Genetic Susceptibility to Multiple Sclerosis: Interactions between Conserved Extended Haplotypes of the MHC and other Susceptibility Regions

Abstract BACKGROUNDTo 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. MEHTODSWTCCC SNP-data 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.RESULTSDifferent 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.CONCLUSIONSGenetic-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.