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

Abstract

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-DO-subregion reflected by the well-established risk haplotype HLA-DRB1*15,DQ81*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=8.4 × 10-10). 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=7 × 10-12) 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. © 2007 Brynedal et al.