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,John B Harley,Xiaoxia Zuo,Shuichiro Nakabo,Shuji Akizuki,Celi Sun,Loren L Looger,Chikashi Terao,Kazuhiko Yamamoto,Edward K Wakeland,Kek Heng Chua,Yukinori Okada,Betty P Tsao,Won Tae Chung,Lauren L Porter,Akari Suzuki,Hong Zhang,Yuta Kochi,Young Mo Kang,Prithvi Raj,Nan Shen,Swapan K Nath,So Young Bang ,Jung Yoon Choe ,Chang Hee Suh ,Xu‐Jie Zhou ,Hye Soon Lee ,Sang Cheol Bae ,Shin Seok Lee ,Kwang-Woo Kim ,Seung Cheol Shim ,Yong Bum Park ,Quan Zhen Li

doi:10.1371/journal.pgen.1008092

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.

Highlights

Systemic lupus erythematosus (SLE, “lupus”, OMIM 608437) is a complex autoimmune disease disproportionately affecting individuals of East Asian and African ancestry, more frequently and with greater severity[1]
In spite of multiple systemic lupus erythematosus (SLE) association signals identified in the Human leukocyte antigen (HLA) region, only amino-acid residues within HLA-DRB1 have been described previously
We identified a characteristic SLE risk residue signature as well as a pattern of specific nRNP and Ro/La autoantibody residues located in the peptide-binding grooves, suggesting their key involvement in autoantibody production

Summary

Introduction

Systemic lupus erythematosus (SLE, “lupus”, OMIM 608437) is a complex autoimmune disease disproportionately affecting individuals of East Asian and African ancestry, more frequently and with greater severity[1]. The MHC region, at 6p21.3, contains >200 genes, including nine classical HLA genes (three Class I: HLA-A, HLA-B, HLA-C; three Class II pairs: HLA-DPA1/DPB1, HLA-DQA1/DQB1, HLA-DRA1/DRB1). The complexity of the MHC region, stemming from large allelic diversity (e.g. total known HLA alleles are >15,000) and high levels of linkage disequilibrium (LD), has made it challenging to identify the causal basis of disease risk. A recent study characterizing SLE risk in the HLA region across European, African, and Hispanic ancestries found notable risk-allele heterogeneity[6] within DQA1/DQB1 and DRB1. In our previous study of SLE in three Asian cohorts[7, 8], we localized strong signals at Class II loci, and confirmed HLA-DRB1 15:01 (primary residues 11-13-26) and HLA-DQB1 06:02[7]. The effects of HLA variants on autoantibody profiles have not been comprehensively investigated

Results

Discussion

Conclusion