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

Publication ,  Journal Article
Haines, JL; Terwedow, HA; Burgess, K; Pericak-Vance, MA; Rimmler, JB; Martin, ER; Oksenberg, JR; Lincoln, R; Zhang, DY; Banatao, DR; Gatto, N ...
Published in: Hum Mol Genet
August 1998

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.

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Published In

Hum Mol Genet

DOI

ISSN

0964-6906

Publication Date

August 1998

Volume

7

Issue

8

Start / End Page

1229 / 1234

Location

England

Related Subject Headings

  • Multiple Sclerosis
  • Male
  • Major Histocompatibility Complex
  • Humans
  • Genetics & Heredity
  • Genetic Variation
  • Genetic Linkage
  • Female
  • Alleles
  • 3105 Genetics
 

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Haines, J. L., Terwedow, H. A., Burgess, K., Pericak-Vance, M. A., Rimmler, J. B., Martin, E. R., … Hauser, S. L. (1998). Linkage of the MHC to familial multiple sclerosis suggests genetic heterogeneity. The Multiple Sclerosis Genetics Group. Hum Mol Genet, 7(8), 1229–1234. https://doi.org/10.1093/hmg/7.8.1229
Haines, J. L., H. A. Terwedow, K. Burgess, M. A. Pericak-Vance, J. B. Rimmler, E. R. Martin, J. R. Oksenberg, et al. “Linkage of the MHC to familial multiple sclerosis suggests genetic heterogeneity. The Multiple Sclerosis Genetics Group.Hum Mol Genet 7, no. 8 (August 1998): 1229–34. https://doi.org/10.1093/hmg/7.8.1229.
Haines JL, Terwedow HA, Burgess K, Pericak-Vance MA, Rimmler JB, Martin ER, et al. Linkage of the MHC to familial multiple sclerosis suggests genetic heterogeneity. The Multiple Sclerosis Genetics Group. Hum Mol Genet. 1998 Aug;7(8):1229–34.
Haines, J. L., et al. “Linkage of the MHC to familial multiple sclerosis suggests genetic heterogeneity. The Multiple Sclerosis Genetics Group.Hum Mol Genet, vol. 7, no. 8, Aug. 1998, pp. 1229–34. Pubmed, doi:10.1093/hmg/7.8.1229.
Haines JL, Terwedow HA, Burgess K, Pericak-Vance MA, Rimmler JB, Martin ER, Oksenberg JR, Lincoln R, Zhang DY, Banatao DR, Gatto N, Goodkin DE, Hauser SL. Linkage of the MHC to familial multiple sclerosis suggests genetic heterogeneity. The Multiple Sclerosis Genetics Group. Hum Mol Genet. 1998 Aug;7(8):1229–1234.
Journal cover image

Published In

Hum Mol Genet

DOI

ISSN

0964-6906

Publication Date

August 1998

Volume

7

Issue

8

Start / End Page

1229 / 1234

Location

England

Related Subject Headings

  • Multiple Sclerosis
  • Male
  • Major Histocompatibility Complex
  • Humans
  • Genetics & Heredity
  • Genetic Variation
  • Genetic Linkage
  • Female
  • Alleles
  • 3105 Genetics