Polymorphisms of the CTLA-4 exon 1 and promoter gene in systemic lupus erythematosus

Abstract

The objective of this study was to determine whether the polymorphisms of the CTLA-4 exon 1 (/49) and promoter (7318) are associated with susceptibility to systemic lupus erythematosus (SLE) and its clinical features. Polymerase chain reaction of genomic DNA-restriction fragment length polymorphism was used to determine genotypes of the CTLA-4 exon 1 (/49) and promoter (7318) in 80 SLE patients and 86 healthy control subjects. The genotype distribution of the CTLA-4 exon 1 (/49) differed between SLE patients and controls (w² = 6.74, 2 degrees of freedom (d.f.), P = 0.03). The CTLA-4 AG genotype occurred more frequently in patients with SLE (46.3% vs 33.7% controls). On the other hand, the CTLA-4 AA genotype as well as the CTLA-4 GG genotype was less frequent among SLE patients than among control subjects (1.3% vs 9.3% and 52.5% vs 57.0%, respectively). The genotype distribution of the CTLA-4 promoter (-318) different between SLE patients and control subjects (CT, TT, CC; genotype 27.5%, 0%, 72.5% vs 16.3%, 4.7%, 79.1% controls respectively, w² = 6.36 2 d.f., P = 0.04). However, Fisher's exact or w² P-values for each genotypes of the CTLA-4 exon l (+49) and promoter (-318) between SLE and control group < 0.05. Clinically, in the lupus patients there was no significant difference according to the CTLA-4 polymorphism.

In conclusion, no correlation was found between CTLA-4 exon 1 (+49) and promoter (-318) polymorphisms and SLE in our study.

Keywords

systematic lupus erythematosus CTLA-4 polymorphisms

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References

Thompson CB , Allison JP . The emerging role of CTLA-4 as an immune attenuator . Immunity 1997; 7: 445–450 .

Tivol EA , Schweitzer AN , Sharpe AH . Costimulation and autoimmunity . Curr Opin Immunol 1996; 8: 822–830 .

Waterhouse P , Penninger JM , Timms E et al. Lymphoproliferative disorders with early lethality in mice deficient in CTLA-4 . Science 1995; 270: 985–988 .

Daikh DI , Finck BK , Linsley PS , Hollenbaugh D , Wofsy D . Long-term inhibition of murine lupus by brief simultaneous blockade of the B7=CD28 and CD40=gp39 costimulation pathways . J Immunol 1997; 159: 3104–3108 .

Finck BK , Linsley PS , Wofsy D . Treatment of murine lupus with CTLA4Ig . Science 1994; 265: 1225–1227 .

Harlan DM , Abe R , Lee KP , June CH . Potential roles of the B7 and CD28 receptor families in autoimmunity and immune evasion . Clin Immunol Immunopathol 1995; 75: 99–111 .

Yanagawa T , Aniyama M , Enomoto S et al. CTLA-4 gene polymorphism confers susceptibility to Grave's disease in Japanese . Thyroid 1997; 7: 843–846 .

Nistico L , Buzzetti R , Pritchard LE et al. The CTLA-4 gene region of chromosome 2q33 is linked to and associated with type 1 diabetes . Hum Mol Genet 1996; 7: 1075-1080 .

Tan EM , Cohen AD , Fries JF et al. The 1982 revised criteria for the classification of systemic lupus erythematosus . Arthritis Rheum 1982; 25: 1271–1277 .

10.

Bombardier C , Gladman DD , Urowitz MB , Caron D , Chang CH . Derivation of the SLEDAI. A disease acitivity index for lupus patients. The committee on prognosis studies in SLE . Arthritis Rheum 1992; 35: 630–640 .

11.

Gladman D , Ginzler E , Goldsmith C et al. The development and initial validation of the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index for systemic lupus erythematosus . Arthritis Rheum 1996; 39: 363–369 .

12.

Gribben JG , Freeman GJ , Boussiotis VA et al. CTLA-4 mediates antigen-specific apoptosis of human T cells . Proc Natl Acad Sci USA 1995; 92: 811–815 .

13.

Dariavach P , Mattei MG , Golstein P , Lefrane MP . Human Ig super-family CTLA-4 gene: chromosomal localization and identity of protein sequence between murine and human CTLA-4 cytoplasmic domains . Eur J Immunol 1988; 18: 1901–1905 .

14.

Polymeropoulos MH , Xiao H , Rath DS , Merril CR . Dinucleotide repeat polymorphism at the human CTLA-4 gene . Nucleic Acids Res 1991; 19: 4018–4018 .

15.

Deichman K , Heinzmann A , Bruggenolte E , Forster J , Kurhr J . An Mse I RFLP in the human CTLA-4 promoter . Biochem Biophys Res Commun 1996; 225: 817–818 .

16.

Tan FK , Arnett FC . The generics of lupus . Curr Opin Rheumatol 1998; 10: 399–408 .

17.

Heward J , Gordon C , Allahabadia A , Barnett AH , Franklyn JA , Gough SCL . The A-G polymorphism in exon 1 of the CTLA-4 gene is not associated with systemic lupus erythematosus . Ann Rheum Dis 1999; 58: 193–195 .

18.

Mehrian R , Quismorio FP , Strassmann G et al. Synergistic effect between IL-10 and bcl-2 genotypes in determining susceptibility to systemic lupus erythematosus . Arthritis Rheum 1998; 41: 596–602 .

19.

Yanagawa T , Hidaka Y , Guimaraes V , Soliman M , DeGroot LJ . CTLA-4 gene polymorphism associated with Grave's disease in a Caucasian population . J Clin Endocrinol Metab 1995; 80: 41-45 .

20.

Shaw G , Kamen R . A conserved AU sequence from the 30 untranslated region of GM-CSF mRNA mediates selective mRNA degradation . Cell 1986; 46: 659–667 .