ArticlePLoS genetics2019
Amino acid signatures of HLA Class-I and II molecules are strongly associated with SLE susceptibility and autoantibody production in Eastern Asians.
Article in PLoS genetics, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.
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Who cites it
34 citing papers in PubMed, 61 citations in OpenAlex.
- Genome-wide pharmacogenetics of anti-drug antibody response to bococizumab highlights key residues in HLA DRB1 and DQB1.Scientific reports · 2022Trial
- Identifying condition-related cell-cell communication events using supervised tensor analysis.American journal of human genetics · 2026Article
- Predominant HLA class I associations with lupus nephritis susceptibility, histology class and reduced renal function in patients with systemic lupus erythematosus: a retrospective case-control study.Rheumatology international · 2026Article
- [Role of HLA genetic variants in autoimmune diseases].Zhong nan da xue xue bao. Yi xue ban = Journal of Central South University. Medical sciences · 2026Review
- Association of HLA-DRB1 pocket structures with susceptibility and prognosis of Graves' and Hashimoto's disease.Endocrine journal · 2026Article
- Immunopathogenesis and Therapeutics of Systemic Lupus Erythematosus: an Integrative Review.Clinical reviews in allergy & immunology · 2025Review
- Orchestration of Skin Pathology in Cutaneous Lupus Erythematosus by HLA Class I Down-Regulated Senescent Epidermal Basal Cells.Arthritis & rheumatology (Hoboken, N.J.) · 2025Article
- Immunopathogenesis of Systemic Lupus Erythematosus: Interplay of Innate and Adaptive Immunity, Microbiome Dysbiosis, and Emerging Therapeutic Targets.Pathophysiology : the official journal of the International Society for Pathophysiology · 2025Review
- Article
- Single-cell RNA sequencing reveals the heterogeneity and regulatory modules of cell-specific RNA-binding proteins in patients with systemic lupus erythematosus.Biochemistry and biophysics reports · 2025Article
- Systemic lupus erythematosus: updated insights on the pathogenesis, diagnosis, prevention and therapeutics.Signal transduction and targeted therapy · 2025Review
- HLA DRB1* Allele Lupus Erythematosus, Rheumatoid Arthritis, and other Autoimmune Disorders with Skin Involvement.Mediterranean journal of rheumatology · 2025Review
- An overview on Sjögren's syndrome and systemic lupus erythematosus' genetics.Toxicology research · 2025Review
- Article
- Potential contribution of gut microbiota in the development of autoantibodies in T1D children carrying HLA-DRB1/DQB1 risk alleles: an experimental and in silico analysis.Immunogenetics · 2024Article
- Systemic lupus erythematosus genetics: insights into pathogenesis and implications for therapy.Nature reviews. Rheumatology · 2024Review
- Early human migration determines the risk of being attacked by wolves: ethnic gene diversity on the development of systemic lupus erythematosus.Journal of rheumatic diseases · 2024Review
- A Summary on the Genetics of Systemic Lupus Erythematosus, Rheumatoid Arthritis, Systemic Sclerosis, and Sjögren's Syndrome.Clinical reviews in allergy & immunology · 2023Review
- Disentangling the Pathogenesis of Systemic Lupus Erythematosus: Close Ties between Immunological, Genetic and Environmental Factors.Medicina (Kaunas, Lithuania) · 2023Review
- Immunogenetic Profiling of SLE and LN among Jordanian Patients.Journal of personalized medicine · 2022Article
Corrections and comments
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Authors and funding
33 authors at 20 institutions in 5 countries.
Funding
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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