HLA-A confers an HLA-DRB1 independent influence on the risk of multiple sclerosis

PLoS One. 2007 Jul 25;2(7):e664. doi: 10.1371/journal.pone.0000664.


A recent high-density linkage screen confirmed that the HLA complex contains the strongest genetic factor for the risk of multiple sclerosis (MS). In parallel, a linkage disequilibrium analysis using 650 single nucleotide polymorphisms (SNP) markers of the HLA complex mapped the entire genetic effect to the HLA-DR-DQ subregion, reflected by the well-established risk haplotype HLA-DRB1*15,DQB1*06. Contrary to this, in a cohort of 1,084 MS patients and 1,347 controls, we show that the HLA-A gene confers an HLA-DRB1 independent influence on the risk of MS (P = 8.4x10(-10)). This supports the opposing view, that genes in the HLA class I region indeed exert an additional influence on the risk of MS, and confirms that the class I allele HLA-A*02 is negatively associated with the risk of MS (OR = 0.63, P = 7x10(-12)) not explained by linkage disequilibrium with class II. The combination of HLA-A and HLA-DRB1 alleles, as represented by HLA-A*02 and HLA-DRB1*15, was found to influence the risk of MS 23-fold. These findings imply complex autoimmune mechanisms involving both the regulatory and the effector arms of the immune system in the triggering of MS.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • DNA Primers / genetics
  • Gene Frequency
  • Genetic Linkage
  • Genetic Predisposition to Disease
  • HLA-A Antigens / genetics
  • HLA-A Antigens / immunology*
  • HLA-DQ Antigens / genetics
  • HLA-DR Antigens / genetics
  • HLA-DR Antigens / immunology*
  • HLA-DRB1 Chains
  • Humans
  • Linkage Disequilibrium
  • Middle Aged
  • Multiple Sclerosis / epidemiology
  • Multiple Sclerosis / genetics*
  • Multiple Sclerosis / immunology*
  • Polymorphism, Single Nucleotide
  • Reference Values
  • Regression Analysis
  • Risk Factors
  • Sweden


  • DNA Primers
  • HLA-A Antigens
  • HLA-DQ Antigens
  • HLA-DR Antigens
  • HLA-DRB1 Chains