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

PLoS Genet. 2013 Nov;9(11):e1003926. doi: 10.1371/journal.pgen.1003926. Epub 2013 Nov 21.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Chromosome Mapping
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study*
  • HLA-DP beta-Chains / genetics
  • HLA-DRB1 Chains / genetics*
  • Haplotypes
  • Histocompatibility Antigens Class I / genetics
  • Humans
  • Linkage Disequilibrium
  • Major Histocompatibility Complex / genetics*
  • Membrane Proteins / genetics
  • Multiple Sclerosis / genetics*
  • Multiple Sclerosis / pathology
  • Polymorphism, Single Nucleotide
  • Receptors, Tumor Necrosis Factor, Type I / genetics

Substances

  • HLA-DP beta-Chains
  • HLA-DPB1 antigen
  • HLA-DRB1 Chains
  • Histocompatibility Antigens Class I
  • LST1 protein, human
  • MICB antigen
  • Membrane Proteins
  • Receptors, Tumor Necrosis Factor, Type I
  • TNFRSF1A protein, human