Identification of Additional Independent Loci in the Major Histocompatibility Complex in Multiple Sclerosis Susceptibility

Abstract

Multiple sclerosis (MS) is characterized as an autoimmune neurodegenerative disease. The disease manifests as demyelination or degradation of the myelin sheath in the central nervous system. The Major Histocompatibility Complex (MHC) was associated with MS in the mid-1970’s; the association was later refined to the HLA-DRB1*1501-DQB*0602 haplotype. The MHC region is riddled with complicating factors including high gene content, extreme levels of polymorphism, and a dense pattern of linkage disequilibrium (LD). These characteristics make this region difficult for differentiating whether a single allele or an entire haplotype contributes to disease association. Despite these challenges it is clear that the MHC region harbors MS susceptibility loci in addition to the HLA-DRB1*1501 region. Using the strong LD in this region we can test a model that predicts residual odds ratios (ORs) for a marker in LD with a disease allele such as HLA-DRB1*1501. Comparing the correlation between the observed OR and the calculated OR for multiple SNPs in the MHC region, we hypothesize those SNPs that appear as outliers are suggestive of additional effects independent from the HLA-DRB1*1501 region. We examined ~2,300 SNPs in 1,479 cases and 1,482 controls in the 28 Mb to 36 Mb region on chromosome 6 containing the MHC. The ORs for the SNPs were grouped based on the amount of LD with the HLA-DRB1 surrogate SNP (rs3135388). We identified nine outlying SNPs, which had observed ORs much larger than the calculated OR. These nine SNPs are in six different genes that suggest susceptibility to MS independent of HLA-DRB1*1501.