Refining the association of MHC with multiple sclerosis in African Americans

Abstract

Multiple sclerosis (MS) is a common demyelinating disease of the central nervous system mediated by autoimmune and neurodegenerative pathogenic mechanisms. Multiple genes account for its moderate heritability, but the only genetic region shown to have a large replicable effect on MS susceptibility is the major histocompatibility complex (MHC). Strong linkage disequilibrium (LD) across the MHC has made it difficult to fully characterize individual genetic contributions of this region to MS risk in previous studies. African Americans are at a lower risk for MS when compared with northern Europeans and Americans of European descent, but greater haplotypic diversity and distinct patterns of LD suggest that this population may be particularly informative for fine-mapping efforts. To examine the role of the MHC in African American MS, a case-control association study was performed with 499 African American MS patients and 750 African American controls that were genotyped for 6040 MHC region single nucleotide polymorphisms (SNPs). A replication data set consisting of 451 African American patients and 718 African American controls was genotyped for selected SNPs. Two MHC class II SNPs, rs2647040 and rs3135021, were significant in the replication cohort and partially tagged DRB1*15 alleles. Surprisingly, in comparison to similar studies of individuals of European descent, the MHC seems to play a smaller role in MS susceptibility in African Americans, consistent with pervasive genetic heterogeneity across ancestral groups, and may explain the difference in MS susceptibility between African Americans and individuals of European descent.

Figure 1.

Linkage disequilibrium decay. LD (D′) was calculated pair-wise between SNPs within 300 kb of each other using 2822 common polymorphic SNPs for 42 individuals from each population. HapMap populations: ASW, African American; CEU, European; YRI, Yoruban; AAMS, African American individuals in the current study.

Figure 2.

MHC-wide MS association analysis results in the discovery cohort. The first principal component, which was derived from principal component analysis of 4248 non-chromosome 6 SNPs and is highly correlated with percent European ancestry, was included as a covariate in the logistic regression models. Red and blue dots indicate the –log₁₀ (P-value) for the genotypic and trend models, respectively. (A) No SNPs in the model. (B) Most significant SNP from first model in the model.