LINKAGE OF THE MHC TO FAMILIAL MULTIPLE-SCLEROSIS SUGGESTS GENETIC-HETEROGENEITY

Multiple sclerosis (MS) is a demyelinating autoimmune disease of the c entral nervous system, While its etiology is not well understood, gene tic factors are clearly involved, Until recently, most genetic studies in MS have been association studies using the case-control design tes ting specific candidate genes and studying only sporadic cases, The on ly consistently replicated finding has been an association with the HL A-DR2 allele within the major histocompatibility complex (MHC) on chro mosome 6, Using the genetic linkage design, however, evidence for and against linkage of the MHC to MS has been found, fostering suggestions that sporadic and familial MS have different etiologies, Most recentl y, two of four genomic screens demonstrated linkage to the MHC, althou gh specific allelic associations were not tested. Here, a dataset of 9 8 multiplex families was studied to test for an association to the HLA -DR2 allele in familial MS and to determine if genetic linkage to the MHC was due solely to such an association, Three highly polymorphic ma rkers (HLA-DR, D6S273 and TNF beta) in the MHC demonstrated strong gen etic linkage (parametric lod scores of 4.60, 2.20 and 1.24, respective ly) and a specific association with the HLA-DR2 allele was confirmed ( TDT; P < 0.001), Stratifying the results by HLA-DR2 status showed that the linkage results were limited to families segregating HLA-DR2 alle les, These results demonstrate that genetic linkage to the MHC can be explained by the HLA-DR2 allelic association. They also indicate that sporadic and familial MS share a common genetic susceptibility. In add ition, preliminary calculations suggest that the MHC explains between 17 and 62% of the genetic etiology of MS, This heterogeneity is also s upported by the minority of families showing no linkage or association with loci within the MHC.