Genetic susceptibility to multiple sclerosis: interactions between conserved extended haplotypes of the MHC and other susceptibility regions

Abstract

Background: To study the accumulation of MS-risk resulting from different combinations of MS-associated conserved-extended-haplotypes (CEHs) of the MHC and three non-MHC “risk-haplotypes” nearby genes EOMES, ZFP36L1, and CLEC16A. Many haplotypes are MS-associated despite having population-frequencies exceeding the percentage of genetically-susceptible individuals. The basis of this frequency-disparity requires explanation. Methods: The SNP-data from the WTCCC was phased at the MHC and three non-MHC susceptibility-regions. CEHs at the MHC were classified into five haplotype-groups: (HLA-DRB1*15:01 ~ DQB1*06:02 ~ a1)-containing (H +); extended-risk (ER); all-protective (AP); neutral (0); and the single-CEH (c1). MS-associations for different “risk-combinations” at the MHC and other non-MHC “risk-loci” and the appropriateness of additive and multiplicative risk-accumulation models were assessed. Results: Different combinations of “risk-haplotypes” produce a final MS-risk closer to additive rather than multiplicative risk-models but neither model was consistent. Thus, (H +)-haplotypes had greater impact when combined with (0)-haplotypes than with (H +)-haplotypes, whereas, (H +)-haplotypes had greater impact when combined with a (c1)-haplotypes than with (0)-haplotypes. Similarly, risk-genotypes (0,H +), (c1,H +), (H + ,H +) and (0,c1) were additive with risks from non-MHC risk-loci, whereas risk-genotypes (ER,H +) and (AP,c1) were unaffected. Conclusions: Genetic-susceptibility to MS is essential for MS to develop but actually developing MS depends heavily upon both an individual’s particular combination of “risk-haplotypes” and how these loci interact.