Mapping multiple sclerosis susceptibility to the HLA-DR locus in African Americans

Abstract

An underlying complex genetic susceptibility exists in multiple sclerosis (MS), and an association with the HLA-DRB1*1501-DQB1*0602 haplotype has been repeatedly demonstrated in high-risk (northern European) populations. It is unknown whether the effect is explained by the HLA-DRB1 or the HLA-DQB1 gene within the susceptibility haplotype, which are in strong linkage disequilibrium (LD). African populations are characterized by greater haplotypic diversity and distinct patterns of LD compared with northern Europeans. To better localize the HLA gene responsible for MS susceptibility, case-control and family-based association studies were performed for DRB1 and DQB1 loci in a large and well-characterized African American data set. A selective association with HLA-DRB1*15 was revealed, indicating a primary role for the DRB1 locus in MS independent of DQB1*0602. This finding is unlikely to be solely explained by admixture, since a substantial proportion of the susceptibility chromosomes from African American patients with MS displayed haplotypes consistent with an African origin.

Figure 1

Molecular structures of MS-prone HLA-DRβ1 alleles. A, HLA-DRβ1*1501 and -DRβ1*1503 allelic structure are superimposed using MINRMS, a program for finding minimal root mean squared distance alignments between two proteins as a function of the number of matching residue pairs within a heuristically limited search space. The resulting structures were displayed as rods through use of Chimera (UCSF Chimera Home Page), an interactive molecular graphics program (Chiang et al. 2003). The structure of DRβ*1503 was developed from the DRβ*1501 crystal structure (Protein Data Bank [PDB] ID 1BX2) by mutating the residue at position 30 from Tyr to His, using the software Swiss PDB-viewer. The distinctive residues at position 30—Tyr for *1501 and His for *1503—are shown in green and magenta, respectively. Polymorphic residue Val β86 (critical for the hydrophobic pocket characteristic of DR2 and DR3 alleles) is shown in green. MBP peptide 85-99 and its electronic cloud are shown in gray. B, HLA-DRβ1*1501 (green) is superimposed on DRβ1*0301 (PDB ID 1A6A; red) in a top view, and their differences are highlighted in dark green and yellow, respectively. Most of the allele-specific residues are in close proximity to the peptide and thus likely affect the MBP binding affinity. Residue DRβ1*0301Val 86 is shown in red. Residue labels are colored according to that of their respective molecule. For clarity, the DRα chain was omitted in these representations.