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HLA-DQ?1 amino acid position 87 and DQB1*0301 are associated with Chinese Han SLE.

ABSTRACT: BACKGROUND:Several susceptibility loci have been identified associated with Chinese Han systemic lupus erythematosus (SLE). METHODS:We carried out imputation of classical HLA alleles, amino acids and Single Nucleotide Polymorphisms (SNPs) across the MHC region in Chinese Han SLE genome-wide association study (GWAS) of mainland and Hong Kong populations for the first time using newly constructed Han-MHC reference panel followed by stepwise conditional analysis. RESULTS:We mapped the most significant independent association to HLA-DQ?1 at amino acid position (Phe87, p = 7.807 × 10-17 ) and an independent association at HLA-DQB1*0301 (Pcondiational = 1.43 × 10-7 ). CONCLUSION:Our study illustrates the value of population-specific HLA reference panel for fine-mapping causal variants in the MHC.

SUBMITTER: Sun J

PROVIDER: S-EPMC6081216 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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HLA-DQβ1 amino acid position 87 and DQB1*0301 are associated with Chinese Han SLE.

Sun Jingying J Yang Chao C Fei Wenmin W Zhang Xuelei X Sheng Yujun Y Zheng Xiaodong X Tang Huayang H Yang Wanling W Yang Sen S Fan Xing X Zhang Xuejun X

Molecular genetics & genomic medicine 20180419

<h4>Background</h4>Several susceptibility loci have been identified associated with Chinese Han systemic lupus erythematosus (SLE).<h4>Methods</h4>We carried out imputation of classical HLA alleles, amino acids and Single Nucleotide Polymorphisms (SNPs) across the MHC region in Chinese Han SLE genome-wide association study (GWAS) of mainland and Hong Kong populations for the first time using newly constructed Han-MHC reference panel followed by stepwise conditional analysis.<h4>Results</h4>We ma ...[more]

PMID: 29676044

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Project description: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.

Project description:Multiple sclerosis (MS), a common central nervous system inflammatory disease, has a major heritable component. Susceptibility is associated with the MHC class II region, especially HLA-DRB5*0101-HLA-DRB1*1501-HLA-DQA1*0102-HLA-DQB1*0602 haplotypes(hereafter DR2), which dominate genetic contribution to MS risk. Marked linkage disequilibrium (LD) among these loci makes identification of a specific locus difficult. The once-leading candidate, HLA-DRB1*15, localizes to risk, neutral, and protective haplotypes. HLA-DRB1*15 and HLA-DQB1*0602, nearly always located together on a small ancestral chromosome segment, are strongly MS-associated. One intervening allele on this haplotype, viz. HLA-DQA1*0102, shows no primary MS association. Two Canadian cohorts (n = 830 and n = 438 trios) genotyped for HLA-DRB1, HLA-DQA1 and HLA-DQB1 alleles were tested for association using TDT. To evaluate epistasis involving HLA-DRB1*15, transmissions from HLA-DRB1*15-negative parents were stratified by the presence/absence of HLA-DRB1*15 in affected offspring. All 3 alleles contribute to MS susceptibility through novel epistatic interactions. HLA-DQA1*0102 increased disease risk when combined with HLA-DRB1*1501 in trans, thereby unambiguously implicating HLA-DQ in MS susceptibility. Three-locus haplotypes demonstrated that HLA-DRB1*1501 and HLA-DQB1*0602 each influence risk. Transmissions of rare morcellated DR2 haplotypes showed no interaction with HLA-DQA1*0102. Incomplete haplotypes bearing only HLA-DRB1*1501 or HLA-DQB1*0602 did not predispose to MS. Balanced reciprocal transmission distortion can mask epistatic allelic association. These findings implicate epistasis among HLA class II alleles in human immune responses generally, provide partial explanation for intense linkage disequilibrium in the MHC, have relevance to animal models, and demonstrate key roles for DR2-specific interactions in MS susceptibility. MHC disease associations may be more generally haplotypic or diplotypic.

Dataset Information

HLA-DQ?1 amino acid position 87 and DQB1*0301 are associated with Chinese Han SLE.

Publications

HLA-DQβ1 amino acid position 87 and DQB1*0301 are associated with Chinese Han SLE.

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