Fine-mapping SLE-MHC associations revealed independent contributions of HLA missense variants and C4 copy number variations

Systemic lupus erythematosus (SLE) is a complex autoimmune disease with strong genetic associations within the major histocompatibility complex (MHC) region. Despite significant advances, precisely pinpointing the genetic variants that contribute to SLE risk within the MHC remains challenging. This study aimed to comprehensively profile SLE-driving variants using a newly developed East Asian MHC imputation reference panel, capable of simultaneously imputing diverse MHC variants, including multi-level variants of HLA genes and copy number variations (CNVs) of C4 elements, with high imputation accuracy. Applying this panel to two SLE genome-wide association study datasets, we uncovered the independent contributions from six amino acid positions altering the epitope-binding surfaces of HLA-DRB1 and HLA-C. Additionally, reduced C4A copy numbers and increased HERV copy numbers, collectively lowering C4 protein levels, were associated with increased SLE risk, independent of HLA variants. Our refined MHC-SLE association model provided superior explanations for SLE risk over previous association models. In summary, this study enhanced the understanding of HLA and C4 in SLE pathogenesis and holds promise for advancing MHC association studies for immune-mediated inflammatory disorders in East Asians using our MHC panel (https://coda.nih.go.kr/usab/kis/intro.do).