Abstract
A number of association studies have explored the relationship between the CCR5-Δ32 allele and the risk of developing multiple sclerosis (MS), with varying results. In light of the results of several studies that have analyzed the role of the allele in MS, it has been proposed that the allele is involved in the etiopathogeny of the disease. Our study revealed a statistically significant difference between the study group and the control group for the carriers of at least one deleted allele (P = 0.027). The allele was more frequent in the control group, which suggests a possible protective effect of this deletion against MS. When ethnic origin was taken into account in the same analysis, we saw that the bulk of the difference was attributable to the Basque group, although the trend was also visible in the control group. Consideration of ethnic origin is therefore essential for the analysis of our sample. CCR5-Δ32 allele distribution was higher in the Basque control population than in the Basque MS population, which suggests that it confers a protective effect against MS. Relevant values were a P value of 0.008 and an odds ratio of 0.168 (95% confidence interval, 0.038 to 0.737).
Similar content being viewed by others
References
Fernandez O, Luque G, San RC, Bravo M, Dean G (1994) The prevalence of multiple sclerosis in the Sanitary District of Velez-Malaga, southern Spain. Neurology 44(3 Pt 1):425–429
Rodríguez-Antiguedad AR (1999) Esclerosis múltiple, análisis clínico retrospectivo y prospectivo de una serie hospitalaria de base poblacional. Dissertation, UPV/EHU
Goertsches R, Villoslada P, Comabella M, Montalban X, Navarro A, De La Concha EG et al (2003) A genomic screen of Spanish multiple sclerosis patients reveals multiple loci associated with the disease. J Neuroimmunol 143(1–2):124–128
Oksenberg JR, Barcellos LF, Cree BA, Baranzini SE, Bugawan TL, Khan O et al (2004) Mapping multiple sclerosis susceptibility to the HLA-DR locus in African Americans. Am J Hum Genet 74(1):160–167
Villoslada P, Barcellos LF, Rio J, Begovich AB, Tintore M, Sastre-Garriga J et al (2002) The HLA locus and multiple sclerosis in Spain. Role in disease susceptibility, clinical course and response to interferon-beta. J Neuroimmunol 130(1–2):194–201
de Bakker PI, McVean G, Sabeti PC, Miretti MM, Green T, Marchini J et al (2006) A high-resolution HLA and SNP haplotype map for disease association studies in the extended human MHC. Nat Genet 38(10):1166–1172
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(1–2):137–143
Gerard C, Rollins BJ (2001) Chemokines and disease. Nat Immunol 2:108–115
Simpson J, Newcombe J, Cuzner ML, Woodroofe M (2000) Expression of the intereferon-gamma-inducible chemokines IP-10 and Mig and their receptor, CXCR3, in multiple sclerosis lesions. Neuropathol Appl Neurobiol 26:133–142
Weiss J, Downie S, Lyman W, Berman J (1998) Astrocyte-derived monocyte-chemottractant protein-1 directs the transmigration of leukocytes across a model of the human blood-brain barrier. J Immunol 161:6896–6903
Sawcer S, Maranian M, Setakis E, Curwen V, Akesson E, Hensiek A et al (2002) A whole genome screen for linkage disequilibrium in multiple sclerosis confirms disease associations with regions previously linked to susceptibility. Brain 125(Pt 6):1337–1347
Ebers GC, Kukay K, Bulman DE, Sadovnick AD, Rice G (1996) A full genome search in multiple sclerosis. Nat Genet 13:472–476
Benkirane M, jin D, Chun R, Koup R, Jeang K (1997) Mechanism of transdominant inhibition of CCR5-mediated HIV-1 infection by CCR5Ä32. J Biol Chem 272:30603–30606
Zapico I, Coto E, Rodriguez A, Alvarez V, Torre J, Alvarez C (2000) CCR5 (chemochine receptor-5) DNA-polymorphisms influences the severity of rheumatoid arthritis. Genes Immun 1:288–289
Reynes J, Portales P, Segondy M (2001) CD4 T cell surface CCR5 density as a host factor in HIV-1 disease progression. Aids 15:1627–1634
Jalonen T, Pulkkinen K, Ukkonen M, Saarela M, Elovaara I (2002) Differential intracellular expression of CCR5 and chemokines in multiple sclerosis subtypes. J Neurol 249:576–583
Pulkkinen K, Luomala M, Kuusisto H, Lehtimaki T, Saarela J, Jalonen T et al (2004) Increase in CCR5 Ä32/Ä32 genotype in multiple sclerosis. Acta Neurol Scand 109:342–347
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(2):149–152
Gade-Andavolu R, Comings DE, MacMurray J, Rostamkhani M, Cheng L, Tourtellotte W et al (2004) Association of CCR5 Ä32 deletion with early death in multiple sclerosis. Genet Med 3:126–131
Favorova OO, Favorov AV, Boiko AN, Andreewski TV, Sudomoina MA, Alekseenkov AD et al (2006) Three allele combinations associated with multiple sclerosis. BMC Med Genet 7(1):63
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(1):121–127
Kurtzke JF (1983) Rating neurologic impairment in multiple sclerosis. An expanded disability status scale (EDSS). Neurology 33:144–152
Otaegui D, Saenz A, Martinez-Zabaleta M, Villoslada P, Fernandez-Manchola I, Alvarez dA et al (2004) Mitochondrial haplogroups in Basque multiple sclerosis patients. Mult Scler 10(5):532–535
Ristic S, Lovrecic L, Starcevic-Cizmarevic N, Brajenovic-Milic 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(3):360–362
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(4–5):281–288
Mahad DJ, Trebst C, Kivisakk P, Staugaitis SM, Tucky B, Wei T et al (2004) Expression of chemokine receptors CCR1 and CCR5 reflects differential activation of mononuclear phagocytes in pattern II and pattern III multiple sclerosis lesions. J Neuropathol Exp Neurol 63(3):262–273
Kantor R, Bakhanashvili M, Achiron A (2003) A mutated CCR5 gene may have favorable prognostic implications in MS. Neurology 61(2):238–240
Elovaara I, Kuusisto H, Paalavuo R, Sarkijarvi S, Lehtimaki T, Huhtala H et al (2006) Effect of high-dose methylprednisolone treatment on CCR5 expression on blood cells in MS exacerbation. Acta Neurol Scand 113(3):163–166
Julia E, Montalban X, Al-Zayat H, Issazadeh-Navikas S, Goertsches R, Martin R et al (2006) Deficient Fas expression by CD4+ CCR5+ T cells in multiple sclerosis. J Neuroimmunol 180:147–158
Otaegui D, Saenz A, Ruiz-Martinez J, Olaskoaga J, Lopez de Munain A (2006) UCP2 and mitochondrial haplogroups as an MS risk-factor. Mult Scler (in press)
Peterlin B, Ristic S, Sepcic J, Koncan Vracko B, Rako A, Lovrecic L et al (2006) Region with persistent high frequency of multiple sclerosis in Croatia and Slovenia. J Neurol Sci 247:169–172
Kurtzke JF (2000) Epidemiology of multiple sclerosis. Does this really point toward an etiology? Neurol Sci 21:383–403
Paisan-Ruiz C, Jain S, Evans E, Gilks W, Simon J, Van der Brug M et al (2004) Cloning of the gene containing mutations that cause PARK8-linked Parkinson’s disease. Neuron 44(4):595–600
Cobo AM, Saenz A, Poza JJ, Urtasun M, Indakoetxea B, Urtizberea JA et al (2004) A common haplotype associated with the Basque 2362AG → TCATCT mutation in the muscular calpain-3 gene. Hum Biol 76(5):731–741
Urtasun M, Saenz A, Roudaut C, Poza JJ, Urtizberea JA, Cobo AM et al (1998) Limb-girdle muscular dystrophy in Guipuzcoa (Basque Country, Spain). Brain 121(Pt 9):1735–1747
Saenz A, Leturcq F, Cobo AM, Poza JJ, Ferrer X, Otaegui D et al (2005) LGMD2A: genotype-phenotype correlations based on a large mutational survey on the calpain 3 gene. Brain 128(Pt 4):732–742
Acknowledgments
We thank the patients who took part in the study, Sabin Urcelay for her help in obtaining control samples, and Dr. Villoslada, Dr. Alvarez de Arcaya, Dr. Bergaretxe, Dr. Urtasun, Dr. Martí-Massó, and Dr. Carrera y Mantxola for their help in obtaining samples from patients. We also thank Asunción Iribarren and Olaia Zuriarrain for their invaluable technical assistance, and Marisa Martínez and Nati Coll for their help with obtaining samples. David Otaegui is a predoctoral student with a grant from the Basque Government. This study was partially funded by the Ilundain Fundazioa foundation and the Fundación Salud 2000.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Otaegui, D., Ruíz-Martínez, J., Olaskoaga, J. et al. Influence of CCR5-Δ32 genotype in Spanish population with multiple sclerosis. Neurogenetics 8, 201–205 (2007). https://doi.org/10.1007/s10048-007-0085-1
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10048-007-0085-1