Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review
  • Published:

Multiple sclerosis genetics: leaving no stone unturned

Genes & Immunity volume 6, pages 375–387 (2005)Cite this article

Abstract

Compelling epidemiologic and molecular data indicate that genes play a primary role in determining who is at risk for developing multiple sclerosis (MS), how the disease progresses, and how someone responds to therapy. The genetic component of MS etiology is believed to result from the action of allelic variants in several genes. Their incomplete penetrance and moderate individual effect probably reflects epistatic interactions, post-transcriptional regulatory mechanisms, and significant environmental influences. Equally significant, it is also likely that locus heterogeneity exists, whereby specific genes influence susceptibility and pathogenesis in some individuals but not in others. With the aid of novel analytical algorithms, the combined study of genomic, transcriptional, proteomic, and phenotypic information in well-controlled study groups will define a useful conceptual model of pathogenesis and a framework for understanding the mechanisms of action of existing therapies for this disorder, as well as the rationale for novel curative strategies.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2

Similar content being viewed by others

References

  1. Hauser SL, Goodin DS . Multiple sclerosis and other demyelinating diseases. In: Kasper DL, Braunwald E, Fauci AD, Hauser SL, Longo DL, Jameson JL (eds). Harrison's Principle of Internal Medicine, 16th edn. Mc-Graw Hill: New York, 2005.

    Google Scholar 

  2. Rosati G . The prevalence of multiple sclerosis in the world: an update. Neurol Sci 2001; 22: 117–139.

    CAS  PubMed  Google Scholar 

  3. Sotgiu S, Pugliatti M, Sotgiu A, Sanna A, Rosati G . Does the ‘hygiene hypothesis’ provide an explanation for the high prevalence of multiple sclerosis in Sardinia? Autoimmunity 2003; 36: 257–260.

    PubMed  Google Scholar 

  4. Milanov I, Topalov N, Kmetski T . Prevalence of multiple sclerosis in Gypsies and Bulgarians. Epidemiology 1999; 18: 218–222.

    CAS  Google Scholar 

  5. Kurtzke JF, Beebe GW, Norman Jr JE . Epidemiology of multiple sclerosis in US veterans: 1. Race, sex, and geographic distribution. Neurology 1979; 29: 1228–1235.

    CAS  PubMed  Google Scholar 

  6. Detels R, Visscher BR, Malmgren RM, Coulson AH, Lucia MV, Dudley JP . Evidence for lower susceptibility to multiple sclerosis in Japanese-Americans. Am J Epidemiol 1977; 105: 303–310.

    CAS  PubMed  Google Scholar 

  7. Sadovnick AD, Ebers GC, Dyment DA, Risch NJ, Group CCS. Evidence for genetic basis of multiple sclerosis. Lancet 1996; 347: 1728–1730.

    CAS  PubMed  Google Scholar 

  8. Robertson NP, Fraser M, Deans J, Clayton D, Walker N, Compston DAS . Age-adjusted recurrence risks for relatives of patients with multiple sclerosis. Brain 1996; 119: 449–455.

    PubMed  Google Scholar 

  9. Sadovnick AD, Yee IM, Ebers GC . Factors influencing sib risks for multiple sclerosis. Clin Genet 2000; 58: 431–435.

    CAS  PubMed  Google Scholar 

  10. Risch N . Corrections to linkage strategies for genetically complex traits. III. The effect of marker polymorphism on analysis of affected relative pairs. Am J Hum Genet 1992; 51: 673–675.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Ebers GC, Sadovnick AD, Risch NJ . A genetic basis for familial aggregation in multiple sclerosis. Nature 1995; 377: 150–151.

    CAS  PubMed  Google Scholar 

  12. Ebers GC, Yee IM, Sadovnick AD, Duquette P . Conjugal multiple sclerosis: population-based prevalence and recurrence risks in offspring. Canadian Collaborative Study Group. Ann Neurol 2000; 48: 927–931.

    CAS  PubMed  Google Scholar 

  13. Willer CJ, Dyment DA, Sadovnick AD, Rothwell PM, Murray TJ, Ebers GC . Timing of birth and risk of multiple sclerosis: population based study. BMJ 2005; 330: 120.

    PubMed  PubMed Central  Google Scholar 

  14. Sadovnick AD, Armstrong H, Rice GP et al. A population-based study of multiple sclerosis in twins: update. Ann Neurol 1993; 33: 281–285.

    CAS  PubMed  Google Scholar 

  15. Mumford CJ, Wood NW, Kellar-Wood H et al. The British Isles survey of multiple sclerosis in twins. Neurology 1994; 44: 11–15.

    CAS  PubMed  Google Scholar 

  16. Willer CJ, Dyment DA, Risch NJ, Sadovnick AD, Ebers GC . Twin concordance and sibling recurrence rates in multiple sclerosis. Proc Natl Acad Sci USA 2003; 100: 12877–12882.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Hupperts R, Broadley S, Mander A, Clayton D, Compston DA, Robertson NP . Patterns of disease in concordant parent–child pairs with multiple sclerosis. Neurology 2001; 57: 290–295.

    CAS  PubMed  Google Scholar 

  18. Ebers GC, Sadovnick AD, Dyment DA, Yee IM, Willer CJ, Risch N . Parent-of-origin effect in multiple sclerosis: observations in half-siblings. Lancet 2004; 363: 1773–1774.

    CAS  PubMed  Google Scholar 

  19. Kantarci OH, Barcellos LF, Oksenberg JR et al. Men with MS transmit the disease more often to their children then women: The Carter effect. Mult Scler 2004; 10: S203.

    Google Scholar 

  20. Brassat D, Azais-Vuillemin C, Yaouanq J et al. Familial factors influence disability in MS multiplex families. Neurology 1999; 52: 1632–1636.

    CAS  PubMed  Google Scholar 

  21. Barcellos LF, Oksenberg JR, Green AJ et al. Genetic basis for clinical expression in multiple sclerosis. Brain 2002; 125: 150–158.

    CAS  PubMed  Google Scholar 

  22. Kantarci OH, de Andrade M, Weinshenker BG . Identifying disease modifying genes in multiple sclerosis. J Neuroimmunol 2002; 123: 144–159.

    CAS  PubMed  Google Scholar 

  23. Ebers GC, Kukay K, Bulman DE et al. A full genome search in multiple sclerosis. Nat Genet 1996; 13: 472–476.

    CAS  PubMed  Google Scholar 

  24. Haines JL, Ter-Minassian M, Bazyk A et al. A complete genomic screen for multiple sclerosis underscores a role for the major histocompatibility complex. Nat Genet 1996; 13: 469–471.

    CAS  PubMed  Google Scholar 

  25. 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.

    CAS  PubMed  Google Scholar 

  26. Transatlantic multiple Sclerosis Genetics Cooperative. A meta-analysis of whole genome linkage screens in multiple sclerosis. J Neuroimmunol 2003; 143: 39–46.

  27. Rasmussen TE, Hallett Jr JW, Tazelaar HD et al. Human leukocyte antigen class II immune response genes, female gender, and cigarette smoking as risk and modulating factors in abdominal aortic aneurysms. J Vasc Surg 2002; 35: 988–993.

    PubMed  Google Scholar 

  28. Barcellos LF, Oksenberg JR, Begovich AB et al. HLA-DR2 dose effect on susceptibility to multiple sclerosis and influence on disease course. Am J Hum Genet 2003; 72: 710–716.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Modin H, Olsson W, Hillert J, Masterman T . Modes of action of HLA-DR susceptibility specificities in multiple sclerosis. Am J Hum Genet 2004; 74: 1321–1322.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Allen M, Sandberg-Wollheim M, Sjogren K, Herlich HA, Petterson U, Gyllensten U . Association of susceptibility to multiple sclerosis in Sweden with HLA class II DRB1 and DQB1 alleles. Hum Immunol 1994; 39: 41–48.

    CAS  PubMed  Google Scholar 

  31. Spurkland A, Ronningen K, Vandvik B, Thorsby E, Vartdal F . HLA-DQA1 and HLA-DQB1 genes may jointly determine susceptibility to develop multiple sclerosis. Hum Immunol 1991; 30: 69–75.

    CAS  PubMed  Google Scholar 

  32. Boon M, Nolte IM, Bruinenberg M et al. Mapping of a susceptibility gene for multiple sclerosis to the 51 kb interval between G511525 and D6S1666 using a new method of haplotype sharing analysis. Neurogenetics 2001; 3: 221–230.

    CAS  PubMed  Google Scholar 

  33. Ligers A, Dyment DA, Willer CJ et al. Evidence of linkage with HLA-DR in DRB1*15-negative families with multiple sclerosis. Am J Hum Genet 2001; 69: 900–903.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. de Jong BA, Huizinga TW, Zanelli E et al. Evidence for additional genetic risk indicators of relapse-onset MS within the HLA region. Neurology 2002; 59: 549–555.

    CAS  PubMed  Google Scholar 

  35. Palacio LG, Rivera D, Builes JJ et al. Multiple sclerosis in the tropics: genetic association to STR's loci spanning the HLA and TNF. Mult Scler 2002; 8: 249–255.

    CAS  PubMed  Google Scholar 

  36. Shinar Y, Pras E, Siev-Ner I et al. Analysis of allelic association between D6S461 marker and multiple sclerosis in Ashkenazi and Iraqi Jewish patients. J Mol Neurosci 1998; 11: 265–269.

    CAS  PubMed  Google Scholar 

  37. Fogdell-Hahn A, Ligers A, Gronning M, Hillert J, Olerup O . Multiple sclerosis: a modifying influence of HLA class I genes in an HLA class II associated autoimmune disease. Tissue Antigens 2000; 55: 140–148.

    CAS  PubMed  Google Scholar 

  38. Marrosu MG, Murru R, Murru MR et al. Dissection of the HLA association with multiple sclerosis in the founder isolated population of Sardinia. Hum Mol Genet 2001; 10: 2907–2916.

    CAS  PubMed  Google Scholar 

  39. Rubio JP, Bahlo M, Butzkueven H et al. Genetic dissection of the human leukocyte antigen region by use of haplotypes of Tasmanians with multiple sclerosis. Am J Hum Genet 2002; 70: 1125–1137.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Lie BA, Akselsen HE, Bowlus CL, Gruen JR, Thorsby E, Undlien DE . Polymorphisms in the gene encoding thymus-specific serine protease in the extended HLA complex: a potential candidate gene for autoimmune and HLA-associated diseases. Genes Immun 2002; 3: 306–312.

    CAS  PubMed  Google Scholar 

  41. Walsh EC, Mather KA, Schaffner SF et al. An integrated haplotype map of the human major histocompatibility complex. Am J Hum Genet 2003; 73: 580–590.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Miretti MM, Walsh EC, Ke X et al. A high-resolution linkage-disequilibrium map of the human major histocompatibility complex and first generation of tag single-nucleotide polymorphisms. Am J Hum Genet 2005; 76: 634–646.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Oksenberg JR, Barcellos LF, Cree BA et al. Mapping multiple sclerosis susceptibility to the HLA-DR locus in African Americans. Am J Hum Genet 2004; 74: 160–167.

    CAS  PubMed  Google Scholar 

  44. Wallin MT, Page WF, Kurtzke JF . Multiple sclerosis in US veterans of the Vietnam era and later military service: race, sex, and geography. Ann Neurol 2004; 55: 65–71.

    PubMed  Google Scholar 

  45. Patterson N, Hattangadi N, Lane B et al. Methods for high-density admixture mapping of disease genes. Am J Hum Genet 2004; 74: 979–1000.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Seldin MF, Morii T, Collins-Schramm HE et al. Putative ancestral origins of chromosomal segments in individual African Americans: implications for admixture mapping. Genome Res 2004; 14: 1076–1084.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Allegretta M, Nicklas JA, Sriram S, Albertini RJ . T cells responsive to myelin basic protein in patients with multiple sclerosis. Science 1990; 247: 718–721.

    CAS  PubMed  Google Scholar 

  48. Pette M, Fujita K, Kitze B, Whitaker JN, Kappos A, Wekerle H . Myelin basic protein specific T cell lines from MS patients and healthy individuals. Neurology 1990; 40: 1770–1776.

    CAS  PubMed  Google Scholar 

  49. Oksenberg JR, Panzara MA, Begovich AB et al. Selection for T-cell receptor VB-DB-JB gene rearrangements with specificity for a myelin basic protein peptide in brain lesions of multiple sclerosis. Nature 1993; 362: 68–70.

    CAS  PubMed  Google Scholar 

  50. Krogsgaard M, Wucherpfennig KW, Canella B et al. Visualization of myelin basic protein (MBP) T cell epitopes in multiple sclerosis lesions using a monoclonal antibody specific for the human histocompatibility leukocyte antigen (HLA)-DR2-MBP 85-99 complex. J Exp Med 2000; 191: 1395–1412.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Smith KJ, Pyrdol J, Gauthier L, Wiley DC, Wucherpfennig KW . Crystal structure of HLA-DR2 (DRA*0101, DRB1*1501) complexed with a peptide from human myelin basic protein. J Exp Med 1998; 188: 1511–1520.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Verreck FA, Termijtelen A, Koning F . HLA-DR beta chain residue 86 controls DR alpha beta dimer stability. Eur J Immunol 1993; 23: 1346–1350.

    CAS  PubMed  Google Scholar 

  53. Wucherpfennig KW, Sette A, Southwood S et al. Structural requirements for binding of an immunodominant myelin basic protein peptide to DR 2 isotypes and for its recognition by human T cell clones. J Exp Med 1994; 179: 279–290.

    CAS  PubMed  Google Scholar 

  54. Teutsch SM, Bennetts BH, Buhler MM, Heard RN, Stewart GJ . The DRB1 Val86/Val86 genotype associates with multiple sclerosis in Australian patients. Hum Immunol 1999; 60: 715–722.

    CAS  PubMed  Google Scholar 

  55. Nelson JL . Microchimerism and HLA relationships of pregnancy: implications for autoimmune diseases. Curr Rheumatol Rep 2001; 3: 222–229.

    CAS  PubMed  Google Scholar 

  56. Nelson JL, Furst DE, Maloney S et al. Microchimerism and HLA-compatible relationships of pregnancy in scleroderma. Lancet 1998; 351: 559–562.

    CAS  PubMed  Google Scholar 

  57. Haines JL, Terwedow HA, Burgess K et al. Linkage of the MHC to familial multiple sclerosis suggests genetic heterogeneity. Hum Mol Genet 1998; 7: 1229–1234.

    CAS  PubMed  Google Scholar 

  58. Barcellos LF, Begovich AB, Reynolds RL et al. Linkage and association with the NOS2A locus on chromosome 17q11 in multiple sclerosis. Ann Neurol 2004; 55: 793–800.

    CAS  PubMed  Google Scholar 

  59. Mirel DB, Barcellos LF, Wang J, Hauser SL, Oksenberg JR, Erlich HA . Analysis of IL4R haplotypes in predisposition to multiple sclerosis. Genes Immun 2004; 5: 138–141.

    CAS  PubMed  Google Scholar 

  60. Zhou Q, Rammohan K, Lin S et al. CD24 is a genetic modifier for risk and progression of multiple sclerosis. Proc Natl Acad Sci USA 2003; 100: 15041–15046.

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Cunningham S, Patterson CC, McDonnell G, Hawkins S, Vandenbroeck K . Haplotype analysis of the preprotachykinin-1 (TAC1) gene in multiple sclerosis. Genes Immun 2005; 6: 265–270.

    CAS  PubMed  Google Scholar 

  62. Vyshkina T, Shugart YY, Birnbaum G, Leist TP, Kalman B . Association of haplotypes in the beta-chemokine locus with multiple sclerosis. Eur J Hum Genet 2005; 13: 240–247.

    CAS  PubMed  Google Scholar 

  63. Swanberg M, Lidman O, Padyukov L et al. MHC2TA is associated with differential MHC molecule expression and susceptibility to rheumatoid arthritis, multiple sclerosis and myocardial infarction. Nat Genet 2005; 37: 486–494.

    CAS  PubMed  Google Scholar 

  64. Dyment DA, Steckley JL, Willer CJ et al. No evidence to support CTLA-4 as a susceptibility gene in MS families. J Neuroimmunol 2002; 123: 193–198.

    CAS  PubMed  Google Scholar 

  65. Begovich AB, Caillier SJ, Alexander HC et al. The R620W polymorphism of the Protein Tyrosine Phosphatase PTPN22 is not associated with multiple sclerosis. Am J Hum Genet 2005; 76: 184–187.

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Daly MJ, Rioux JD, Schaffner SF, Hudson TJ, Lander ES . High-resolution haplotype structure in the human genome. Nat Genet 2001; 29: 229–232.

    CAS  PubMed  Google Scholar 

  67. Rioux JD, Daly MJ, Silverberg MS et al. Genetic variation in the 5q31 cytokine gene cluster confers susceptibility to Crohn's disease. Nat Genet 2001; 29: 223–228.

    CAS  PubMed  Google Scholar 

  68. Gabriel SB, Schaffner SF, Nguyen H et al. The structure of haplotype blocks in the human genome. Science 2002; 296: 2225–2229.

    CAS  PubMed  Google Scholar 

  69. Carlson CS, Eberle MA, Kruglyak L, Nickerson DA . Mapping complex disease loci in whole-genome association studies. Nature 2004; 429: 446–452.

    CAS  PubMed  Google Scholar 

  70. Godde R, Rohde K, Becker C et al. Association of the HLA region with multiple sclerosis as confirmed by a genome screen using >10 000 SNPs on DNA chips. J Mol Med 2005 (in press).

  71. Fredman D, White SJ, Potter S, Eichler EE, Den Dunnen JT, Brookes AJ . Complex SNP-related sequence variation in segmental genome duplications. Nat Genet 2004; 36: 861–866.

    CAS  PubMed  Google Scholar 

  72. Stefansson H, Helgason A, Thorleifsson G et al. A common inversion under selection in Europeans. Nat Genet 2005; 37: 129–137.

    CAS  PubMed  Google Scholar 

  73. Mummert SK, Lobanenkov VA, Feinberg AP . Association of chromosome arm 16q loss with loss of imprinting of insulin-like growth factor-II in Wilms tumor. Genes Chromosomes Cancer 2005; 43: 155–161.

    CAS  PubMed  Google Scholar 

  74. Iafrate AJ, Feuk L, Rivera MN et al. Detection of large-scale variation in the human genome. Nat Genet 2004; 36: 949–951.

    CAS  PubMed  Google Scholar 

  75. Carrel L, Willard HF . X-inactivation profile reveals extensive variability in X-linked gene expression in females. Nature 2005; 434: 400–404.

    CAS  PubMed  Google Scholar 

  76. Kira J, Kanai T, Nishimura Y et al. Western vs Asian types of multiple sclerosis: immunogenetically and clinically distinct disorders. Ann Neurol 1996; 40: 569–574.

    CAS  PubMed  Google Scholar 

  77. McDonnell GV, Hawkins SA . Clinical study of primary progressive multiple sclerosis in Northern Ireland, UK. J Neurol Neurosurg Psychiatry 1998; 64: 451–454.

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Brassat D, Salemi G, Barcellos L et al. The HLA locus and multiple sclerosis in Sicily. Neurology 2005; 64: 361–363.

    CAS  PubMed  Google Scholar 

  79. Engell T, Raun NE, Thomsen M, Platz P . HLA and heterogeneity of multiple sclerosis. Neurology 1982; 32: 1043–1046.

    CAS  PubMed  Google Scholar 

  80. Duquette P, Decary F, Pleines J et al. Clinical sub-groups of multiple sclerosis in relation to HLA: DR alleles as possible markers of disease progression. Can J Neurol Sci 1985; 12: 106–110.

    CAS  PubMed  Google Scholar 

  81. Madigand M, Oger JJ, Fauchet R, Sabouraud O, Genetet B . HLA profiles in multiple sclerosis suggest two forms of disease and the existence of protective haplotypes. J Neurol Sci 1982; 53: 519–529.

    CAS  PubMed  Google Scholar 

  82. Masterman T, Ligers A, Olsson T, Andersson M, Olerup O, Hillert J . HLA-DR15 is associated with lower age at onset in multiple sclerosis. Ann Neurol 2000; 48: 211–219.

    CAS  PubMed  Google Scholar 

  83. Hensiek AE, Sawcer SJ, Feakes R et al. HLA-DR 15 is associated with female sex and younger age at diagnosis in multiple sclerosis. J Neurol Neurosurg Psychiatry 2002; 72: 184–187.

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Celius EG, Harbo HF, Egeland T, Vartdal F, Vandivik B, Spurkland A . Sex and age at diagnosis are correlated with the HLA-DR2, DQ6 haplotype in multiple sclerosis. J Neurol Sci 2000; 178: 132–135.

    CAS  PubMed  Google Scholar 

  85. McDonnell GV, Mawhinney H, Graham CA, Hawkins SA, Middleton D . A study of the HLA-DR region in clinical subgroups of multiple sclerosis and its influence on prognosis. J Neurol Sci 1999; 165: 77–83.

    CAS  PubMed  Google Scholar 

  86. Poser S, Ritter G, Bauer HJ, Grosse-Wilde H, Kuwert EK, Raun NE . HLA-antigens and the prognosis of multiple sclerosis. J Neurol 1981; 225: 219–221.

    CAS  PubMed  Google Scholar 

  87. Runmarker B, Martinsson T, Wahlstrom J, Andersen O . HLA and prognosis in multiple sclerosis. J Neurol 1994; 241: 385–390.

    CAS  PubMed  Google Scholar 

  88. Weinshenker BG, Santrach P, Bissonet AS et al. Major histocompatibility complex class II alleles and the course and outcome of MS: a population-based study. Neurology 1998; 51: 742–747.

    CAS  PubMed  Google Scholar 

  89. Villoslada P, Barcellos L, Rio J et al. The HLA locus and multiple sclerosis in Spain. Role in disease susceptibility, clinical course and response to interferon-beta. J Neuroimmunol 2002; 130: 194.

    CAS  PubMed  Google Scholar 

  90. Ascherio A, Munger KL, Lennette ET et al. Epstein–Barr virus antibodies and risk of multiple sclerosis: a prospective study. JAMA 2001; 286: 3083–3088.

    CAS  PubMed  Google Scholar 

  91. Levin LI, Munger KL, Rubertone MV et al. Temporal relationship between elevation of epstein-barr virus antibody titers and initial onset on neurological symptoms in multiple sclerosis. JAMA 2005; 293: 2496–2500.

    CAS  PubMed  Google Scholar 

  92. Cepok S, Zhou D, Srivastava R et al. Identification of Epstein–Barr virus proteins as putative targets of the immune response in multiple sclerosis. J Clin Invest 2005; 115: 1352–1360.

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Hernan MA, Olek MJ, Ascherio A . Cigarette smoking and incidence of multiple sclerosis. Am J Epidemiol 2001; 154: 69–74.

    CAS  PubMed  Google Scholar 

  94. Steinman L . Assessment of animal models for MS and demyelinating disease in the design of rational therapy. Neuron 1999; 24: 511–514.

    CAS  PubMed  Google Scholar 

  95. Sobel RA . Genetic and epigenetic influence on EAE phenotypes induced with different encephalitogenic peptides. J Neuroimmunol 2000; 108: 45–52.

    CAS  PubMed  Google Scholar 

  96. Blankenhorn EP, Butterfield RJ, Rigby R et al. Genetic analysis of the influence of pertussis toxin on experimental allergic encephalomyelitis susceptibility: an environmental agent can override genetic checkpoints. J Immunol 2000; 164: 3420–3425.

    CAS  PubMed  Google Scholar 

  97. Teuscher C, Bunn JY, Fillmore PD, Butterfield RJ, Zachary JF, Blankenhorn EP . Gender, age, and season at immunization uniquely influence the genetic control of susceptibility to histopathological lesions and clinical signs of experimental allergic encephalomyelitis: implications for the genetics of multiple sclerosis. Am J Pathol 2004; 165: 1593–1602.

    PubMed  PubMed Central  Google Scholar 

  98. Encinas JA, Weiner HL, Kuchroo VK . Inheritance of susceptibility to experimental autoimmune encephalomyelitis. J Neurosci Res 1996; 45: 655–669.

    CAS  PubMed  Google Scholar 

  99. Andersson A, Karlsson J . Genetics of experimental autoimmune encephalomyelitis in the mouse. Arch Immunol Ther Exp (Warsz) 2004; 52: 316–325.

    CAS  Google Scholar 

  100. Bieber AJ, Ure DR, Rodriguez M . Genetically dominant spinal cord repair in a murine model of chronic progressive multiple sclerosis. J Neuropathol Exp Neurol 2005; 64: 46–57.

    CAS  PubMed  Google Scholar 

  101. Butterfield RJ, Blankenhorn EP, Roper RJ, Zachary JF, Doerge RW, Teuscher C . Identification of genetic loci controlling the characteristics and severity of brain and spinal cord lesions in experimental allergic encephalomyelitis. Am J Pathol 2000; 157: 637–645.

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Graumann U, Reynolds R, Steck AJ, Schaeren-Wiemers N . Molecular changes in normal appearing white matter in multiple sclerosis are characteristic of neuroprotective mechanisms against hypoxic insult. Brain Pathol 2003; 13: 554–573.

    CAS  PubMed  Google Scholar 

  103. Lindberg RL, De Groot CJ, Certa U et al. Multiple sclerosis as a generalized CNS disease—comparative microarray analysis of normal appearing white matter and lesions in secondary progressive MS. J Neuroimmunol 2004; 152: 154–167.

    CAS  PubMed  Google Scholar 

  104. Lock C, Hermans G, Pedotti R et al. Gene-microarray analysis of multiple sclerosis lesions yields new targets validated in autoimmune encephalomyelitis. Nat Med 2002; 8: 500–508.

    CAS  PubMed  Google Scholar 

  105. Baranzini SE, Hauser SL . Large-scale gene-expression studies and the challenge of multiple sclerosis. Genome Biol 2002; 3: 1027.

    Google Scholar 

  106. Baranzini SE . Gene expression profiling in neurological disorders: toward a systems-level understanding of the brain. Neuromol Med 2004; 6: 31–52.

    CAS  Google Scholar 

  107. Chabas D, Baranzini SE, Mitchell D et al. The influence of the proinflammatory cytokine, osteopontin, on autoimmune demyelinating disease. Science 2001; 294: 1731–1735.

    CAS  PubMed  Google Scholar 

  108. van Noort JM, van Sechel AC, Bajramovic JJ et al. The small heat-shock protein alpha B-crystallin as candidate autoantigen in multiple sclerosis. Nature 1995; 375: 798–801.

    CAS  PubMed  Google Scholar 

  109. Jansen RC, Nap JP . Genetical genomics: the added value from segregation. Trends Genet 2001; 17: 388–391.

    CAS  PubMed  Google Scholar 

  110. Schadt EE, Monks SA, Drake TA et al. Genetics of gene expression surveyed in maize, mouse and man. Nature 2003; 422: 297–302.

    CAS  PubMed  Google Scholar 

  111. Bystrykh L, Weersing E, Dontje B et al. Uncovering regulatory pathways that affect hematopoietic stem cell function using ‘genetical genomics’. Nat Genet 2005; 37: 225–232.

    CAS  PubMed  Google Scholar 

  112. Hubner N, Wallace CA, Zimdahl H et al. Integrated transcriptional profiling and linkage analysis for identification of genes underlying disease. Nat Genet 2005; 37: 243–253.

    CAS  PubMed  Google Scholar 

  113. Chesler EJ, Lu L, Shou S et al. Complex trait analysis of gene expression uncovers polygenic and pleiotropic networks that modulate nervous system function. Nat Genet 2005; 37: 233–242.

    CAS  PubMed  Google Scholar 

  114. Cheung VG, Conlin LK, Weber TM et al. Natural variation in human gene expression assessed in lymphoblastoid cells. Nat Genet 2003; 33: 422–425.

    CAS  PubMed  Google Scholar 

  115. Polman CH, Herndon RM, Pozzilli C . Interferons. In: Rudick RA, Goodkin DE (eds). Multiple Sclerosis Therapeutics. Martin Dunitz: London, 1999, pp 243–276.

    Google Scholar 

  116. Fusco C, Andreone V, Coppola G et al. HLA-DRB1*1501 and response to copolymer-1 therapy in relapsing-remitting multiple sclerosis. Neurology 2001; 57: 1976–1979.

    CAS  PubMed  Google Scholar 

  117. Sriram U, Barcellos LF, Villoslada P et al. Pharmacogenomic analysis of interferon receptor polymorphisms in multiple sclerosis. Genes Immun 2003; 4: 147–152.

    CAS  PubMed  Google Scholar 

  118. Baranzini SE, Mousavi P, Rio J et al. Transcription-based prediction of response to IFN beta using supervised computational methods. PLoS Biol 2005; 3: e2.

    PubMed  Google Scholar 

  119. Mann CL, Davies MB, Boggild MD et al. Glutathione S-transferase polymorphisms in MS: their relationship to disability. Neurology 2000; 54: 552–557.

    CAS  PubMed  Google Scholar 

  120. Schrijver HM, Crusius JB, Uitdehaag BM et al. Association of interleukin-1beta and interleukin-1 receptor antagonist gene with disease severity in MS. Neurolology 1999; 52: 595–599.

    CAS  Google Scholar 

  121. Kantarci OH, Atkinson EJ, Hebrink DD, McMurray CT, Weinshenker BG . Association of two variants in IL-1beta and IL-1 receptor antagonist genes with multiple sclerosis. J Neuroimmunol 2000; 106: 220–227.

    CAS  PubMed  Google Scholar 

  122. Sciacca FL, Ferri C, Vandenbroeck K et al. Relevance of interleukin 1 receptor antagonist intron 2 polymorphism in Italian MS patients. Neurology 1999; 52: 1896–1898.

    CAS  PubMed  Google Scholar 

  123. Feakes R, Sawcer S, Broadley S et al. Interleukin 1 receptor antagonist (IL-1ra) in multiple sclerosis. J Neuroimmunol 2000; 105: 96–101.

    CAS  PubMed  Google Scholar 

  124. Barcellos LF, Schito AM, Rimmler JB et al. CC-chemokine receptor 5 polymorphism and age of onset in familial multiple sclerosis. Immunogenetics 2000; 51: 281–288.

    CAS  PubMed  Google Scholar 

  125. Kantor R, Bakhanashvili M, Achiron A . A mutated CCR5 gene may have favorable prognostic implications in MS. Neurology 2003; 61: 238–240.

    CAS  PubMed  Google Scholar 

  126. Sellebjerg F, Madsen HO, Jensen CV, Jensen J, Garred P . CCR5 delta32, matrix metalloproteinase-9 and disease activity in multiple sclerosis. J Neuroimmunol 2000; 102: 98–106.

    CAS  PubMed  Google Scholar 

  127. Haase CG, Schmidt S, Faustmann PM . Frequencies of the G-protein beta3 subunit C825T polymorphism and the delta 32 mutation of the chemokine receptor-5 in patients with multiple sclerosis. Neurosci Lett 2002; 330: 293–295.

    CAS  PubMed  Google Scholar 

  128. Schreiber K, Otura AB, Ryder LP et al. Disease severity in Danish multiple sclerosis patients evaluated by MRI and three genetic markers (HLA-DRB1*1501, CCR5 deletion mutation, apolipoprotein E). Mult Scler 2002; 8: 295–298.

    CAS  PubMed  Google Scholar 

  129. Gade-Andavolu R, Comings DE, MacMurray J et al. Association of CCR5 delta32 deletion with early death in multiple sclerosis. Genet Med 2004; 6: 126–131.

    CAS  PubMed  Google Scholar 

  130. Caillier S, Barcellos LF, Baranzini SE et al. Osteopontin polymorphisms and disease course in multiple sclerosis. Genes Immun 2003; 4: 312–315.

    CAS  PubMed  Google Scholar 

  131. Niino M, Kikuchi S, Fukazawa T, Yabe I, Tashiro K . Genetic polymorphisms of osteopontin in association with multiple sclerosis in Japanese patients. J Neuroimmunol 2003; 136: 125–129.

    CAS  PubMed  Google Scholar 

  132. Hensiek AE, Roxburgh R, Meranian M et al. Osteopontin gene and clinical severity of multiple sclerosis. J Neurol 2003; 250: 943–947.

    CAS  PubMed  Google Scholar 

  133. Vandenbroeck k, Martino G, Marrosu A et al. Occurrence and clinical relevance of an interleukin-4 gene polymorphism in patients with multiple sclerosis. J Neuroimmunol 1997; 76: 189–192.

    PubMed  Google Scholar 

  134. Kantarci OH, Schaefer-Klein JL, Hebrink DD et al. A population-based study of IL4 polymorphisms in multiple sclerosis. J Neuroimmunol 2003; 137: 134–139.

    CAS  PubMed  Google Scholar 

  135. Hauser SL, Oksenberg JR, Lincoln R et al. Interaction between HLA-DR2 and abnormal brain MRI in optic neuritis and early MS. Optic Neuritis Study Group. Neurology 2000; 54: 1859–1861.

    CAS  PubMed  Google Scholar 

  136. Olerup O, Hillert J, Fredrikson S et al. Primarily chronic progressive and relapsing/remitting multiple sclerosis: two immunogenetically distinct disease entities. Proc Natl Acad Sci USA 1989; 86: 7113–7117.

    CAS  PubMed  PubMed Central  Google Scholar 

  137. de la Concha EG, Arroyo R, Crusius JBA et al. Combined effect of HLA-DRB1*1501 and interleukin-1 receptor antagonist gene allele 2 in susceptibility to relapsing/remitting multiple sclerosis. J Neuroimmunol 1997; 80: 172–178.

    CAS  PubMed  Google Scholar 

  138. Greer JM, Pender MP . The presence of glutamic acid at positions 71 or 74 in pocket 4 of the HLA-DR{beta}1 chain is associated with the clinical course of multiple s. J Neurol Neurosurg Psychiatry 2005; 76: 656–662.

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Kikuchi S, Fukazawa T, Niino M et al. Estrogen receptor gene polymorphism and multiple sclerosis in Japanese patients: interaction with HLA-DRB1*1501 and disease modulation. J Neuroimmunol 2002; 128: 77–81.

    CAS  PubMed  Google Scholar 

  140. Polanczyk M, Yellayi S, Zamora A et al. Estrogen receptor-1 (Esr1) and -2 (Esr2) regulate the severity of clinical experimental allergic encephalomyelitis in male mice. Am J Pathol 2004; 164: 1915–1924.

    CAS  PubMed  PubMed Central  Google Scholar 

  141. Mattila KM, Luomala M, Lehtimaki T, Laippala P, Koivula T, Elovaara I . Interaction between ESR1 and HLA-DR2 may contribute to the development of MS in women. Neurology 2001; 56: 1246–1247.

    CAS  PubMed  Google Scholar 

  142. Kantarci OH, Hebrink DD, Achenbach SJ et al. CD95 polymorphisms are associated with susceptibility to MS in women. A population-based study of CD95 and CD95L in MS. J Neuroimmunol 2004; 146: 162–170.

    CAS  PubMed  Google Scholar 

  143. Giess R, Maurer M, Linker R et al. Association of a null mutation in the CNTF gene with early onset of multiple sclerosis. Arch Neurol 2002; 59: 407–409.

    PubMed  Google Scholar 

  144. Hoffmann V, Hardt C . A null mutation in the CNTF gene is not associated with early onset of multiple sclerosis. Arch Neurol 2002; 59: 1974.

    PubMed  Google Scholar 

  145. van Veen T, van Winsen L, Crusius JB et al. [Alpha]B-crystallin genotype has impact on the multiple sclerosis phenotype. Neurology 2003; 61: 1245–1249.

    CAS  PubMed  Google Scholar 

  146. Kantarci OH, Goris A, Hebrink DD et al. IFNG polymorphisms are associated with gender differences in susceptibility to multiple sclerosis. Genes Immun 2005; 6: 153–161.

    CAS  PubMed  Google Scholar 

  147. Shinar Y, Livneh A, Villa Y et al. Common mutations in the familial Mediterranean fever gene associate with rapid progression to disability in non-Ashkenazi Jewish multiple sclerosis patients. Genes Immun 2003; 4: 197–203.

    CAS  PubMed  Google Scholar 

  148. Chapman J, Vinokurov S, Achiron A et al. APOE genotype is a major predictor of long-term progression of disability in MS. Neurology 2001; 56: 312–316.

    CAS  PubMed  Google Scholar 

  149. Enzinger C, Ropele S, Strasser-Fuchs S et al. Lower levels of N-acetylaspartate in multiple sclerosis patients with the apolipoprotein E epsilon4 allele. Arch Neurol 2003; 60: 65–70.

    PubMed  Google Scholar 

  150. Enzinger C, Ropele S, Smith S et al. Accelerated evolution of brain atrophy and ‘black holes’ in MS patients with APOE-epsilon4. Ann Neurol 2004; 55: 563–569.

    CAS  PubMed  Google Scholar 

  151. Evangelou N, Jackson M, Beeson D, Palace J . Association of the APOE epsilon4 allele with disease activity in multiple sclerosis. J Neurol Neurosurg Psychiatry 1999; 67: 203–205.

    CAS  PubMed  PubMed Central  Google Scholar 

  152. Fazekas F, Strasser-Fuchs S, Schmidt H et al. Apolipoprotein E genotype related differences in brain lesions of multiple sclerosis. J Neurol Neurosurg Psychiatry 2000; 69: 25–28.

    CAS  PubMed  PubMed Central  Google Scholar 

  153. Fazekas F, Strasser-Fuchs S, Kollegger H et al. Apolipoprotein E epsilon 4 is associated with rapid progression of multiple sclerosis. Neurology 2001; 57: 853–857.

    CAS  PubMed  Google Scholar 

  154. Hogh P, Oturai A, Schreiber K et al. Apoliprotein E and multiple sclerosis: impact of the epsilon-4 allele on susceptibility, clinical type and progression rate. Mult Scler 2000; 6: 226–230.

    CAS  PubMed  Google Scholar 

  155. Cocco E, Sotgiu A, Costa G et al. HLA-DR, DQ and APOE genotypes and gender influence in Sardinian primary progressive MS. Neurology 2005; 64: 564–566.

    CAS  PubMed  Google Scholar 

  156. Ferri C, Sciacca FL, Veglia F et al. APOE epsilon2-4 and -491 polymorphisms are not associated with MS. Neurology 1999; 53: 888–889.

    CAS  PubMed  Google Scholar 

  157. Savettieri G, Andreoli V, Bonavita S et al. Apolipoprotein E genotype does not influence the progression of multiple sclerosis. J Neurol 2003; 250: 1094–1098.

    CAS  PubMed  Google Scholar 

  158. Masterman T, Zhang Z, Hellgren D et al. APOE genotypes and disease severity in multiple sclerosis. Mult Scler 2002; 8: 98–103.

    CAS  PubMed  Google Scholar 

  159. Weatherby SJ, Mann CL, Davies MB et al. Polymorphisms of apolipoprotein E; outcome and susceptibility in multiple sclerosis. Mult Scler 2000; 6: 32–36.

    CAS  PubMed  Google Scholar 

  160. Ballerini C, Campani D, Rombola G et al. Association of apolipoprotein E polymorphism to clinical heterogeneity of multiple sclerosis. Neurosci Lett 2000; 296: 174–176.

    CAS  PubMed  Google Scholar 

  161. Schmidt S, Barcellos LF, DeSombre K et al. Association of polymorphisms in the apolipoprotein E region with susceptibility to and progression of multiple sclerosis. Am J Hum Genet 2002; 70: 708–717.

    CAS  PubMed  PubMed Central  Google Scholar 

  162. Kantarci OH, Hebrink DD, Achenbach SJ et al. Association of APOE polymorphisms with disease severity in MS is limited to women. Neurology 2004; 62: 811–814.

    CAS  PubMed  Google Scholar 

  163. Green AJ, Barcellos LF, Rimmler JB et al. Sequence variation in the transforming growth factor-beta1 (TGFB1) gene and multiple sclerosis susceptibility. J Neuroimmunol 2001; 116: 116–124.

    CAS  PubMed  Google Scholar 

  164. Schrijver HM, Crusius JB, Garcia-Gonzalez MA et al. Gender-related association between the TGFB1+869 polymorphism and multiple sclerosis. J Interferon Cytokine Res 2004; 24: 536–542.

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Neurology, School of Medicine, University of California at San Francisco, San Francisco, USA

    J R Oksenberg

  2. Division of Epidemiology, School of Public Health, University of California at Berkeley, Berkeley, USA

    L F Barcellos

Authors
  1. J R Oksenberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. L F Barcellos
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to J R Oksenberg.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Oksenberg, J., Barcellos, L. Multiple sclerosis genetics: leaving no stone unturned. Genes Immun 6, 375–387 (2005). https://doi.org/10.1038/sj.gene.6364237

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.gene.6364237

This article is cited by

Search

Advanced search

Quick links