Progress in deciphering the genetics of multiple sclerosis

Current Opinion in Neurology

Volumn 16, Issue 3, 2003, Pages 253-258

  Herrera, Blanca M ^a   Ebers, George C ^b  

^a UNIVERSITY OF OXFORD   (United Kingdom)

^b RADCLIFFE INFIRMARY   (United Kingdom)

Author keywords

Candidate gene; Complex trait; Genome scan; Multiple sclerosis

Indexed keywords

AUTOIMMUNITY; DIABETES MELLITUS; DISEASE ASSOCIATION; DNA MICROARRAY; DOWN SYNDROME; ENDOCRINE SYSTEM; GENETIC HETEROGENEITY; GENETIC SUSCEPTIBILITY; GENETICS; HAPLOTYPE; HUMAN; MAJOR HISTOCOMPATIBILITY COMPLEX; MULTIPLE SCLEROSIS; NEUROENDOCRINE SYSTEM; REVIEW;

DIABETES MELLITUS; DISEASE PROGRESSION; DOWN SYNDROME; GENETIC PREDISPOSITION TO DISEASE; HAPLOTYPES; HLA-D ANTIGENS; HUMANS; MAJOR HISTOCOMPATIBILITY COMPLEX; MITOCHONDRIA; MULTIPLE SCLEROSIS; RECEPTORS, ESTROGEN;

EID: 0038796895     PISSN: 13507540     EISSN: None     Source Type: Journal    
DOI: 10.1097/00019052-200306000-00002     Document Type: Review

References (67)

1. Jersild C, Svejgaard A, Fog T. HLA antigens and multiple sclerosis. Lancet 1972; 1:1240-1241.
2. 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.
3. Schiekelman P, Slatkin M. Multiplex relative risk and estimation of the number of loci underlying an inherited disease. Am J Hum Genet 2002; 71:1369-1385.
4. Dyment, DA, Sadovnick AD, Ebers GC. Genetics of multiple sclerosis. Hum Mol Genet 1997; 6:1693-1698.
5. Willer C, Ebers G. Susceptibility to MS: interplay between genes and environment. Curr Opin Neurol 2000; 13:241-247.
6. Hammond SR, de Wytt C, Maxwell IC, et al. The epidemiology of multiple sclerosis in Queensland, Australia. J Neurol Sci 1987; 80:185-204.
7. 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. This study confirms previous indications of an MHC class I association in MS in a large Australian sample using microsatellites densely located in this region.
8. Robinson SL, Gutowski SJ, van Oorschot RA, et al. Genetic diversity among selected ethnic subpopulations of Australia: evidence from three highly polymorphic DNA loci. Hum Biol 1996; 68:489-508.
9. Marrosu MG, Murru MR, Costa G, et al. Multiple sclerosis in Sardinia is associated and linked with HLA-DR3 and -DR4. Am J Hum Gen 1997; 61:454-457.
10. 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.
11. Pugliatti M, Solinas G, Sotgiu S, et al. Multiple sclerosis distribution in northern Sardinia: spatial cluster analysis of prevalence. Neurology 2002; 58:277-282. This is a thorough investigation and analysis of the distribution and prevalence of MS in northern Sardinia.
12. Laaksonen M, Pastinen T, Sjoroos M, et al. HLA class II associated risk and protection against multiple sclerosis - a Finnish family study. J Neuroimmunol 2002; 122:140-145. This provides supporting evidence for a mild predisposing effect for the DRB1*04-DQB1*0302 allele, and a protective effect for the DRB1*13-DQB1*0603 allele.
13. Fogdell-Hahn A, Ligers A, Gronning M, et al. Multiple sclerosis: a modifying influence of HLA class I genes in an HLA class II associated autoimmune disease. Tissue Antigens 2000; 55:140-148.
14. Ebers GC, Kukay K, Bulman DE, et al. A full genome search in multiple sclerosis. Nat Genet 1996; 13:472-476.
15. Chataway J, Feakes R, Coraddu F, et al. The genetics of multiple sclerosis: principles, background and updated results of the United Kingdom systematic genome screen. Brain 1998; 121 (Pt 10):1869-1887.
16. 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.
17. Larsen F, Oturai A, Ryder LP, et al. Linkage analysis of a candidate region in Scandinavian sib pairs with multiple sclerosis reveals linkage to chromosome 17q. Genes Immun 2000; 1:456-459.
18. Dyment DA, Willer CJ, Scott B, et al. Genetic susceptibility to MS: a second stage analysis in Canadian MS families. Neurogenetics 2001; 3:145-151.
19. Saarela J, Schoenberg Fejzo M, Chen D, et al. Fine mapping of a multiple sclerosis locus to 2.5 Mb on chromosome 17q22-q24. Hum Mol Genet 2002; 11:2257-2267. This paper presents the identification of a 4 cM region in 73.3% of the affected of a small number of Finnish families, giving strong evidence for linkage.
20. He B, Giedratis V, Arturs L, et al. Sharing of a conserved haplotype suggests a susceptibility gene for multiple sclerosis at chromosome 17p11. Eur J Hum Genet 2002; 10:271-275. This paper provides additional support for a chromosome-17 locus.
21. Bjartmar C, Yin X, Trapp BD. Axonal pathology in myelin disorders. J Neurocytol 1999; 28:383-395.
22. Viskochil D. Genetics of neurofibromatosis 1 and the NF1 gene. J Child Neurol 2002; 17:562-570.
23. Vitale E, Cook S, Sun R, et al. Linkage analysis conditional on HLA status in a large North American pedigree supports the presence of a multiple sclerosis susceptibility locus on chromosome 12p12. Hum Mol Genet 2002; 11:295-300. This article describes a rare family with eight affected members, suggesting linkage to chromosome 12.
24. Dyment DA, Cader MZ, Willer CJ, et al. A multigenerational family with multipte sclerosis. Brain 2002; 125 (Pt 7):1474-1482. This paper describes the largest familial aggregation in a single pedigree, consistent with Mendelian inheritance, and shows a strong MHC requirement but the heritability of a modifier.
25. Sawcer S, Maranian M, Setakis E, et al. A genome screen for multiple sclerosis in Sardinian multiplex families. Eur J Hum Genet 2001; 9:621-626.
26. Goedde R, Sawcer S, Boehringer S, et al. A genome screen for linkage disequilibrium in HLA-DRB1*15-positive Germans with multiple sclerosis based on 4666 microsatellite markers. Hum Genet 2002; 111:270-277. This paper presents further findings on MS association obtained using a DNA pooling technique.
27. 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.
28. Vandenbroeck K, Fiten P, Heggarty S, et al. Chromosome 7q21-22 and multiple sclerosis: evidence for a genetic susceptibility effect in vicinity to the protachykinin-1 gene. J Neuroimmunol 2002; 125:141-148. This is a two-stage study focusing on a previously identified area, suggesting two candidate genes for susceptibility to MS in the 7q21-22 region.
29. Lieb J. Substance P and histamine induce interleukin-6 expression in human astrocytoma cells by a mechanism involving protein kinase C and nuclear factor-IL-6. J Neurochem 1998; 70:1577-1583.
30. Lieb K, Fiebich BL, Berger M, et al. The neuropeptide substance P activates transcription factor NF-kappa B and kappa B-dependent gene expression in human astrocytoma cells. J Immunol 1997; 159:4952-4958.
31. Luomala M, Elovaara I, Ukkonnen M, et al. Plasminogen activator inhibitor 1 gene and risk of MS in women. Neurology 2000; 54:1862-1864.
32. Gveric D, Hanemaaijer R, Newcombe J, et al. Plasminogen activators in multiple sclerosis lesions: implications for the inflammatory response and axonal damage. Brain 2001; 124:1978-1988.
33. Hoehe MR, Plaetke R, Otterud B, et al. Genetic linkage of the human gene for phenylethanolamine N-methyltransferase (PNMT), the adrenaline-synthesizing enzyme, to DNA markers on chromosome 17q21-q22. Hum Mol Genet 1992; 1:175-178.
34. 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.
35. Mann M, Wu S, Rostamkhani M, et al. Association between the phenylethanolamine N-methyltransferase gene and multiple sclerosis. J Neuroimmunol 2002; 124:101-105.
36. LaDu MJ, Shah JA, Reardon CA, et al. Apolipoprotein E and apolipoprotein E receptors modulate A beta-induced glial neuroinflammatory responses. Neurochem Int 2001; 39:427-434.
37. Nathan B, Jiang Y, Wong GK, et al. Apolipoprotein E4 inhibits, and apolipoprotein E3 promotes neurite outgrowth in cultured adult mouse cortical neurons through the low-density lipoprotein receptor-related protein. Brain Res 2002; 928:96-105.
38. Gaillard O, Gervais A, Meillet D, et al. Apolipoprotein E and multiple sclerosis: a biochemical and genetic investigation. J Neurol Sci 1998; 158:180-186.
39. Corder EH, Saunders AM, Strittmatter WJ, et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science 1993; 261:921-923.
40. 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.
41. Schmidt S, Barcellos L, De Sombre 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.
42. 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 U S A 1998; 95:9979-9984.
43. Becker KG. APOE genotype is a major predictor of long-term progression of disability in MS. Neurology 2001; 57:2148-2149.
44. 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.
45. Sendtner M, Carroll P, Holtmann B, et al. Ciliary neurotrophic factor. J Neurobiol 1994; 25:1436-1453.
46. Stankoff B, Aigrot MS, Noel F, et al. Ciliary neurotrophic factor (CNTF) enhances myelin formation: a novel role for CNTF and CNTF-related molecules. J Neurosci 2002; 22:9221-9227.
47. Linker RA, Maurer M, Gaupp S, et al. CNTF is a major protective factor in demyelinating CNS disease: a neurotrophic cytokine as modulator in neuroinflammation. Nat Med 2002; 8:620-624.
48. Hoffmann V, Pohlau D, Przuntek H, et al. A null mutation within the ciliary neurotrophic factor (CNTF)-gene: implications for susceptibility and disease severity in patients with multiple sclerosis. Genes Immun 2002; 3:53-55.
49. Hensiek AE, Sawcer S, Feakes R, et al. HLA-DR15 is associated with female sex and younger age at diagnosis in multiple sclerosis. J Neurol Neurosurg Psychiatry 2002; 72:184-187. This confirms earlier reports that HLA-DR15 is present slightly, though significantly, more in female patients with MS.
50. Celius EG, Harbo HF, Egeland T, et al. Sex and age at diagnosis are correlated with the HLA-DR2, DQ6 haplotype in multiple sclerosis. J Neurol Sci 2000; 178:132-135.
51. Perron H, Garson JA, Bedin F, et al. Molecular identification of a novel retrovirus repeatedly isolated from patients with multiple sclerosis. The Collaborative Research Group on Multiple Sclerosis. Proc Natl Acad Sci U S A 1997; 94:7583-7588.
52. Dolei A, Serra C, Mameli G, et al. Multiple sclerosis-associated retrovirus (MSRV) in Sardinian patients. Neurology 2002; 58:471-473.
53. 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.
54. Mattila KM, Luomala M, Lehtimaki T, et al. Interaction between ESR1 and HLA-DR2 may contribute to the development of MS in women. Neurology 2001; 56:1246-1247.
55. Levin-Allerhand J, McEwen BS, Lominska CE, et al. Brain region-specific up-regulation of mouse apolipoprotein E by pharmacological estrogen treatments. J Neurochem 2001; 79:796-803.
56. Kalman B, Li S, Chatterjee D, et al. Large scale screening of the mitochondrial DNA reveals no pathogenic mutations but a haplotype associated with multiple sclerosis in Caucasians. Acta Neurol Scand 1999; 99:16-25.
57. Kalman B, Mandler R. Studies of mitochondrial DNA in Devic's disease revealed no pathogenic mutations, but polymorphisms also found in association with multiple sclerosis. Ann Neurol 2002; 51:661-862.
58. Marrosu MG, Cocco E, Lai M, et al. Patients with multiple sclerosis and risk of type 1 diabetes mellitus in Sardinia, Italy: a cohort study. Lancet 2002; 359:1461-1465. Sardinia seems to be an exception to the general rule that MS stands more or less alone among putative autoimmune disorders. A strong co-association with type I diabetes is demonstrated in this population.
59. Graham J, Kockum I, Sanjeevi C, et al. Negative association between type 1 diabetes and H LA DQB1*0602-DQA1*0102 is attenuated with age at onset. Swedish Childhood Diabetes Study Group. Eur J Immunogenet 1999; 26:117-127.
60. Lernmark A. Multiple sclerosis and type 1 diabetes: an unlikely alliance. Lancet 2002; 359:1450-1451.
61. Friedman DL, Kastner T, Pond WS, O'Brien DR. Thyroid dysfunction in individuals with Down syndrome. Arch Intern Med 1989; 149:1990-1993.
62. Van Goor JC, Massa GG, Hirasing R. Increased incidence and prevalence of diabetes mellitus in Down's syndrome [letter]. Arch Dis Child 1997; 77:186.
63. Shield JP, Wadsworth EJ, Hassold TJ, et al. Is disomic homozygosity at the APECED locus the cause of increased autoimmunity in Down's syndrome? Arch Dis Child 1999; 81:147-150.
64. Solaro C, Uccelli MM, Mancardi GL. A patient with multiple sclerosis and Down's syndrome with a rare paroxysmal symptom at onset. Eur J Neurol 1999; 6:505-507.
65. Weilbach FX, Toyka KV. Does Down's syndrome protect against multiple sclerosis? Eur Neurol 2002; 47:52-55. This study is somewhat surprising but indicates that Down's syndrome is under-represented amongst MS patients, and the effect seems large enough to make it not easily dismissed on the basis of ascertainment bias.
66. Reeves RH, Yao J, Crowley MR, et al. Astrocytosis and axonal proliferation in the hippocampus of S100b transgenic mice. Proc Natl Acad Sci U S A 1994; 91:5359-5363.
67. 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. This is an excellent study employing new technology to obtain information on previously unknown effectors in the pathology of MS.