The HLA-DRβ1 amino acid positions 11–13–26 explain the majority of SLE–MHC associations

Abstract

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 have not yet been discovered. Here we conduct the first fine-mapping study, which thoroughly investigates the SLE-MHC associations down to the amino acid level of major HLA genes in 5,342 unrelated Korean case-control subjects, taking advantages of HLA imputation with a newly constructed Asian HLA reference panel. The most significant association is mapped to amino acid position 13 of HLA-DRb1 (P ¼ 2.48 Â 10 À 17 ) and its proxy position 11 (P ¼ 4.15 Â 10 À 17 ), followed by position 26 in a stepwise conditional analysis (P ¼ 2.42 Â 10 À 9 ).Haplotypes defined by amino acid positions 11-13-26 support the reported effects of most classical HLA-DRB1 alleles in Asian and European populations. In conclusion, our study identifies the three amino acid positions at the epitope-binding groove of HLA-DRb1 that are responsible for most of the association between SLE and MHC.

New insights into the genetic component of non-infectious uveitis through an Immunochip strategy

“…Both proxy positions lie within the peptide binding groove of the HLA-DR molecule and therefore, a functional role can be more reliably ascribed to them. Indeed, these same amino acid positions have been reported to be the most relevant for SLE susceptibility 41. Additionally, a previous fine-mapping of the HLA region in MS identified the position 71 of DRβ1 as the most significant conferring risk 42.…”

The MHC locus and genetic susceptibility to autoimmune and infectious diseases

“…After the development of wide-screen genotyping platforms and imputation pipelines, MHC imputation and fine-mapping were performed in European and Asian populations for most common autoimmune diseases, including RA [19, 25, 33, 34], CeD [35], psoriasis [36], ankylosing spondylitis (AS) [37], systemic lupus erythematosus (SLE) [33, 38–41], T1D [42, 43], multiple sclerosis (MS) [44, 45], Graves’ disease [24], inflammatory bowel disease (IBD) [46], and dermatomyositis (DM) [47]. Table 1 shows the main associated variants and independently associated loci for autoimmune diseases.…”

MergeReference: A Tool for Merging Reference Panels for HLA Imputation

“…In a previous study, Kim et al . [13] also evaluated the gain in performance of merging reference panels for HLA imputation, although they did not provide a software pipeline. Similar to our work, their results supported the utility of merging panels, particularly when the ethnicities are similar.…”

“…Similar to our work, their results supported the utility of merging panels, particularly when the ethnicities are similar. However, merging Asian panels with a European panel did not provide better performance for imputing HLA in Asian samples [13]. Therefore, determining whether merging multiple panels increases the accuracy depends on how similar the ethnicities of the panels are.…”