Session Type: Abstract Submissions (ACR)
Background/Purpose: Genetic association of the major histocompatibility complex (MHC) locus is well-established in systemic lupus erythematosus (SLE), but the causal functional variants in this region remain yet to be identified. This study aimed to examine the contribution of amino acid variants in major HLA genes (HLA-A, -B, -C, -DPA1, -DPB1, -DQA1, -DQB1 and -DRB1) to SLE susceptibility and dissect the association signals within the extended MHC locus.
Methods: We inferred HLA classical alleles, amino acid residues and MHC SNPs from the genotyped data of 5,342 unrelated Korean subjects including 849 SLE cases and 4,493 controls. For accurate imputation for the Korean population, we newly constructed an Asian HLA reference panel from two recent HLA reference panels from Korean (n=413; unpublished) and Southeast Asian (n=441) for use with the SNP2HLA software. The dosage effect of binary markers on SLE risk was assessed by a logistic regression and the overall difference of amino acid residues at each amino acid position between case and control groups was examined by a log-likelihood ratio test comparing the fit between null model and full model with amino acids effects.
Results: The new Asian reference panel demonstrated a reliable imputation accuracy, showing high concordance rates between genotyped and imputed alleles of 61 East Asian HapMap3 individuals (98.5% at 2-digit resolution and 93.2% at 4-digit resolution) and a subset of the study subjects (n=1306; 97.9% at 2-digit resolution and 94.1% at 4-digit resolution at HLA-DRB1). We found the primary association signal within HLA-DRB1. When adjusted with all classical alleles of HLA-DRB1, no signal passed a genome-wide significance threshold in our study. At the amino acid level, the most significant association with SLE susceptibility was mapped to the amino acid position 13 of HLA-DR beta chain 1 (HLA-DRβ1; P = 2.48×10-17). The amino acid position 13 explained the SLE risk better than any single HLA allele or SNP. Among six possible residues at the position 13, Arg/Tyr and Ser/His conferred the risk and protective effects on SLE susceptibility, respectively (OR=1.63, P=1.15×10-15 for Arg+Tyr and OR=0.65, P=4.15×10-14 for Ser+His). We validated the association and residue effects at the position 13 using an independent Korean population including 105 SLE cases and 391 controls who were genotyped for HLA-DRB1. In a conditional analysis, the position 26 was remained to be significantly associated with SLE (P = 2.42×10−9) after conditioning on the amino acid positions 13 and its tightly correlated position 11. We observed 10 common haplotypes defined by the amino acid position 11-13-26. The reported SLE-risk HLA-DRB1 alleles *15:01 and *03:01 belong to the SLE-risk haplotypes Pro-Arg-Phe and Ser- Ser-Tyr, respectively.
Conclusion: Our study identified the three amino acid positions 11, 13 and 26 at the antigen-binding groove of HLA-DRβ1 were responsible for most of the association between SLE and MHC.
S. Y. Bang,
H. S. Lee,
W. Y. Saw,
P. I. de Bakker,
Y. Y. Teo,
S. C. Bae,
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-amino-acid-positions-11-13-and-26-of-hla-dr-beta-chain-1-explain-the-majority-of-the-association-between-systemic-lupus-erythematosus-and-the-major-histocompatibility-complex-locus/