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CCR5-Delta32 Allele is Associated with the Risk of Developing Multiple Sclerosis in the Iranian Population

  • Majid ShahbaziEmail author
  • Hamid Ebadi
  • Davood Fathi
  • Danial Roshandel
  • Mana Mahamadhoseeni
  • Azam Rashidbaghan
  • Narges Mahammadi
  • Mahammad Reza Mahammadi
  • Mahdi Zamani
Original Paper

Abstract

The 32-base pair deletion on the C–C chemokine receptor 5 gene (CCR5-delta32) is known as a protective allele against immune system disorders. We have studied this variation in Iranian multiple sclerosis (MS) patients and healthy controls. DNA samples were prepared from the whole blood of 254 patients with MS and 380 healthy controls. We amplified the fragment including the CCR5-delta32 polymorphism and visualized the products in a documentation system after agarose gel electrophoresis. Data were analysed using one-way ANOVA and Fisher’s exact tests with SPSS-v13 and STATA-v8 software. The delta32 allele was more frequent in MS patients when compared with controls (OR = 2.3, P < 0.0001). Also, we found a significant difference in the frequency of the delta32/delta32 genotype among patients and controls (OR = 7.4, P < 0.001). The mean age at onset and progression index was not significantly different between patients with various genotypes. According to our study, the delta32 allele of the CCR5 gene might be a predisposing factor for MS development in the Iranian population. However, there were no associations between this polymorphism and the clinical course of the disease in this study.

Keywords

Multiple sclerosis (MS) Polymorphism Genetic susceptibility CCR5-delta32 Iranian population 

References

  1. Alshubaili AF, Alramzy K, Ayyad YM, Gerish Y (2005) Epidemiology of multiple sclerosis in Kuwait: new trends in incidence and prevalence. Eur Neurol 53:125–131CrossRefPubMedGoogle Scholar
  2. Balashov KE, Rottman JB, Weiner HL, Hancock WW (1999) CCR5 (+) and CXCR3 (+) T cells are increased in multiple sclerosis and their ligands MIP-1alpha and IP-10 are expressed in demyelinating brain lesions. Proc Natl Acad Sci USA 96:6873–6878CrossRefPubMedGoogle Scholar
  3. Barcellos LF, Schito AM, Rimmler JB, Vittinghoff E, Shih A, Lincoln R et al (2000) CC-chemokine receptor 5 polymorphism and age of onset in familial multiple sclerosis. Multiple Sclerosis Genetics Group. Immunogenetics 51:281–288CrossRefPubMedGoogle Scholar
  4. Bennetts BH, Teutsch SM, Buhler MM, Heard RN, Stewart GJ (1997) The CCR5 deletion mutation fails to protect against multiple sclerosis. Hum Immunol 58:52–59CrossRefPubMedGoogle Scholar
  5. Bonecchi R, Bianchi G, Bordignon PP, D’Ambrosio D, Lang R, Borsatti A et al (1998) Differential expression of chemokine receptors and chemotactic responsiveness of type 1 T helper cells (Th1 s) and Th2 s. J Exp Med 187:129–134CrossRefPubMedGoogle Scholar
  6. Calabresi PA, Martin R, Jacobson S (1999) Chemokines in chronic progressive neurological diseases: HTLV-1 associated myelopathy and multiple sclerosis. J Neurovirol 5:102–108CrossRefPubMedGoogle Scholar
  7. Deng H, Liu R, Ellmeier W, Choe S, Unutmaz D, Burkhart M et al (1996) Identification of a major co-receptor for primary isolates of HIV-1. Nature 381:661–666CrossRefPubMedGoogle Scholar
  8. Duszczyszyn DA, Beck JD, Antel J, Bar-Or A, Lapierre Y, Gadag V, Haegert DG (2006) Altered naive CD4 and CD8 T cell homeostasis in patients with relapsing-remitting multiple sclerosis: thymic versus peripheral (non-thymic) mechanisms. Clin Exp Immunol 143:305–313CrossRefPubMedGoogle Scholar
  9. Favorova OO, Andreewski TV, Boiko AN, Sudomoina MA, Alekseenkov AD, Kulakova OG et al (2002) The chemokine receptor CCR5 deletion mutation is associated with MS in HLA-DR4-positive Russians. Neurology 59:1652–1655PubMedGoogle Scholar
  10. Gerard C, Rollins BJ (2001) Chemokines and disease. Nat Immunol 2:108–115CrossRefPubMedGoogle Scholar
  11. Grytten N, Glad SB, Aarseth JH, Nyland H, Midgard R, Myhr KM (2006) A 50-year follow-up of the incidence of multiple sclerosis in Hordaland County, Norway. Neurology 66:182–186CrossRefPubMedGoogle Scholar
  12. Hansen T, Skytthe A, Stenager E, Petersen HC, Brønnum-Hansen H, Kyvik KO (2005) Concordance for multiple sclerosis in Danish twins: an update of a nationwide study. Mult Scler 11:504–510CrossRefPubMedGoogle Scholar
  13. Kantarci OH, Morales Y, Ziemer PA, Hebrink DD, Mahad DJ, Atkinson EJ et al (2005) CCR5Delta32 polymorphism effects on CCR5 expression, patterns of immunopathology and disease course in multiple sclerosis. J Neuroimmunol 169:137–143CrossRefPubMedGoogle Scholar
  14. Kantor R, Bakhanashvili M, Achiron A (2003) A mutated CCR5 gene may have favorable prognostic implications in MS. Neurology 61:238–240PubMedGoogle Scholar
  15. Karpus WJ, Ransohoff RM (1998) Chemokine regulation of experimental autoimmune encephalomyelitis: temporal and spatial expression patterns govern disease pathogenesis. J Immunol 161:2667–2671PubMedGoogle Scholar
  16. Liu R, Paxton WA, Choe S, Ceradini D, Martin SR, Horuk R et al (1996) Homozygous defect in HIV-1 coreceptor accounts for resistance of some multiply-exposed individuals to HIV-1 infection. Cell 86:367–377CrossRefPubMedGoogle Scholar
  17. McDonald WI, Compston A, Edan G, Goodkin D, Hartung HP, Lublin FD et al (2001) Recommended diagnostic criteria for multiple sclerosis: guidelines from the international panel on the diagnosis of multiple sclerosis. Ann Neurol 50:121–127CrossRefPubMedGoogle Scholar
  18. Otaegui D, Ruíz-Martínez J, Olaskoaga J, Emparanza JI, de Munain AL (2007) Influence of CCR5-Delta32 genotype in Spanish population with multiple sclerosis. Neurogenetics 8:201–205CrossRefPubMedGoogle Scholar
  19. Pulkkinen K, Luomala M, Kuusisto H, Lehtimäki T, Saarela M, Jalonen TO, Elovaara I (2004) Increase in CCR5 Delta32/Delta32 genotype in multiple sclerosis. Acta Neurol Scand 109:342–347CrossRefPubMedGoogle Scholar
  20. Ristić S, Lovrecić L, Starcević-Cizmarević N, Brajenović-Milić B, Jazbec SS, Barac-Latas V et al (2006) No association of CCR5delta32 gene mutation with multiple sclerosis in Croatian and Slovenian patients. Mult Scler 12:360–362CrossRefPubMedGoogle Scholar
  21. Rottman JB, Ganley KP, Williams K, Wu L, Mackay CR, Ringler DJ (1997) Cellular localization of the chemokine receptor CCR5. Correlation to cellular targets of HIV-1 infection. Am J Pathol 151:1341–1351PubMedGoogle Scholar
  22. Samson M, Libert F, Doranz BJ, Rucker J, Liesnard C, Farber CM et al (1996) Resistance to HIV-1 infection in caucasian individuals bearing mutant alleles of the CCR-5 chemokine receptor gene. Nature 382:722–725CrossRefPubMedGoogle Scholar
  23. Sellebjerg F, Madsen HO, Jensen CV, Jensen J, Garred P (2000) CCR5 delta32, matrix metalloproteinase-9 and disease activity in multiple sclerosis. J Neuroimmunol 102:98–106CrossRefPubMedGoogle Scholar
  24. Shahbazi M, Pravica V, Nasreen N, Fakhoury H, Fryer AA, Strange RC et al (2002) Association between functional polymorphism in EGF gene and malignant melanoma. Lancet 359:397–401CrossRefPubMedGoogle Scholar
  25. Silversides JA, Heggarty SV, McDonnell GV, Hawkins SA, Graham CA (2004) Influence of CCR5 delta32 polymorphism on multiple sclerosis susceptibility and disease course. Mult Scler 10:149–152CrossRefPubMedGoogle Scholar
  26. Simpson J, Rezaie P, Newcombe J, Cuzner ML, Male D, Woodroofe MN (2000) Expression of the beta-chemokine receptors CCR2, CCR3 and CCR5 in multiple sclerosis central nervous system tissue. J Neuroimmunol 108:192–200CrossRefPubMedGoogle Scholar
  27. Sørensen TL, Tani M, Jensen J, Pierce V, Lucchinetti C, Folcik VA et al (1999) Expression of specific chemokines and chemokine receptors in the central nervous system of multiple sclerosis patients. J Clin Invest 103:807–815CrossRefPubMedGoogle Scholar
  28. Strunk T, Bubel S, Mascher B, Schlenke P, Kirchner H, Wandinger KP (2000) Increased numbers of CCR5+ interferon-gamma- and tumor necrosis factor-alpha-secreting T lymphocytes in multiple sclerosis patients. Ann Neurol 47:269–273CrossRefPubMedGoogle Scholar
  29. Viglietta V, Baecher-Allan C, Weiner HL, Hafler DA (2004) Loss of functional suppression by CD4+ CD25+ regulatory T cells in patients with multiple sclerosis. J Exp Med 199:971–979CrossRefPubMedGoogle Scholar
  30. Willer CJ, Dyment DA, Risch NJ, Sadovnick AD, Ebers GC, Canadian Collaborative Study Group (2003) Twin concordance and sibling recurrence rates in multiple sclerosis. Proc Natl Acad Sci USA 100:12877–12882CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Majid Shahbazi
    • 1
    Email author
  • Hamid Ebadi
    • 2
  • Davood Fathi
    • 2
  • Danial Roshandel
    • 1
  • Mana Mahamadhoseeni
    • 1
  • Azam Rashidbaghan
    • 1
  • Narges Mahammadi
    • 1
  • Mahammad Reza Mahammadi
    • 2
  • Mahdi Zamani
    • 3
  1. 1.Medical Cellular & Molecular Research CenterGolestan University of Medical SciencesGorganIran
  2. 2.Department of Neurology, 5 Azar University HospitalGolestan University of Medical SciencesGorganIran
  3. 3.Neurogenetics Research CenterTehran University of Medical SciencesTehranIran

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