Fine-Mapping the Genetic Association of the Major Histocompatibility Complex in Multiple Sclerosis: HLA and Non-HLA Effects

The major histocompatibility complex (mhc) region is strongly associated with multiple sclerosis (ms) susceptibility. hla-drb1*15:01 has the strongest effect,and several other alleles have been reported at different levels of validation. using snp data from genome-wide studies,we imputed and tested classical alleles and amino acid polymorphisms in 8 classical human leukocyte antigen (hla) genes in 5,091 cases and 9,595 controls. we identified 11 statistically independent effects overall: 6 hla-drb1 and one dpb1 alleles in class ii,one hla-a and two b alleles in class i,and one signal in a region spanning from micb to lst1. this genomic segment does not contain any hla class i or ii genes and provides robust evidence for the involvement of a non-hla risk allele within the mhc. interestingly,this region contains the tnf gene,the cognate ligand of the well-validated tnfrsf1a ms susceptibility gene. the classical hla effects can be explained to some extent by polymorphic amino acid positions in the peptide-binding grooves. this study dissects the independent effects in the mhc,a critical region for ms susceptibility that harbors multiple risk alleles.