Linkage of the MHC to familial multiple sclerosis suggests genetic heterogeneity. The Multiple Sclerosis Genetics Group

Multiple sclerosis (MS) is a demyelinating autoimmune disease of thecentral nervous system. While its etiology is not well understood, geneticfactors are clearly involved. Until recently, most genetic studies in MShave been association studies using the case-control design testingspecific candidate genes and studying only sporadic cases. The onlyconsistently replicated finding has been an association with the HLA-DR2allele within the major histocompatibility complex (MHC) on chromosome 6.Using the genetic linkage design, however, evidence for and against linkageof the MHC to MS has been found, fostering suggestions that sporadic andfamilial MS have different etiologies. Most recently, two of four genomicscreens demonstrated linkage to the MHC, although specific allelicassociations were not tested. Here, a dataset of 98 multiplex families wasstudied to test for an association to the HLA-DR2 allele in familial MS andto determine if genetic linkage to the MHC was due solely to such anassociation. Three highly polymorphic markers (HLA-DR, D6S273 and TNFbeta)in the MHC demonstrated strong genetic linkage (parametric lod scores of4.60, 2.20 and 1.24, respectively) and a specific association with theHLA-DR2 allele was confirmed (TDT; P < 0.001). Stratifying the resultsby HLA-DR2 status showed that the linkage results were limited to familiessegregating HLA-DR2 alleles. These results demonstrate that genetic linkageto the MHC can be explained by the HLA-DR2 allelic association. They alsoindicate that sporadic and familial MS share a common geneticsusceptibility. In addition, preliminary calculations suggest that the MHCexplains between 17 and 62% of the genetic etiology of MS. Thisheterogeneity is also supported by the minority of families showing nolinkage or association with loci within the MHC.