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

Julio E. Molineros; Loren L. Looger; Kwangwoo Kim; Yukinori Okada; Chikashi Terao; Celi Sun; Xu jie Zhou; Prithvi Raj; Yuta Kochi; Akari Suzuki; Shuji Akizuki; Shuichiro Nakabo; So Young Bang; Hye Soon Lee; Young Mo Kang; Chang Hee Suh; Won Tae Chung; Yong Beom Park; Jung Yoon Choe; Seung Cheol Shim; Shin Seok Lee; Xiaoxia Zuo; Kazuhiko Yamamoto; Quan Zhen Li; Nan Shen; Lauren L. Porter; John B. Harley; Kek Heng Chua; Hong Zhang; Edward K. Wakeland; Betty P. Tsao; Sang Cheol Bae; Swapan K. Nath

doi:10.1371/journal.pgen.1008092

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

Julio E. Molineros, Loren L. Looger, Kwangwoo Kim, Yukinori Okada, Chikashi Terao, Celi Sun, Xu jie Zhou, Prithvi Raj, Yuta Kochi, Akari Suzuki, Shuji Akizuki, Shuichiro Nakabo, So Young Bang, Hye Soon Lee, Young Mo Kang, Chang Hee Suh, Won Tae Chung, Yong Beom Park, Jung Yoon Choe, Seung Cheol ShimShin Seok Lee, Xiaoxia Zuo, Kazuhiko Yamamoto, Quan Zhen Li, Nan Shen, Lauren L. Porter, John B. Harley, Kek Heng Chua, Hong Zhang, Edward K. Wakeland, Betty P. Tsao, Sang Cheol Bae, Swapan K. Nath

Department of Internal Medicine

Research output: Contribution to journal › Article › peer-review

31 Citations (Scopus)

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 HLADRB1*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 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.

Original language	English
Article number	e1008092
Journal	PLoS Genetics
Volume	15
Issue number	4
DOIs	https://doi.org/10.1371/journal.pgen.1008092
Publication status	Published - 2019

Bibliographical note

Funding Information:
This research was supported in part by the grants of the US NIH grants R01 AR060366, R01 MD007909, R01 AI024717, R21 AR073941, U01 AI130830, U01 HG008666, & P50 AR070549; US Department of Veterans Affairs Merit Award, I01 BX003346; Presbyterian Health Foundation Seed Fund; Korean National Research Foundation (NRF) funded by the Ministry of Science & ICT (NRF-2017M3A9B4050335, NRF 2015R1C1A1A02036527) and the Korea Healthcare Technology R&D Project funded by the Ministry for Health & Welfare (HI15C3182) in Republic of Korea. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Publisher Copyright:
© 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.

All Science Journal Classification (ASJC) codes

Ecology, Evolution, Behavior and Systematics
Molecular Biology
Genetics
Genetics(clinical)
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1371/journal.pgen.1008092

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Molineros, J. E., Looger, L. L., Kim, K., Okada, Y., Terao, C., Sun, C., Zhou, X. J., Raj, P., Kochi, Y., Suzuki, A., Akizuki, S., Nakabo, S., Bang, S. Y., Lee, H. S., Kang, Y. M., Suh, C. H., Chung, W. T., Park, Y. B., Choe, J. Y., ... Nath, S. 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), Article e1008092. https://doi.org/10.1371/journal.pgen.1008092

@article{0af11f9b4b0b47d1951ead033865155c,

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

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 HLADRB1*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 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.",

author = "Molineros, {Julio E.} and Looger, {Loren L.} and Kwangwoo Kim and Yukinori Okada and Chikashi Terao and Celi Sun and Zhou, {Xu jie} and Prithvi Raj and Yuta Kochi and Akari Suzuki and Shuji Akizuki and Shuichiro Nakabo 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 Xiaoxia Zuo and Kazuhiko Yamamoto and Li, {Quan Zhen} and Nan Shen and Porter, {Lauren L.} and Harley, {John B.} and Chua, {Kek Heng} and Hong Zhang and Wakeland, {Edward K.} and Tsao, {Betty P.} and Bae, {Sang Cheol} and Nath, {Swapan K.}",

note = "Funding Information: This research was supported in part by the grants of the US NIH grants R01 AR060366, R01 MD007909, R01 AI024717, R21 AR073941, U01 AI130830, U01 HG008666, & P50 AR070549; US Department of Veterans Affairs Merit Award, I01 BX003346; Presbyterian Health Foundation Seed Fund; Korean National Research Foundation (NRF) funded by the Ministry of Science & ICT (NRF-2017M3A9B4050335, NRF 2015R1C1A1A02036527) and the Korea Healthcare Technology R&D Project funded by the Ministry for Health & Welfare (HI15C3182) in Republic of Korea. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Publisher Copyright: {\textcopyright} 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.",

year = "2019",

doi = "10.1371/journal.pgen.1008092",

language = "English",

volume = "15",

journal = "PLoS Genetics",

issn = "1553-7390",

publisher = "Public Library of Science",

number = "4",

}

Molineros, JE, Looger, LL, Kim, K, Okada, Y, Terao, C, Sun, C, Zhou, XJ, Raj, P, Kochi, Y, Suzuki, A, Akizuki, S, Nakabo, S, Bang, SY, Lee, HS, Kang, YM, Suh, CH, Chung, WT, Park, YB, Choe, JY, Shim, SC, Lee, SS, Zuo, X, Yamamoto, K, Li, QZ, Shen, N, Porter, LL, Harley, JB, Chua, KH, Zhang, H, Wakeland, EK, Tsao, BP, Bae, SC & Nath, SK 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, vol. 15, no. 4, e1008092. https://doi.org/10.1371/journal.pgen.1008092

TY - JOUR

T1 - Amino acid signatures of HLA Class-I and II molecules are strongly associated with SLE susceptibility and autoantibody production in Eastern Asians

AU - Molineros, Julio E.

AU - Looger, Loren L.

AU - Kim, Kwangwoo

AU - Okada, Yukinori

AU - Terao, Chikashi

AU - Sun, Celi

AU - Zhou, Xu jie

AU - Raj, Prithvi

AU - Kochi, Yuta

AU - Suzuki, Akari

AU - Akizuki, Shuji

AU - Nakabo, Shuichiro

AU - Bang, So Young

AU - Lee, Hye Soon

AU - Kang, Young Mo

AU - Suh, Chang Hee

AU - Chung, Won Tae

AU - Park, Yong Beom

AU - Choe, Jung Yoon

AU - Shim, Seung Cheol

AU - Lee, Shin Seok

AU - Zuo, Xiaoxia

AU - Yamamoto, Kazuhiko

AU - Li, Quan Zhen

AU - Shen, Nan

AU - Porter, Lauren L.

AU - Harley, John B.

AU - Chua, Kek Heng

AU - Zhang, Hong

AU - Wakeland, Edward K.

AU - Tsao, Betty P.

AU - Bae, Sang Cheol

AU - Nath, Swapan K.

N1 - Funding Information: This research was supported in part by the grants of the US NIH grants R01 AR060366, R01 MD007909, R01 AI024717, R21 AR073941, U01 AI130830, U01 HG008666, & P50 AR070549; US Department of Veterans Affairs Merit Award, I01 BX003346; Presbyterian Health Foundation Seed Fund; Korean National Research Foundation (NRF) funded by the Ministry of Science & ICT (NRF-2017M3A9B4050335, NRF 2015R1C1A1A02036527) and the Korea Healthcare Technology R&D Project funded by the Ministry for Health & Welfare (HI15C3182) in Republic of Korea. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Publisher Copyright: © 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.

PY - 2019

Y1 - 2019

N2 - 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 HLADRB1*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 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.

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 HLADRB1*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 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.

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UR - http://www.scopus.com/inward/citedby.url?scp=85065810063&partnerID=8YFLogxK

U2 - 10.1371/journal.pgen.1008092

DO - 10.1371/journal.pgen.1008092

M3 - Article

C2 - 31022184

AN - SCOPUS:85065810063

SN - 1553-7390

VL - 15

JO - PLoS Genetics

JF - PLoS Genetics

IS - 4

M1 - e1008092

ER -

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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