Uncoupling the Roles of HLA-DRB1 and HLA-DRB5 Genes in Multiple Sclerosis

Abstract

Genetic susceptibility to multiple sclerosis (MS) is associated with the MHC located on chromosome 6p21. This signal maps primarily to a 1-Mb region encompassing the HLA class II loci, and it segregates often with the HLA-DQB1*0602, -DQA1*0102, -DRB1*1501, -DRB5*0101 haplotype. However, the identification of the true predisposing gene or genes within the susceptibility haplotype has been handicapped by the strong linkage disequilibrium across the locus. African Americans have greater MHC haplotypic diversity and distinct patterns of linkage disequilibrium, which make this population particularly informative for fine mapping efforts. The purpose of this study was to establish the telomeric boundary of the HLA class II region affecting susceptibility to MS by assessing genetic association with the neighboring HLA-DRB5 gene as well as seven telomeric single nucleotide polymorphisms in a large, well-characterized African American dataset. Rare DRB5*null individuals were previously described in African populations. Although significant associations with both HLA-DRB1 and HLA-DRB5 loci were present, HLA-DRB1*1503 was associated with MS in the absence of HLA-DRB5, providing evidence for HLA-DRB1 as the primary susceptibility gene. Interestingly, the HLA-DRB5*null subjects appear to be at increased risk for developing secondary progressive MS. Thus, HLA-DRB5 attenuates MS severity, a finding consistent with HLA-DRB5’s proposed role as a modifier in experimental autoimmune encephalomyelitis. Additionally, conditional haplotype analysis revealed a susceptibility signal at the class III AGER locus independent of DRB1. The data underscore the power of the African American MS dataset to identify disease genes by association in a region of high linkage disequilibrium.

Molecular mechanisms for contribution of MHC molecules to autoimmune diseases

“…The most significant variant in the MHC was the HLA-DRB1 * 15:01 allele, consistent with many prior studies [22,23]. Statistically independent effects for five other HLA-DRB1 alleles (*03:01, *13:03, *04:04, *04:01, *14:01) were also identified.…”

Multiple sclerosis susceptibility alleles in African Americans

“…The average age of onset of MS was 32.4 years and the mean age at time of analysis was 44 years for cases and 43 years for controls ( t test, P = 0.081). The majority of the cases (85%) had either relapsing remitting or secondary progressive MS. We genotyped all individuals for the presence of DRB1*1501 or *1503 , since these alleles are associated with MS in African Americans 16, 17…”

“…In African Americans, previous studies have demonstrated the association of MHC class II HLA-DRB1*15 alleles with disease susceptibility and progression 16, 17. In addition, the presence of HLA-DRB1*15 alleles in African American patients correlates with the disseminated MS phenotype compared to opticospinal MS 18.…”

The Receptor for Advanced Glycation Endproducts (RAGE) and Mediation of Inflammatory Neurodegeneration

“…In human subjects, the AGER rs2070600 SNP was associated with MS in several studies [72,106]. However, in a different study of a Hungarian community, this SNP was not identified.…”