A second MHC susceptibility locus for multiple sclerosis. S.J. Sawcer for the International Multiple Sclerosis Genetics Consortium (IMSGC). Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom.
   Variation in the Major Histocompatibility Complex (MHC) on chromosome 6p21 influences susceptibility to multiple sclerosis, with the DR15 haplotype (HLA-A3-B7-Cw7-DR15) being the most consistently identified risk factor. The high gene content, extreme polymorphism and extensive linkage disequilibrium (LD) that characterise the MHC have confounded efforts to resolve the nature of this association. The strongest effect originates in the class II region, with the DRB1 gene identified as the primary susceptibility locus. The possibility that other genes in the MHC independently influence susceptibility to multiple sclerosis has been suggested but remains unconfirmed. Here we show that the class I Human Leukocyte Antigen (HLA) gene, HLA-C, exerts an independent effect on susceptibility to multiple sclerosis. After excluding effects attributable to the DR15 haplotype we found residual evidence for association, maximal in the region of HLA-C, in independent simple nuclear family cohorts from the US (n=450) and UK (n=480). By extending analysis of the classical loci into 721 additional sporadic cases, and utilizing data from 3660 controls, we refined this secondary signal and show that it is partly due to allelic heterogeneity at the HLA-DRB1 locus, and partly due to an independent effect from the HLA-C locus (p=5.9x10^-5). Our results enhance understanding of the established DRB1 association in multiple sclerosis and identify a novel second susceptibility locus for this disease. The identification of HLA-C as a risk factor in multiple sclerosis implicates innate immune mechanism in particular the killer cell immunoglobulin-like receptors (KIRs). These results open up new opportunities for future research activities.