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

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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 languageEnglish
Article numbere1008092
JournalPLoS Genetics
Volume15
Issue number4
DOIs
Publication statusPublished - 2019 Jan 1

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All Science Journal Classification (ASJC) codes

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

Cite this

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), [e1008092]. https://doi.org/10.1371/journal.pgen.1008092