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

Abstract

Multiple sclerosis (MS) is a demyelinating autoimmune disease of the central nervous system. While its etiology is not well understood, genetic factors are clearly involved. Until recently, most genetic studies in MS have been association studies using the case-control design testing specific candidate genes and studying only sporadic cases. The only consistently replicated finding has been an association with the HLA-DR2 allele within the major histocompatibility complex (MHC) on chromosome 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 recently, two of four genomic screens demonstrated linkage to the MHC, although specific allelic associations were not tested. Here, a dataset of 98 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 markers (HLA-DR, D6S273 and TNFbeta) in the MHC demonstrated strong genetic linkage (parametric lod scores of 4.60, 2.20 and 1.24, respectively) 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 alleles. 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 addition, preliminary calculations suggest that the MHC explains between 17 and 62% of the genetic etiology of MS. This heterogeneity is also supported by the minority of families showing no linkage or association with loci within the MHC.

Novel Quantitative Trait Loci Controlling Development of Experimental Autoimmune Encephalomyelitis and Proportion of Lymphocyte Subpopulations

“…Single cell suspensions were prepared, and RBCs were depleted using 0.84% NH 4 Cl. The number of splenocytes were counted in a cell counter (Sysmex CDA 500; Toa Medical Electronics, Kobe, Japan), and cells were cultured in DMEM supplemented with 10% FCS, antibiotics, HEPES, and 2-ME (cell culture medium).…”

HLA class I alleles tag HLA-DRB1 * 1501 haplotypes for differential risk in multiple sclerosis susceptibility

“…It is widely believed that MS is a CD4 ϩ Th1-mediated autoimmune disease (1,2). This is supported by many studies based on experimental autoimmune encephalomyelitis (EAE) models (3,4), and by genetic studies showing HLA class II genes represent the strongest risk for MS (5)(6)(7)(8)(9). It is often assumed that the MS DRassociation is secondary to a role in antigen-presentation to CD4 ϩ T cells responding to a myelin protein (2).…”

Multiple sclerosis genetics: leaving no stone unturned

“…57 In either case, much of the genetic effect in MS remains to be explained, but there is no consensus on which are the best-supported non-MHC regions in the genome. Unfortunately, the direct testing by association of possibly relevant candidate genes, identified by speculation based upon concepts of pathogenesis, has been also unproductive for gene identification in this disease.…”