Recent advances in genetic analysis of multiple sclerosis: Genetic associations and therapeutic implications

Expert Review of Neurotherapeutics

Volumn 7, Issue 9, 2007, Pages 1175-1188

  Niino, Masaaki ^a   Fukazawa, Toshiyuki ^b   Kikuchi, Seiji ^c   Sasaki, Hidenao ^d  

^a HOKKAIDO UNIVERSITY HOSPITAL   (Japan)

^b Nishimaruyama Hospital   (Japan)

^c HOKKAIDO MEDICAL CENTER   (Japan)

^d HOKKAIDO UNIVERSITY GRADUATE SCHOOL OF MEDICINE   (Japan)

Author keywords

Ethnicity; Genetics; HLA; Multiple sclerosis; Pharmacogenetics; Susceptibility genes; Therapy

Indexed keywords

APOLIPOPROTEIN E; CHEMOKINE; CHEMOKINE RECEPTOR; CYTOKINE; CYTOKINE RECEPTOR; GLUCOCORTICOID; MYELIN BASIC PROTEIN; MYELOPEROXIDASE; NEUROPEPTIDE; NEUROTROPHIN; NITRIC OXIDE SYNTHASE; SYNAPSIN; THROMBOCYTE ACTIVATING FACTOR; VITAMIN D BINDING PROTEIN; VITAMIN D RECEPTOR;

GENE DELETION; GENE INSERTION; GENETIC ANALYSIS; GENETIC ASSOCIATION; GENETIC SUSCEPTIBILITY; HISTOCOMPATIBILITY GENE; MULTIPLE SCLEROSIS; PHARMACOGENETICS; PUBLICATION; REVIEW; SINGLE NUCLEOTIDE POLYMORPHISM;

GENE TARGETING; GENE THERAPY; GENETIC PREDISPOSITION TO DISEASE; HUMANS; MULTIPLE SCLEROSIS; NERVE TISSUE PROTEINS;

EID: 34548853712     PISSN: 14737175     EISSN: 17448360     Source Type: Journal    
DOI: 10.1586/14737175.7.9.1175     Document Type: Review

References (145)

1. Smith MW, Patterson N, Lautenberger JA et al. A high-density admixture map for disease gene discovery in African Americans. Am. J. Hum. Genet. 74, 1001-1013 (2004).
2. Niino M, Kikuchi S, Fukazawa T, Tashiro K. Genetic susceptibility to multiple sclerosis: implications of genetic research on MS therapy. Expert Rev. Neurotherapeutics 2, 89-98 (2002).
3. GAMES; Transatlantic Multiple Sclerosis Genetics Cooperative. A meta-analysis of whole genome linkage screens in multiple sclerosis. J. Neuroimmunol. 143, 39-46 (2003).
4. Hermanowski J, Bouzigon E, Forabosco P, Ng MY, Fisher SA, Lewis CM. Meta-analysis of genome-wide linkage studies for multiple sclerosis, using an extended GSMA method. Eur. J. Hum. Genet. 15, 703-710 (2007). • Demonstrates a recent meta-analysis of genome-wide linkage studies.
5. International Multiple Sclerosis Genetics Consortium. A high-density screen for linkage in multiple sclerosis. Am. J. Hum. Genet. 77, 454-467 (2005). • Largest linkage screen ever performed for multiple sclerosis. Even this most powerful screen revealed significant linkage only in the MHC on chromosome 6p21.
6. Reich D, Patterson N, De Jager PL et al. A whole-genome admixture scan finds a candidate locus for multiple sclerosis susceptibility. Nat. Genet. 37, 1113-1118 (2005). • Shows data using a new tool, admixture mapping.
7. Smith MW, O'Brien SJ. Mapping by admixture linkage disequilibrium: advances, limitations and guidelines. Nat. Rev. Genet. 6, 623-632 (2005).
8. Hafler DA, De Jager PL. Applying a new generation of genetic maps to understand human inflammatory disease. Nat. Rev. Immunol. 5, 83-91 (2005).
9. Hirschhorn JN, Daly MJ. Genome-wide association studies for common diseases and complex traits. Nat. Rev. Genet. 6, 95-108 (2005). •• Reviews the rationale for genome-wide association studies and discusses issues of their power, efficiency, comprehensiveness, interpretation and analysis.
10. Harbo HF, Utsi E, Lorentzen AR et al. Low frequency of the disease-associated DRB1*15-DQB1*06 haplotype may contribute to the low prevalence of multiple sclerosis in Sami. Tissue Antigens 69, 299-304 (2007).
11. Dunne C, McGuigan C, Crowley J et al. Human leucocyte antigen class II polymorphism in Irish patients with multiple sclerosis. Tissue Antigens 68, 257-262 (2006).
12. Oksenberg JR, Barcellos LF, Cree BA et al. Mapping multiple sclerosis susceptibility to the HLA-DR locus in African-Americans. Am. J. Hum. Genet. 74, 160-167 (2004).
13. 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. 70, 1125-1137 (2002).
14. Harbo HF, Lie BA, Sawcer S et al. Genes in the HLA class I region may contribute to the HLA class II-associated genetic susceptibility to multiple sclerosis. Tissue Antigens 63, 237-247 (2004).
15. International Multiple Sclerosis Genetics Consortium. A second major histocompatibility complex susceptibility locus for multiple sclerosis. Ann. Neurol. 61, 228-236 (2007).
16. 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. 37, 486-494 (2005).
17. Akkad DA, Jagiello P, Szyld P et al. Promoter polymorphism rs3087456 in the MHC class II transactivator gene is not associated with susceptibility for selected autoimmune diseases in German patient groups. Int. J. Immunogenet. 33, 59-61 (2006).
18. Cocco E, Mancosu C, Fadda E et al. Lack of evidence for a role of the myelin basic protein gene in multiple sclerosis susceptibility in Sardinian patients. J. Neurol. 249, 1552-1555 (2002).
19. Guerini FR, Ferrante P, Losciale L et al. Myelin basic protein gene is associated with MS in DR4- and DR5-positive Italians and Russians. Neurology 61, 520-526 (2003).
20. Mäurer M, Ponath A, Kruse N, Rieckmann P. CTLA4 exon 1 dimorphism is associated with primary progressive multiple sclerosis. J. Neuroimmunol. 131, 213-215 (2002).
21. Kantarci OH, Hebrink DD, Achenbach SJ et al. CTLA4 is associated with susceptibility to multiple sclerosis. J. Neuroimmunol. 134, 133-141 (2003).
22. Suppiah V, Alloza I, Heggarty S et al. The CTLA4 +49 A/G*G-CT60*G haplotype is associated with susceptibility to multiple sclerosis in Flanders. J. Neuroimmunol. 164, 148-153 (2005).
23. Dini E, Živkovi M, Stankovi M et al. Association of polymorphisms in CTLA-4, IL-1ra and IL-1β genes with multiple sclerosis in Serbian population. J. Neuroimmunol. 177, 146-150 (2006).
24. Dyment DA, Steckley JL, Willer CJ et al. No evidence to support CTLA-4 as a susceptibility gene in MS families: the Canadian Collaborative Study. J. Neuroimmunol. 123, 193-198 (2002).
25. Masterman T, Ligers A, Zhang Z et al. CTLA4 dimorphisms and the multiple sclerosis phenotype. J. Neuroimmunol. 131, 208-212 (2002).
26. van Veen T, Crusius JB, van Winsen L et al. CTLA-4 and CD28 gene polymorphisms in susceptibility, clinical course and progression of multiple sclerosis. J. Neuroimmunol. 140, 188-193 (2003).
27. Luomala M, Lehtimaki T, Huhtala H et al. Promoter polymorphism of IL-10 and severity of multiple sclerosis. Acta Neurol. Scand. 108, 396-400 (2003).
28. Teutsch SM, Booth DR, Bennetts BH, Heard RN, Stewart GJ. Association of common T cell activation gene polymorphisms with multiple sclerosis in Australian patients. J. Neuroimmunol. 148, 218-230 (2004).
29. Bilinska M, Frydecka I, Noga L et al. Progression of multiple sclerosis is associated with exon 1 CTLA-4 gene polymorphism. Acta Neurol. Scand. 110, 67-71 (2004).
30. Lorentzen AR, Celius EG, Ekstrom PO et al. Lack of association with the CD28/CTLA4/ICOS gene region among Norwegian multiple sclerosis patients. J. Neuroimmunol. 166, 197-201 (2005).
31. Fukazawa T, Kikuchi S, Miyagishi R et al. CTLA-4 gene polymorphism is not associated with conventional multiple sclerosis in Japanese. J. Neuroimmunol. 159, 225-229 (2005).
32. Roxburgh RH, Sawcer S, Maranian M et al. No evidence of a significant role for CTLA-4 in multiple sclerosis. J. Neuroimmunol. 171, 193-197 (2006).
33. Alizadeh M, Babron MC, Birebent B et al. Genetic interaction of CTLA-4 with HLA-DR15 in multiple sclexrosis patients. Ann. Neurol. 54, 119-122 (2003).
34. Heggarty S, Suppiah V, Silversides J et al. CTLA4 gene polymorphisms and multiple sclerosis in Northern Ireland. J. Neuroimmunol. 187, 187-191 (2007).
35. Otaegui D, Saenz A, Camano P et al. CD24 V/V is an allele associated with the risk of developing multiple sclerosis in the Spanish population. Mult. Scler. 12, 511-514 (2006).
36. 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 100, 15041-15046 (2003).
37. Goris A, Maranian M, Walton A et al. CD24 Ala/Val polymorphism and multiple sclerosis. J. Neuroimmunol. 175, 200-202 (2006).
38. Ballerini C, Rosati E, Salvetti M et al. Protein tyrosine phosphatase receptor-type C exon 4 gene mutation distribution in an Italian multiple sclerosis population. Neurosci. Lett. 328, 325-327 (2002).
39. Miterski B, Sindern E, Haupts M, Schimrigk S, Epplen JT. PTPRC (CD45) is not associated with multiple sclerosis in a large cohort of German patients. BMC Med. Genet. 3, 3 (2002).
40. Gomez-Lira M, Liguori M, Magnani C et al. CD45 and multiple sclerosis: the exon 4 C77G polymorphism (additional studies and meta-analysis) and new markers. J. Neuroimmunol. 140, 216-221 (2003).
41. Nicholas RS, Partridge J, Donn RP, Hawkins C, Boggild MD. The role of the PTPRC (CD45) mutation in the development of multiple sclerosis in the North West region of the United Kingdom. J. Neurol. Neurosurg. Psychiatry 74, 944-945 (2003).
42. Cocco E, Murru MR, Melis C et al. PTPRC (CD45) C77G mutation does not contribute to multiple sclerosis susceptibility in Sardinian patients. J. Neurol. 251, 1085-1088 (2004).
43. Zhang Z, Duvefelt K, Svensson F et al. Two genes encoding immune-regulatory molecules (LAG3 and IL7R) confer susceptibility to multiple sclerosis. Genes Immun. 6, 145-152 (2005).
44. Lundmark F, Harbo HF, Celius EG et al. Association analysis of the LAG3 and CD4 genes in multiple sclerosis in two independent populations. J. Neuroimmunol. 180, 193-198 (2006).
45. de Jong BA, Huizinga TW, Zanelli E et al. Evidence for additional genetic risk indicators of relapse-onset MS within the HLA region. Neurology 59, 549-555 (2002).
46. Fernandes Filho JA, Vedeler CA, Myhr KM, Nyland H, Pandey JP. TNF-α and -β gene polymorphisms in multiple sclerosis: a highly significant role for determinants in the first intron of the TNF-β gene. Autoimmunity 35, 377-380 (2002).
47. Mihailova S, Ivanova M, Mihaylova A, Quin L, Mikova O, Naumova E. Pro- and anti-inflammatory cytokine gene polymorphism profiles in Bulgarian multiple sclerosis patients. J. Neuroimmunol. 168, 138-143 (2005).
48. Forte GI, Ragonese P, Salemi G et al. Search for genetic factors associated with susceptibility to multiple sclerosis. Ann. NY Acad. Sci. 1067, 264-269 (2006).
49. Risti S, Lovrei L, Starevi-izmarevi N et al. Tumor necrosis factor-α-308 gene polymorphism in croatian and slovenian multiple sclerosis patients. Eur. Neurol. 57, 203-207 (2007).
50. Kamali-Sarvestani E, Nikseresht A, Aflaki E, Sarvari J, Gharesi-Fard B. TNF-α, TNF-β and IL-4 gene polymorphisms in Iranian patients with multiple sclerosis. Acta Neurol. Scand. 115, 161-166 (2007).
51. Drulovic J, Popadic D, Mesaros S et al. Decreased frequency of the tumor necrosis factor-α -308 allele in Serbian patients with multiple sclerosis. Eur. Neurol. 50, 25-29 (2003).
52. Martinez A, Rubio A, Urcelay E et al. TNF-376A marks susceptibility to MS in the Spanish population: a replication study. Neurology 62, 809-810 (2004).
53. Ehling R, Gassner Ch, Lutterotti A et al. Genetic variants in the tumor necrosis factor receptor II gene in patients with multiple sclerosis. Tissue Antigens 63, 28-33 (2004).
54. Mann CL, Davies MB, Stevenson VL et al. Interleukin-1 genotypes in multiple sclerosis and relationship to disease severity. J. Neuroimmunol. 129, 197-204 (2002).
55. Hooper-van Veen T, Schrijver HM, Zwiers A et al. The interleukin-1 gene family in multiple sclerosis susceptibility and disease course. Mult. Scler. 9, 535-539 (2003).
56. Kikuchi S, Niino M, Fukazawa T, Yabe I, Tashiro K. An assessment of the association between IL-2 gene polymorphisms and Japanese patients with multiple sclerosis. J. Neurol. Sci. 205, 47-50 (2002).
57. Fedetz M, Alcina A, Fernandez O, Guerrero M, Delgado C, Matesanz F. Analysis of -631 and -475 interleukin-2 promoter single nucleotide polymorphisms in multiple sclerosis. Eur. J. Immunogenet. 29, 389-390 (2002).
58. Kantarci OH, Schaefer-Klein JL, Hebrink DD et al. A population-based study of IL4 polymorphisms in multiple sclerosis. J. Neuroimmunol. 137, 134-139 (2003).
59. Suppiah V, Goris A, Alloza I et al. Polymorphisms in the interleukin-4 and IL-4 receptor genes and multiple sclerosis: a study in Spanish-Basque, Northern Irish and Belgian populations. Int. J. Immunogenet. 32, 383-388 (2005).
60. Urcelay E, Santiago JL, Mas A et al. Role of interleukin-4 in Spanish multiple sclerosis patients. J. Neuroimmunol. 168, 164-167 (2005).
61. Mirel DB, Barcellos LF, Wang J, Hauser SL, Oksenberg JR, Erlich HA. Analysis of IL-4R haplotypes in predisposition to multiple sclerosis. Genes Immun. 5, 138-141 (2004).
62. Teutsch SM, Booth DR, Bennetts BH, Heard RN, Stewart GJ. Identification of 11 novel and common single nucleotide polymorphisms in the interleukin-7 receptor-α gene and their associations with multiple sclerosis. Eur. J. Hum. Genet. 11, 509-515 (2003).
63. Myshr KM, Vagnes KS, Maroy TH, Aarseth JH, Nyland HI, Vedeler CA. Interleukin-10 promoter polymorphisms in patients with multiple sclerosis. J. Neurol. Sci. 202, 93-97 (2002).
64. de Jong BA, Westendorp RG, Eskdale J, Uitdehaag BM, Huizinga TW. Frequency of functional interleukin-10 promoter polymorphism is different between relapse-onset and primary progressive multiple sclerosis. Hum. Immunol. 63, 281-285 (2002).
65. Kantarci OH, Goris A, Hebrink DD et al. IFNG polymorphisms are associated with gender differences in susceptibility to multiple sclerosis. Genes Immun. 6, 153-161 (2005).
66. Niino M, Kikuchi S, Fukazawa T, Yabe I, Tashiro K. Genetic polymorphisms of osteopontin in association with multiple sclerosis in Japanese patients. J. Neuroimmunol. 136, 125-129 (2003).
67. Hensiek AE, Roxburgh R, Meranian M et al. Osteopontin gene and clinical severity of multiple sclerosis. J. Neurol. 250, 943-947 (2003).
68. Miyagishi R, Niino M, Fukazawa T, Yabe I, Kikuchi S, Tashiro K. C-C chemokine receptor 2 gene polymorphism in Japanese patients with multiple sclerosis. J. Neuroimmunol. 145, 135-138 (2003).
69. Kroner A, Maurer M, Loserth S et al. Analysis of the monocyte chemoattractant protein 1 -2518 promoter polymorphism in patients with multiple sclerosis. Tissue Antigens 64, 70-73 (2004).
70. Bugeja MJ, Booth D, Bennetts B, Heard R, Rubio J, Stewart G. An investigation of polymorphisms in the 17q11.2-12 CC chemokine gene cluster for association with multiple sclerosis in Australians. BMC Med. Genet. 7, 64 (2006).
71. Vyshkina T, Shugart YY, Birnbaum G, Leist TP, Kalman B. Association of haplotypes in the β-chemokine locus with multiple sclerosis. Eur. J. Hum. Genet. 13, 240-247 (2005).
72. Vyshkina T, Kalman B. Haplotypes within genes of β-chemokines in 17q11 are associated with multiple sclerosis: a second phase study. Hum. Genet. 118, 67-75 (2005).
73. Silversides JA, Heggarty SV, McDonnell GV, Hawkins SA, Graham CA. Influence of CCR5 δ32 polymorphism on multiple sclerosis susceptibility and disease course. Mult. Scler. 10, 149-152 (2004).
74. Kantarci OH, Morales Y, Ziemer PA et al. CCR5δ32 polymorphism effects on CCR5 expression, patterns of immunopathology and disease course in multiple sclerosis. J. Neuroimmunol. 169, 137-143 (2005).
75. Risti S, Lovrei L, Starevi-izmarevi N et al. No association of CCR5δ32 gene mutation with multiple sclerosis in Croatian and Slovenian patients. Mult. Scler. 12, 360-362 (2006).
76. Pulkkinen K, Luomala M, Kuusisto H et al. Increase in CCR5δ32/δ32 genotype in multiple sclerosis. Acta Neurol. Scand. 109, 342-347 (2004).
77. Otaegui D, Ruiz-Martinez J, Olaskoaga J, Emparanza JI, de Munain AL. Influence of CCR5-δ32 genotype in Spanish population with multiple sclerosis. Neurogenetics 8(3), 201-205 (2007).
78. Kamali-Sarvestani E, Nikseresht AR, Aliparasti MR, Vessal M. IL-8 (-251 A/T) and CXCR2 (+1208 C/T) gene polymorphisms and risk of multiple sclerosis in Iranian patients. Neurosci. Lett. 404, 159-162 (2006).
79. 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. 76, 184-187 (2005).
80. Hinks A, Barton A, John S et al. Association between the PTPN22 gene and rheumatoid arthritis and juvenile idiopathic arthritis in a UK population: further support that PTPN22 is an autoimmunity gene. Arthritis Rheum. 52, 1694-1699 (2005).
81. Matesanz F, Rueda B, Orozco G et al. Protein tyrosine phosphatase gene (PTPN22) polymorphism in multiple sclerosis. J. Neurol. 252, 994-995 (2005).
82. Criswell LA, Pfeiffer KA, Lum RF et al. Analysis of families in the multiple autoimmune disease genetics consortium (MADGC) collection: the PTPN22 620W allele associates with multiple autoimmune phenotypes. Am. J. Hum. Genet. 76, 561-571 (2005).
83. de Jager PL, Sawcer S, Waliszewska A et al. Evaluating the role of the 620W allele of protein tyrosine phosphatase PTPN22 in Crohn's disease and multiple sclerosis. Eur. J. Hum. Genet. 14, 317-321 (2006).
84. Nejentsev S, Laaksonen M, Tienari PJ et al. Intercellular adhesion molecule-1 K469E polymorphism: study of association with multiple sclerosis. Hum. Immunol. 64, 345-349 (2003).
85. Cournu-Rebeix I, Genin E, Lesca G et al. Intercellular adhesion molecule-1: a protective haplotype against multiple sclerosis. Genes Immun. 4, 518-523 (2003).
86. Galimberti D, Fenoglio C, Clerici R et al. E-selectin A561C and G98T polymorphisms influence susceptibility and course of multiple sclerosis. J. Neuroimmunol. 165, 201-205 (2005).
87. Fiotti N, Zivadinov R, Altamura N et al. MMP-9 microsatellite polymorphism and multiple sclerosis. J. Neuroimmunol. 152, 147-153 (2004).
88. Yeo TW, Maranian M, Singlehurst S, Gray J, Compston A, Sawcer S. Four single nucleotide polymorphisms from the vitamin D receptor gene in UK multiple sclerosis. J. Neurol. 251, 753-754 (2004).
89. Tajouri L, Ovcaric M, Curtain R et al. Variation in the vitamin D receptor gene is associated with multiple sclerosis in an Australian population. J. Neurogenet. 19, 25-38 (2005).
90. Partridge JM, Weatherby SJ, Woolmore JA et al. Susceptibility and outcome in MS: associations with polymorphisms in pigmentation-related genes. Neurology 62, 2323-2325 (2004).
91. Niino M, Kikuchi S, Fukazawa T, Yabe I, Tashiro K. No association of vitamin D-binding protein gene polymorphisms in Japanese patients with MS. J. Neuroimmunol. 127, 177-179 (2002).
92. Tajouri L, Fernandez F, Tajouri S et al. Allelic variation investigation of the estrogen receptor within an Australian multiple sclerosis population. J. Neurol. Sci. 252, 9-12 (2007).
93. Savettieri G, Cittadella R, Valentino P et al. Lack of association between estrogen receptor 1 gene polymorphisms and multiple sclerosis in southern Italy in humans. Neurosci. Lett. 327, 115-118 (2002).
94. 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 56, 1246-1247 (2001).
95. 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. 128, 77-81 (2002).
96. van Veen T, van Winsen L, Crusius JB et al. αB-crystallin genotype has impact on the multiple sclerosis phenotype. Neurology 61, 1245-1249 (2003).
97. Stoevring B, Frederiksen JL, Christiansen M. CRYAB promoter polymorphisms: influence on multiple sclerosis susceptibility and clinical presentation. Clin. Chim. Acta 375, 57-62 (2007).
98. Niino M, Kikuchi S, Fukazawa T, Yabe I, Tashiro K. Polymorphisms of apolipoprotein E and Japanese patients with multiple sclerosis. Mult. Scler. 9, 382-386 (2003).
99. Savettieri G, Andreoli V, Bonavita S et al. Apolipoprotein E genotype does not influence the progression of multiple sclerosis. J. Neurol. 250, 1094-1098 (2003).
100. Zakrzewska-Pniewska B, Styczynska M, Podlecka A et al. Association of apolipoprotein E and myeloperoxidase genotypes to clinical course of familial and sporadic multiple sclerosis. Mult. Scler. 10, 266-271 (2004).
101. Zwemmer JN, van Veen T, van Winsen L et al. No major association of ApoE genotype with disease characteristics and MRI findings in multiple sclerosis. Mult. Scler. 10, 272-277 (2004).
102. Al-Shammri S, Fatania H, Al-Radwan R, Akanji AO. The relationship of APOE genetic polymorphism with susceptibility to multiple sclerosis and its clinical phenotypes in Kuwaiti Arab subjects. Clin. Chim. Acta 351, 203-207 (2005).
103. Sedano MI, Calmarza P, Perez L, Trejo JM. No association of apolipoprotein E ε4 genotype with faster progression or less recovery of relapses in a Spanish cohort of multiple sclerosis. Mult. Scler. 12, 13-18 (2006).
104. 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. 70, 708-717 (2002).
105. Burwick RM, Ramsay PP, Haines JL et al. APOE epsilon variation in multiple sclerosis susceptibility and disease severity: some answers. Neurology 66, 1373-1383 (2006).
106. Kikuchi S, Miyagishi R, Fukazawa T, Yabe I, Miyazaki Y, Sasaki H. TNF-related apoptosis inducing ligand (TRAIL) gene polymorphism in Japanese patients with multiple sclerosis. J. Neuroimmunol. 167, 170-174 (2005).
107. Weber A, Wandinger KP, Mueller W et al. Identification and functional characterization of a highly polymorphic region in the human TRAIL promoter in multiple sclerosis. J. Neuroimmunol. 149, 195-201 (2004).
108. van Veen T, Kalkers NF, Crusius JB et al. The FAS-670 polymorphism influences susceptibility to multiple sclerosis. J. Neuroimmunol. 128, 95-100 (2002).
109. Niino M, Kikuchi S, Fukazawa T, Miyagishi R, Yabe I, Tashiro K. An examination of the Apo-1/Fas promoter Mva I polymorphism in Japanese patients with multiple sclerosis. BMC Neurol. 2, 8 (2002).
110. 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. 146, 162-170 (2004).
111. Lucas M, Zayas MD, De Costa AF et al. A study of promoter and intronic markers of ApoI/Fas gene and the interaction with Fas ligand in relapsing multiple sclerosis. Eur. Neurol. 52, 12-17 (2004).
112. Tajouri L, Ferreira L, Ovcaric M et al. Investigation of a neuronal nitric oxide synthase gene (NOS1) polymorphism in a multiple sclerosis population. J. Neurol. Sci. 218, 25-28 (2004).
113. Sawcer S, Maranian M, Setakis E et al. A whole genome screen for linkage disequilibrium in multiple sclerosis confirms disease associations with regions previously linked to susceptibility. Brain 125, 1337-1347 (2002).
114. Hensiek AE, Roxburgh R, Smilie B et al. Updated results of the United Kingdom linkage-based genome screen in multiple sclerosis. J. Neuroimmunol. 143, 25-30 (2003).
115. Dyment DA, Sadovnick AD, Willer CJ et al. An extended genome scan in 442 Canadian multiple sclerosis-affected sibships: a report from the Canadian Collaborative Study Group. Hum. Mol. Genet. 13, 1005-1015 (2004).
116. Barcellos LF, Begovich AB, Reynolds RL et al. Linkage and association with the NOS2A locus on chromosome 17q11 in multiple sclerosis. Ann. Neurol. 55, 793-800 (2004).
117. Tajouri L, Martin V, Ovcaric M et al. Investigation of an inducible nitric oxide synthase gene (NOS2A) polymorphism in a multiple sclerosis population. Brain Res. Bull. 64, 9-13 (2004).
118. Blanco Y, Yague J, Graus F, Saiz A. No association of inducible nitric oxide synthase gene (NOS2A) to multiple sclerosis. J. Neurol. 250, 598-600 (2003).
119. Bugeja MJ, Booth DR, Bennetts BH, Heard RN, Burgner D, Stewart GJ. An investigation of NOS2A promoter polymorphisms in Australian multiple sclerosis patients. Eur. J. Hum. Genet. 13, 815-822 (2005).
120. Vogler S, Goedde R, Miterski B et al. Association of a common polymorphism in the promoter of UCP2 with susceptibility to multiple sclerosis. J. Mol. Med. 83, 806-811 (2005).
121. Lindquist S, Schott BH, Ban M, Compston DA, Sawcer S, Sailer M. The BDNF-Val66Met polymorphism: implications for susceptibility to multiple sclerosis and severity of disease. J. Neuroimmunol. 167, 183-185 (2005).
122. Blanco Y, Gomez-Choco M, Arostegui JL et al. No association of the Val66Met polymorphism of brain-derived neurotrophic factor (BDNF) to multiple sclerosis. Neurosci. Lett. 396, 217-219 (2006).
123. Liguori M, Fera F, Gioia MC et al. Investigating the role of brain-derived neurotrophic factor in relapsing-remitting multiple sclerosis. Genes Brain Behav. 6, 177-183 (2007).
124. Vanderlocht J, Burzykowski T, Somers V, Stinissen P, Hellings N. No association of leukemia inhibitory factor (LIF) DNA polymorphisms with multiple sclerosis. J. Neuroimmunol. 171, 189-192 (2006).
125. 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. 125, 141-148 (2002).
126. Cunningham S, Patterson CC, McDonnell G, Hawkins S, Vandenbroeck K. Haplotype analysis of the preprotachykinin-1 (TAC1) gene in multiple sclerosis. Genes Immun. 6, 265-270 (2005).
127. Cunningham S, O'Doherty C, Patterson C et al. The neuropeptide genes TAC1, TAC3, TAC4, VIP and PACAP(ADCYAP1), and susceptibility to multiple sclerosis. J. Neuroimmunol. 183, 208-213 (2007).
128. Osoegawa M, Niino M, Ochi H et al. Platelet-activating factor acetylhydrolase gene polymorphism and its activity in Japanese patients with multiple sclerosis. J. Neuroimmunol. 150, 150-156 (2004).
129. Osoegawa M, Miyagishi R, Ochi H et al. Platelet-activating factor receptor gene polymorphism in Japanese patients with multiple sclerosis. J. Neuroimmunol. 161, 195-198 (2005).
130. Barton A, Woolmore JA, Ward D et al. Association of protein kinase C-α (PRKCA) gene with multiple sclerosis in a UK population. Brain 127, 1717-1722 (2004).
131. Ban M, Maranian M, Yeo TW, Gray J, Compston A, Sawcer S. No evidence for association of the protein kinase C-α gene with multiple sclerosis. J. Neurol. 252, 619-620 (2005).
132. Saarela J, Kallio SP, Chen D et al. PRKCA and multiple sclerosis: association in two independent populations. PLoS Genet. 2, E42 (2006).
133. Liguori M, Cittadella R, Manna I et al. Association between synapsin III gene promoter polymorphisms and multiple sclerosis. J. Neurol. 251, 165-170 (2004).
134. Akkad DA, Godde R, Epplen JT. No association between synapsin III gene promoter polymorphisms and multiple sclerosis in German patients. J. Neurol. 253, 1365-1366 (2006).
135. Martinez A, Mas A, de las Heras V et al. Early B-cell factor gene association with multiple sclerosis in the Spanish population. BMC Neurol. 5, 19 (2005).
136. Sriram U, Barcellos LF, Villoslada P et al. Pharmacogenomic analysis of interferon receptor polymorphisms in multiple sclerosis. Genes Immun. 4, 147-152 (2003).
137. Leyva L, Fernandez O, Fedetz M et al. IFNAR1 and IFNAR2 polymorphisms confer susceptibility to multiple sclerosis but not to interferon-β treatment response. J. Neuroimmunol. 163, 165-171 (2005).
138. Cunningham S, Graham C, Hutchinson M et al. Pharmacogenomics of responsiveness to interferon IFN-β treatment in multiple sclerosis: a genetic screen of 100 type I interferon-inducible genes. Clin. Pharmacol. Ther. 78, 635-646 (2005).
139. Weinstock-Guttman B, Tamano-Blanco M, Bhasi K, Zivadinov R, Ramanathan M. Pharmacogenetics of MXA SNPs in interferon-β treated multiple sclerosis patients. J. Neuroimmunol. 182, 236-239 (2007).
140. van Winsen LL, Hooper-van Veen T, van Rossum EF et al. The impact of glucocorticoid receptor gene polymorphisms on glucocorticoid sensitivity is outweighted in patients with multiple sclerosis. J. Neuroimmunol. 167, 150-156 (2005).
141. Macciardi F, Boneschi FM, Cohen D. Pharmacogenetics of autoimmune diseases: research issues in the case of multiple sclerosis and the role of IFN-β. J. Autoimmun. 25, 1-5 (2005).
142. Olsson T, Jagodic M, Piehl F, Wallstrom E. Genetics of autoimmune neuroinflammation. Curr. Opin. Immunol. 18, 643-649 (2006).
143. Marsh S, McLeod HL. Pharmacogenomics: from bedside to clinical practice. Hum. Mol. Genet. 15, R89-R93 (2006).
144. International HapMap Project (Accessed June 2007) www.hapmap.org •• Provides information on the HapMap Project and introduces the newest data in this project.
145. Genetic Analysis of Multiple sclerosis in Europeans (GAMES) www.sciencedirect.com/science?_ob=PublicationURL&_tockey= %23TOC%234851%232003%23998569998%23464948%23FLA%23&_cdi=4851&_pubType= J&view=c&_auth=y&_acct=C000009418&_version=1&_urlVersion= 0&_userid=4311493&md5=7b720507b8c281957d486d23e14c467a