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The HLA-DRβ1 amino acid positions 11–13–26 explain the majority of SLE–MHC associations
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The HLA-DRβ1 amino acid positions 11–13–26 explain the majority of SLE–MHC associations
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Journal Article
The HLA-DRβ1 amino acid positions 11–13–26 explain the majority of SLE–MHC associations
2014
Overview
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-DRβ1 (
P=
2.48 × 10
−17
) and its proxy position 11 (
P=
4.15 × 10
−17
), followed by position 26 in a stepwise conditional analysis (
P=
2.42 × 10
−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-DRβ1 that are responsible for most of the association between SLE and MHC.
Systemic lupus erythematosus (SLE) is an autoimmune disease with a complex genetic basis. Here the authors carry out a fine-mapping analysis of the major histocompatibility complex region and identify amino acids that have a causal role in SLE aetiology.
Publisher
Nature Publishing Group UK
Subject
/ Alleles
/ Asian Continental Ancestry Group - genetics
/ Female
/ Genetic Predisposition to Disease
/ Genome-Wide Association Study
/ HLA-DRB1 Chains - metabolism
/ Humanities and Social Sciences
/ Humans
/ Lupus Erythematosus, Systemic - genetics
/ Lupus Erythematosus, Systemic - metabolism
/ Male
/ Science
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