Absher, Devin M Molineros, Julio E. Looger, Loren L. Kim, Kwangwoo Okada, Yukinori Terao, Chikashi Sun, Celi Zhou, Xu-jie Raj, Prithvi Kochi, Yuta Suzuki, Akari Akizuki, Shuji Nakabo, Shuichiro Bang, So Young Lee, Hye Soon Kang, Young Mo Suh, Chang Hee Chung, Won Tae Park, Yong Beom Choe, Jung Yoon Shim, Seung Cheol Lee, Shin Seok Zuo, Xiaoxia Yamamoto, Kazuhiko Li, Quan Zhen Shen, Nan Porter, Lauren L. Harley, John B. Chua, Kek Heng Zhang, Hong Wakeland, Edward K. Tsao, Betty P. Bae, Sang Cheol Nath, Swapan K.
author_facet	Absher, Devin M Molineros, Julio E. Looger, Loren L. Kim, Kwangwoo Okada, Yukinori Terao, Chikashi Sun, Celi Zhou, Xu-jie Raj, Prithvi Kochi, Yuta Suzuki, Akari Akizuki, Shuji Nakabo, Shuichiro Bang, So Young Lee, Hye Soon Kang, Young Mo Suh, Chang Hee Chung, Won Tae Park, Yong Beom Choe, Jung Yoon Shim, Seung Cheol Lee, Shin Seok Zuo, Xiaoxia Yamamoto, Kazuhiko Li, Quan Zhen Shen, Nan Porter, Lauren L. Harley, John B. Chua, Kek Heng Zhang, Hong Wakeland, Edward K. Tsao, Betty P. Bae, Sang Cheol Nath, Swapan K.
author_sort	Absher, Devin M
title	Amino acid signatures of HLA Class-I and II molecules are strongly associated with SLE susceptibility and autoantibody production in Eastern Asians
title_short	Amino acid signatures of HLA Class-I and II molecules are strongly associated with SLE susceptibility and autoantibody production in Eastern Asians
title_full	Amino acid signatures of HLA Class-I and II molecules are strongly associated with SLE susceptibility and autoantibody production in Eastern Asians
title_fullStr	Amino acid signatures of HLA Class-I and II molecules are strongly associated with SLE susceptibility and autoantibody production in Eastern Asians
title_full_unstemmed	Amino acid signatures of HLA Class-I and II molecules are strongly associated with SLE susceptibility and autoantibody production in Eastern Asians
title_sort	amino acid signatures of hla class-i and ii molecules are strongly associated with sle susceptibility and autoantibody production in eastern asians
publisher	Public Library of Science
publishDate	2019
url	http://eprints.um.edu.my/23970/ https://doi.org/10.1371/journal.pgen.1008092
_version_	1662755204872798208
spelling	my.um.eprints.239702020-03-10T00:58:04Z http://eprints.um.edu.my/23970/ Amino acid signatures of HLA Class-I and II molecules are strongly associated with SLE susceptibility and autoantibody production in Eastern Asians Absher, Devin M Molineros, Julio E. Looger, Loren L. Kim, Kwangwoo Okada, Yukinori Terao, Chikashi Sun, Celi Zhou, Xu-jie Raj, Prithvi Kochi, Yuta Suzuki, Akari Akizuki, Shuji Nakabo, Shuichiro Bang, So Young Lee, Hye Soon Kang, Young Mo Suh, Chang Hee Chung, Won Tae Park, Yong Beom Choe, Jung Yoon Shim, Seung Cheol Lee, Shin Seok Zuo, Xiaoxia Yamamoto, Kazuhiko Li, Quan Zhen Shen, Nan Porter, Lauren L. Harley, John B. Chua, Kek Heng Zhang, Hong Wakeland, Edward K. Tsao, Betty P. Bae, Sang Cheol Nath, Swapan K. R Medicine 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 HLADRB115:01 (P = 1.4x10-27, odds ratio (OR) = 1.57) and HLA-DQB106:02 (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 HLADQB1. 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. © 2019 Molineros et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Public Library of Science 2019 Article PeerReviewed Absher, Devin M and Molineros, Julio E. and Looger, Loren L. and Kim, Kwangwoo and Okada, Yukinori and Terao, Chikashi and Sun, Celi and Zhou, Xu-jie and Raj, Prithvi and Kochi, Yuta and Suzuki, Akari and Akizuki, Shuji and Nakabo, Shuichiro and Bang, So Young and Lee, Hye Soon and Kang, Young Mo and Suh, Chang Hee and Chung, Won Tae and Park, Yong Beom and Choe, Jung Yoon and Shim, Seung Cheol and Lee, Shin Seok and Zuo, Xiaoxia and Yamamoto, Kazuhiko and Li, Quan Zhen and Shen, Nan and Porter, Lauren L. and Harley, John B. and Chua, Kek Heng and Zhang, Hong and Wakeland, Edward K. and Tsao, Betty P. and Bae, Sang Cheol and Nath, Swapan K. (2019) Amino acid signatures of HLA Class-I and II molecules are strongly associated with SLE susceptibility and autoantibody production in Eastern Asians. PLoS Genetics, 15 (4). e1008092. ISSN 1553-7390 https://doi.org/10.1371/journal.pgen.1008092 doi:10.1371/journal.pgen.1008092
score	13.211869

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

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