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 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, DOI

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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. © 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.

Item Type: Article
Funders: 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), Korea Healthcare Technology R&D Project funded by the Ministry for Health & Welfare (HI15C3182) in Republic of Korea
Uncontrolled Keywords: Arthritis, Rheumatoid; Genes; Shared epitope
Subjects: R Medicine
Divisions: Faculty of Medicine
Depositing User: Ms. Juhaida Abd Rahim
Date Deposited: 10 Mar 2020 00:58
Last Modified: 10 Mar 2020 00:58

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