LAUSR

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.