Abstract
Models of disease susceptibility in multiple sclerosis (MS) often assume a dominant action for the
HLA-DRB1*1501 allele and its associated haplotype (
DRB1*1501-
DQB1*0602 or
DR2). A robust and phenotypically well-characterized MS data set was used to explore this model in more detail. A dose effect of
HLA-DR2 haplotypes on MS susceptibility was revealed. This observation suggests that, in addition to the role of
HLA-DR2 in MS, two copies of a susceptibility haplotype further increase disease risk. Second, we report that
DR2 haplotypes modify disease expression. There is a paucity of benign MS and an increase of severe MS in individuals homozygous for
DR2. Concepts of the molecular mechanisms that underlie linkage and association of the human leukocyte antigen (HLA) region to MS need to be revised to accommodate these data.
