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

Research output: Contribution to journalArticle

1 Citation (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 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.

Original languageEnglish (US)
Pages (from-to)e1008092
JournalPLoS genetics
Volume15
Issue number4
DOIs
StatePublished - Apr 1 2019

Fingerprint

lupus erythematosus
antibody formation
HLA Antigens
antigen
Systemic Lupus Erythematosus
Autoantibodies
amino acid
Amino Acids
amino acids
autoantibodies
HLA antigens
allele
Alleles
peptide
odds ratio
alleles
Odds Ratio
peptides
Peptides

ASJC Scopus subject areas

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

Cite this

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

In: PLoS genetics, Vol. 15, No. 4, 01.04.2019, p. e1008092.

Research output: Contribution to journalArticle

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, Q, 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, pp. e1008092. https://doi.org/10.1371/journal.pgen.1008092
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. In: PLoS genetics. 2019 ; Vol. 15, No. 4. pp. e1008092.
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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 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.",
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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.

PY - 2019/4/1

Y1 - 2019/4/1

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 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.

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.

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