Chapter 1 - Major histocompatibility complex and SLE

Abstract

Genome-wide genetic association studies in systemic lupus erythematosus (SLE) demonstrate that variants within the major histocompatibility complex (MHC) region on chromosome 6 confer the greatest genetic risk in susceptibility to SLE (odds ratio ~2.0–2.5). The MHC association with SLE has been known for approximately 50 years, but two factors have hitherto bedeviled attempts to determine the precise nature of the causal genes: first, the strong linkage disequilibrium between polymorphisms across the MHC and second, the presence of structural variation. This latter type of polymorphism means that individuals vary in the number of some MHC genes that they carry, examples include complement C4 and class II HLA-DRB. In European populations, the main association signals arise from the class II and class III regions of the MHC, in the vicinity of the genes HLA-DRB1-DQA1-DQB1 and the RCCX module (which harbors the complement C4 gene), respectively. The linkage disequilibrium at the MHC is extensive in Europeans, but is less so in other populations, with the greatest difference being in those of African ancestry. Examining the pattern of MHC associations across ancestries has allowed us to gain major insight into the genetic mechanisms underlying susceptibility to SLE at the MHC. The results of such cross-ancestry comparisons reveal that genetically determined loss of complement C4 and/or an excess of HLA class II expression are the major genetic factors underlying the MHC association with SLE.