Abstract
Multiple sclerosis is a demyelinating disorder of the central nervous system with a putative autoimmune aetiology in which several genes are thought to be involved. Four published genomic screens have confirmed that a gene influencing MS resides within or close to the HLA class II region in 6p21. Still, this locus is likely to confer only a part of the genetic susceptibility in MS. Further, all four studies identified a number of other regions with possible linkage. We have investigated eight chromosomal intervals syntenic to loci of importance for experimental autoimmune model diseases in the rat in 74 Swedish MS families. Possible linkage (a non-parametric linkage NPL score of 1.16 by GENEHUNTER computer package) was observed with markers in 12p13.3, a region syntenic to the rat Oia2 locus which is importance for oil induced arthritis (OIA). Four markers in the T cell receptor β chain gene region in 7q35 showed possible linkage (highest NPL score of 1.16). This locus is syntenic to the rat Cia3 locus (collagen induced arthritis). These two loci at least partially overlap with chromosomal regions showing indicative evidence for linkage in the previous MS genomic screens. Indeed, both Oia2 and Cia3 were recently found to be linked also with experimental autoimmune encephalomyelitis, a commonly used model for MS. Markers in 2p12, 3p25, 10q11.23, 17q21-25, 19q13.1, and 22q12-13 failed to provide evidence for linkage. We conclude that evidence is amounting that 12p13-12 and 7q34-36 may harbour genes with an importance for MS. The synteny with experimental loci may eventually facilitate their identification.
Similar content being viewed by others
Article PDF
References
Compston A . Genetic epidemiology of multiple sclerosis J Neurol Neurosurg Psychiatry 1997 62: 553–561
Ebers GC, Sadovnick AD, Risch NJ . A genetic basis for familial aggregation in multiple sclerosis. Canadian Collaborative Study Group Nature 1995 377: 150–151
Hillert J . Human leukocyte antigen studies in multiple sclerosis Ann Neurol 1994 36: S15–S17
Oksenberg JR, Baranzini SE, Barcellos LF, Hauser SL . Multiple sclerosis: Genomic rewards J Neuroimmunol 2001 113: 171–184
Sawcer S, Jones HB, Feakes R et al. A genome screen in multiple sclerosis reveals susceptibility loci on chromosome 6p21 and 17q22 Nat Genet 1996 13: 464–468
Haines JL, Ter-Minassian M, Bazyk A et al. A complete genomic screen for multiple sclerosis underscores a role for the major histocompatability complex. The Multiple Sclerosis Genetics Group Nat Genet 1996 13: 469–471
Ebers GC, Kukay K, Bulman DE et al. A full genome search in multiple sclerosis Nat Genet 1996 13: 472–476
Kuokkanen S, Gschwend M, Rioux JD et al. Genomewide scan of multiple sclerosis in Finnish multiplex families Am J Hum Genet 1997 61: 1379–1387
Kuokkanen S, Sundvall M, Terwilliger JD et al. A putative vulnerability locus to multiple sclerosis maps to 5p14-p12 in a region syntenic to the murine locus Eae2 Nat Genet 1996 13: 477–480
Sundvall M, Jirholt J, Yang HT et al. Identification of murine loci associated with susceptibility to chronic experimental autoimmune encephalomyelitis Nat Genet 1995 10: 313–317
Jacob HJ, Pettersson A, Wilson D et al. Genetic dissection of autoimmune type I diabetes in the BB rat Nat Genet 1992 2: 56–60
Pettersson A, Wilson D, Daniels T et al. Thyroiditis in the BB rat is associated with lymphopenia but occurs independently of diabetes J Autoimmun 1995 8: 493–505
Dahlman I, Lorentzen JC, de Graaf KL et al. Quantitative trait loci disposing for both experimental arthritis and encephalomyelitis in the DA rat; impact on severity of myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis and antibody isotype pattern Eur J Immunol 1998 28: 2188–2196
Roth MP, Viratelle C, Dolbois L et al. A genome-wide search identifies two susceptibility loci for experimental autoimmune encephalomyelitis on rat chromosomes 4 and 10 J Immunol 1999 162: 1917–1922
Dahlman I, Jacobsson L, Glaser A et al. Genome-wide linkage analysis of chronic relapsing experimental autoimmune encephalomyelitis in the rat identifies a major susceptibility locus on chromosome 9 J Immunol 1999 162: 2581–2588
Remmers EF, Longman RE, Du Y et al. A genome scan localizes five non-MHC loci controlling collagen-induced arthritis in rats Nat Genet 1996 14: 82–85
Lorentzen JC, Glaser A, Jacobsson L et al. Identification of rat susceptibility loci for adjuvant-oil-induced arthritis Proc Natl Acad Sci USA 1998 95: 6383–6387
Becker KG, Simon RM, Bailey-Wilson JE et al. Clustering of non-major histocompatibility complex susceptibility candidate loci in human autoimmune diseases Proc Natl Acad Sci USA 1998 95: 9979–9984
Dahlman I, Wallstrom E, Weissert R et al. Linkage analysis of myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis in the rat identifies a locus controlling demyelination on chromosome 18 Hum Mol Genet 1999 8: 2183–2190
Poser CM, Paty DW, Scheinberg L et al. New diagnostic criteria for multiple sclerosis: guidelines for research protocols Ann Neurol 1983 13: 227–231
Olerup O, Aldener A, Fogdell A . HLA-DQB1 and -DQA1 typing by PCR amplification with sequence-specific primers (PCR-SSP) in 2 hours Tissue Antigens 1993 41: 119–134
Kruglyak L, Daly MJ, Reeve-Daly MP, Lander ES . Parametric and nonparametric linkage analysis: a unified multipoint approach Am J Hum Genet 1996 58: 1347–1363
Weeks DE, Lange K . The affected-pedigree-member method of linkage analysis Am J Hum Genet 1988 42: 315–326
Sham PC, Curtis D . An extended transmission/disequilibrium test (TDT) for multi-allele marker loci Ann Hum Genet 1995 59: 323–336
He B, Xu C, Yang B et al. Linkage and association analysis of genes encoding cytokines and myelin proteins in multiple sclerosis J Neuroimmunol 1998 86: 13–19
Pajukanta P, Nuotio I, Terwilliger JD et al. Linkage of familial combined hyperlipidaemia to chromosome 1q21-q23 Nat Genet 1998 18: 369–373
Xu C, Dai Y, Fredrikson S, Hillert J . Association and linkage analysis of candidate chromosomal regions in multiple sclerosis: indication of disease genes in 12q23 and 7ptr-15 Eur J Hum Genet 1999 7: 110–116
Seboun E, Robinson MA, Doolittle TH et al. A susceptibility locus for multiple sclerosis is linked to the T cell receptor beta chain complex Cell 1989 57: 1095–1100
Wood NW, Sawcer SJ, Kellar-Wood HF et al. The T-cell receptor beta locus and susceptibility to multiple sclerosis Neurology 1995 45: 1859–1863
Lynch SG, Rose JW, Petajan JH et al. Discordance of T-cell receptor beta-chain genes in familial multiple sclerosis Ann Neurol 1991 30: 402–410
Epplen C, Jackel S, Santos EJ et al. Genetic predisposition to multiple sclerosis as revealed by immunoprinting Ann Neurol 1997 41: 341–352
Hockertz MK, Paty DW, Beall SS . Susceptibility to relapsing-progressive multiple sclerosis is associated with inheritance of genes linked to the variable region of the TcR beta locus: use of affected family-based controls Am J Hum Genet 1998 62: 373–385
Hillert J, Leng C, Olerup O . No association with germline T cell receptor beta-chain gene alleles or haplotypes in Swedish patients with multiple sclerosis J Neuroimmunol 1991 32;: 141–147
Wei S, Charmley P, Birchfield RI, Concannon P . Human T-cell receptor V beta gene polymorphism and multiple sclerosis Am J Hum Genet 1995 56: 963–969
Melvold RW, Jokinen DM, Knobler RL, Lipton HL . Variations in genetic control of susceptibility to Theiler's murine encephalomyelitis virus (TMEV)-induced demyelinating disease. I. Differences between susceptible SJL/J and resistant BALB/c strains map near the T cell beta-chain constant gene on chromosome 6 J Immunol 1987 138: 1429–1433
Rodriguez M, Patick AK, Pease LR, David CS . Role of T cell receptor V beta genes in Theiler's virus-induced demyelination of mice J Immunol 1992 148: 921–927
Baker D, Rosenwasser OA, O'Neill JK, Turk JL . Genetic analysis of experimental allergic encephalomyelitis in mice J Immunol 1995 155: 4046–4051
Griffiths MM, Encinas JA, Remmers EF, Kuchroo VK, Wilder RL . Mapping autoimmunity genes Curr Opin Immunol 1999 11: 689–700
Brown DR, Moskowitz NH, Killeen N, Reiner SL . A role for CD4 in peripheral T cell differentiation J Exp Med 1997 186: 101–107
Ghosh S, Palmer SM, Rodrigues NR et al. Polygenic control of autoimmune diabetes in nonobese diabetic mice Nat Genet 1993 4: 404–409
Kono DH, Burlingame RW, Owens DG et al. Lupus susceptibility loci in New Zealand mice Proc Natl Acad Sci USA 1994 91: 10168–10172
Sudweeks JD, Todd JA, Blankenhorn EP et al. Locus controlling Bordetella pertussis-induced histamine sensitization (Bphs), an autoimmune disease-susceptibility gene, maps distal to T- cell receptor beta-chain gene on mouse chromosome 6 Proc Natl Acad Sci USA 1993 90: 3700–3704
D'Alfonso S, Nistico L, Zavattari P et al. Linkage analysis of multiple sclerosis with candidate region markers in Sardinian and Continental Italian families Eur J Hum Genet 1999 7: 377–385
Lander ES, Kruglyak L . Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results Nat Genet 1995 11: 241–247
Mountz JD, Talal N . Retroviruses, apoptosis and autogenes Immunol Today 1993 14: 532–536
Bell JI, Lathrop GM . Multiple loci for multiple sclerosis Nat Genet 1996 13: 377–378
Oturai A, Larsen F, Ryder LP et al. Linkage and association analysis of susceptibility regions on chromosomes 5 and 6 in 106 Scandinavian sibling pair families with multiple sclerosis Ann Neurol 1999 46: 612–616
Acknowledgements
This study was supported from the Swedish Medical Research Council (project numbers: 11023 and 11220), the European Commission (project number CT97-2422), the Society for the Neurologically Disabled, the Sigurd and Elsa Goljes Minne foundation, the Karolinska Institute, the Magn Bergvalls foundation, the Åke Wiberg foundation, the Bibbi and Nils Jensens Foundation and the Marcus Borgströms foundation.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Xu, C., Dai, Y., Lorentzen, J. et al. Linkage analysis in multiple sclerosis of chromosomal regions syntenic to experimental autoimmune disease loci. Eur J Hum Genet 9, 458–463 (2001). https://doi.org/10.1038/sj.ejhg.5200653
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.ejhg.5200653
Keywords
This article is cited by
-
Dissection of a locus on mouse chromosome 5 reveals arthritis promoting and inhibitory genes
Arthritis Research & Therapy (2009)
-
Follow-up investigation of 12 proposed linkage regions in multiple sclerosis
Genes & Immunity (2006)
-
Intergenomic consensus in multifactorial inheritance loci: the case of multiple sclerosis
Genes & Immunity (2004)
-
TCR β polymorphisms and multiple sclerosis
Genes & Immunity (2004)
-
Linkage analysis suggests a region of importance for multiple sclerosis in 3p14–13
Genes & Immunity (2001)