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.

Multifactor dimensionality reduction reveals gene–gene interactions associated with multiple sclerosis susceptibility in African Americans

“…Human leukocyte antigen was not included in this list of candidates for two reasons. First, the role of HLA in this data set is described in detail in Oksenberg et al 6 Secondly, MDR is sensitive to the inclusion of genes of major effect in the analysis, so inclusion of an SNP with a large main effect could prevent the discovery of novel interactions. Table 2 shows the most significant results of the MDR analysis conducted in our sample.…”

“…These observations, together with the SNP genotyping results mentioned earlier, indicate that the MS patients and controls used in this study were adequately matched. 6 Medical records of all patients were reviewed by one of the authors (SLH or BACC) and in all cases diagnosis was confirmed using McDonald criteria. 32 Ascertainment protocols, and clinical and demographic characteristics are summarized elsewhere.…”

“…This region has shown both linkage and association in multiple genomic screens and candidate gene studies. [3][4][5] The majority of evidence for this effect has been found in high-prevalence white populations of northern European descent, but association has also been shown in African-Americans (AA), 6 who develop MS less frequently. 7 In fact, the unique patterns of linkage disequilibrium (LD) in the AA genome have proven to be a remarkable resource in this disease for the fine mapping of regions of interest, characterization of allelic and clinical heterogeneity, and identification of new susceptibility loci.…”

“…7 In fact, the unique patterns of linkage disequilibrium (LD) in the AA genome have proven to be a remarkable resource in this disease for the fine mapping of regions of interest, characterization of allelic and clinical heterogeneity, and identification of new susceptibility loci. 6,[8][9][10][11] It is estimated that the HLA region accounts for 10-50% of genetic susceptibility in MS. 12 Even at the upper bound of this estimate, much of the complex inheritance of MS remains unexplained. However, the traditional search for main effects by individual genes has been largely unsuccessful, suggesting the need to test for epistatic interactions.…”

Multiple sclerosis genetics: leaving no stone unturned

“…In a recent study of DRB1 and DQB1 alleles and haplotypes in a large and wellcharacterized African-American MS cohort, a selective association with HLA-DRB1*15 was revealed, indicating a primary role for the DRB1 locus in MS independent of DQB1*0602. 43 It is then likely that HLA-DRB1 constitutes the centromeric boundary of the class II DR-DQ association in MS. African-American patients also exhibited an unusual high degree of allelic heterogenity as disease association at the DRB1 locus was found for DRB1*1501, DRB1*1503, and DRB1*0301 alleles. The haplotypic features of the DRB1*1501-DQB1*X (non 0602) and DRB1*1503-positive chromosomes indicated an older African origin for the HLA-associated MS susceptibility gene(s), predating the divergence of human ethnic groups, rather than being solely due to genetic admixture with people of European descent.…”