Multiple sclerosis and the CTLA4 autoimmunity polymorphism CT60: no association in patients from Germany,Hungary and Poland

Abstract

Polymorphisms in the CTLA4 gene region have been associated with susceptibility to autoimmune diseases. The recently described single nucleotide polymorphism CT60, located in the 3' untranslated region of CTLA4 is associated with Graves' disease, thyroiditis, autoimmune diabetes and other autoimmune diseases. A case-control association study was conducted in German, Hungarian and Polish multiple sclerosis (MS) patients and regional control individuals for the CTLA4 CT60 and +49A/G polymorphisms. No significant association of these polymorphisms or respective haplotypes with MS was found. No association of CT60 genotypes with T cell expression of ICOS and CTLA-4 after in vitro stimulation was detected. Multiple Sclerosis 2008; 14: 153—158. http://msj.sagepub.com

Keywords

association CTLA-4 genetics multiple sclerosis polymorphism

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References

Wandstrat A. , Wakeland E. The genetics of complex autoimmune diseases: non-MHC susceptibility genes. Nat Immunol 2001; 2: 802—9.

Brand O. , Gough S. , Heward J. HLA, CTLA-4 and PTPN22: the shared genetic master-key to autoimmunity? Expert Rev Mol Med 2005; 7: 1—15.

Mayo S. , Kohler W. , Kumar V. , Quinn A. Insulin-dependent diabetes loci Idd5 and Idd9 increase sensitivity to experimental autoimmune encephalomyelitis. Clin Immunol 2006; 118: 219—28.

Greve B. , Vijayakrishnan L. , Kubal A. , Sobel RA , Peterson LB , Wicker LS et al. The diabetes susceptibility locus Idd5.1 on mouse chromosome 1 regulates ICOS expression and modulates murine experimental autoimmune encephalomyelitis . J Immunol 2004; 173: 157—63.

Vijayakrishnan L. , Slavik JM , Illes Z. , Greenwald RJ , Rainbow D. , Greve B. et al. An autoimmune disease-associated CTLA-4 splice variant lacking the B7 binding domain signals negatively in T cells . Immunity 2004; 20: 563—75.

Ueda H. , Howson JM , Esposito L. , Heward J. , Snook H. , Chamberlain G. et al. Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease. Nature 2003; 423: 506—11.

Plenge RM , Padyukov L. , Remmers EF , Purcell S. , Lee AT , Karlson EW et al. Replication of putative candidate-gene associations with rheumatoid arthritis in >4,000 samples from North America and Sweden: association of susceptibility with PTPN22, CTLA4, and PADI4. Am J Hum Genet 2005; 77: 1044—60.

Ban Y. , Tozaki T. , Taniyama M. , Tomita M. Association of a CTLA-4 3' untranslated region (CT60) single nucleotide polymorphism with autoimmune thyroid disease in the Japanese population. Autoimmunity 2005; 38: 151—3.

Zhernakova A. , Eerligh P. , Barrera P. , Weseloy JZ , Huizinga TW , Roep BO et al. CTLA4 is differentially associated with autoimmune diseases in the Dutch population. Hum Genet 2005; 118: 58—66.

10.

Petrone A. , Giorgi G. , Galgani A. , Alemanno I. , Corsello SM , Signore A. et al. CT60 single nucleotide polymorphisms of the cytotoxic T-lymphocyte-associated antigen-4 gene region is associated with Graves' disease in an Italian population . Thyroid 2005; 15: 232—8.

11.

Hunt KA , McGovern DP , Kumar PJ , Ghosh S. , Travis SP , Walters JR et al. A common CTLA4 haplotype associated with coeliac disease. Eur J Hum Genet 2005; 13: 440—4.

12.

Amundsen SS , Naluai AT , Ascher H. , Ek J. , Gudjonsdottir AH , Wahlstrom J. et al. Genetic analysis of the CD28/CTLA4/ICOS (CELIAC3) region in coeliac disease. Tissue Antigens 2004; 64: 593—9.

13.

Torres B. , Aguilar F. , Franco E. , Sanchez E. , Sanchez-Roman J. , Jimenez Alonso J. et al. Association of the CT60 marker of the CTLA4 gene with systemic lupus erythematosus. Arthritis Rheum 2004; 50: 2211—5.

14.

Lorentzen AR , Celius EG , Ekstrom PO , Wiencke K. , Lie BA , Myhr KM et al. Lack of association with the CD28/CTLA4/ICOS gene region among Norwegian multiple sclerosis patients. J Neuroimmunol 2005; 166: 197—201.

15.

Bonetti A. , Reunanen K. , Finnila S. , Koivisto K. , Wikstrom J. , Sumelahti ML et al. A two-stage study on multiple sclerosis susceptibility and chromosome 2q33. Genes Immun 2004; 5: 142—6.

16.

Castelli L. , Comi C. , Chiocchetti A. , Nicola S. , Mesturini R. , Giordano M. et al. ICOS gene haplotypes correlate with IL10 secretion and multiple sclerosis evolution. J Neuroimmunol 2007; 186: 193—8.

17.

Kantarci OH , Hebrink DD , Achenbach SJ , Atkinson EJ , Waliszewska A. , Buckle G. et al. CTLA4 is associated with susceptibility to multiple sclerosis. J Neuroimmunol 2003 ; 134: 133—4.

18.

Walsh EC , Guschwan-McMahon S. , Daly MJ , Hafler DA , Rioux JD Genetic analysis of multiple sclerosis. J Autoimmun 2003; 21: 111—6.

19.

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 2004 ; 148: 218—30.

20.

Suppiah V. , Alloza I. , Heggarty S. , Goris A. , Dubois B. , Carton H. et al. The CTLA4 +49 A/G*G-CT60*G haplotype is associated with susceptibility to multiple sclerosis in Flanders. J Neuroimmunol 2005; 164: 148—53.

21.

Roxburgh RH , Sawcer S. , Maranian M. , Seaman S. , Hensiek A. , Yeo T. et al. No evidence of a significant role for CTLA-4 in multiple sclerosis . J Neuroimmunol 2006; 171: 193—7.

22.

Barcellos LF , Kamdar BB , Ramsay PP , DeLoa C. , Lincoln RR , Caillier S. et al. Clustering of autoimmune diseases in families with a high-risk for multiple sclerosis: a descriptive study. Lancet Neurol 2006; 5: 924—31.

23.

Schmidt WP , Roesler A. , Kretzschmar K. , Ladwig KH , Junker R. , Berger K. Functional and cognitive consequences of silent stroke discovered using brain magnetic resonance imaging in an elderly population. J Am Geriatr Soc 2004; 52: 1045—50.

24.

Poser CM , Paty DW , Scheinberg L. , McDonald WI , Davis FA , Ebers GC et al. New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol 1983; 13: 227—31.

25.

McDonald WI , Compston A. , Edan G. , Goodkin D. , Hartung HP , Lublin FD et al. Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis. Ann Neurol 2001; 50: 121—7.

26.

Berg LM , Sanders R. , Alderborn A. Pyrosequencing technology and the need for versatile solutions in molecular clinical research. Expert Rev Mol Diagn 2002 ; 2: 361—9.

27.

Weissert R. , Kuhle J. , de Graaf KL , Wienhold W. , Herrmann MM , Muller C. et al. High immunogenicity of intracellular myelin oligodendrocyte glycoprotein epitopes. J Immunol 2002; 169: 548—56.

28.

Barrett JC , Fry B. , Maller J. , Daly MJ Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 2005; 21: 263—5.

29.

Wicker LS , Chamberlain G. , Hunter K. , Rainbow D. , Howlett S. , Tiffen P. et al. Fine mapping, gene content, comparative sequencing, and expression analyses support Ctla4 and Nramp1 as candidates for Idd5.1 and Idd5.2 in the nonobese diabetic mouse. J Immunol 2004; 173: 164—73.

30.

Oksenberg JR , Baranzini SE , Barcellos LF , Hauser SL Multiple sclerosis: genomic rewards. J Neuroimmunol 2001; 113: 171—84.

31.

Anjos SM , Shao W. , Marchand L. , Polychronakos C. Allelic effects on gene regulation at the autoimmunity-predisposing CTLA4 locus: a re-evaluation of the 3' +6230G>A polymorphism. Genes Immun 2005; 6: 305—11.

32.

Atabani SF , Thio CL , Divanovic S. , Trompette A. , Belkaid Y. , Thomas DL et al. Association of CTLA4 polymorphism with regulatory T cell frequency . Eur J Immunol 2005; 35: 2157—62.

33.

Purohit S. , Podolsky R. , Collins C. , Zheng W. , Schatz D. , Muir A. et al. Lack of correlation between the levels of soluble cytotoxic T-lymphocyte associated antigen-4 (CTLA-4) and the CT-60 genotypes. J Autoimmune Dis 2005; 2: 8.