CTLA-4 Polymorphisms and Systemic Lupus Erythematosus: A Comprehensive Meta-Analysis

Abstract

Objective: The aim of this study was to determine whether the SNPs +49A/G and CT60A/G of the CTLA-4 gene are associated with susceptibility to systemic lupus erythematosus (SLE). Methods: The comprehensive meta-analysis for +49A/G included 1753 cases and 2279 controls, and for CT60A/G included 676 cases and 576 controls. Allelic and genotypic comparisons between cases and controls were evaluated. For +49A/G, we also subdivided it by population. Results: For +49A/G, statistically significant differences were not noted (fixed: odds ratio [OR]: 1.033, 95% confidence interval [95% CI]: 0.937-1.139; random: OR: 1.038, 95% CI: 0.907-1.188). When subdivided into Asia and Europe subgroups, it showed that this polymorphism is still not significantly associated with SLE [for Asia: (fixed: OR: 1.069, 95% CI: 0.932-1.227; random: OR: 1.055, 95% CI: 0.846-1.316); for Europe: (fixed: OR: 0.988, 95% CI: 0.842-1.161; random: OR: 1.015, 95% CI: 0.805-1.281)]. And CT60A/G also did not demonstrate significant differences with SLE (fixed: OR: 1.099, 95% CI: 0.922-1.31; random: OR: 0.918, 95% CI: 0.581-1.448). Conclusion: The results suggest that the CLTA-4 gene was not associated with SLE. Further investigations are required to identify whether other at-risk polymorphisms within CTLA-4 confer a risk of SLE and to clarify the role of the CTLA-4 gene.

Get full access to this article

View all access options for this article.

References

Aguilar

et al. 2003. CTLA4 polymorphism in Spanish patients with systemic lupus erythematosus. Hum Immunol, 64:936-940.

Ahmed

et al. 2001. Association of CTLA-4 but not CD28 gene polymorphisms with systemic lupus erythematosus in the Japanese population. Rheumatology (Oxford), 40:662-667.

Barreto

et al. 2004. Evidence for CTLA4 as a susceptibility gene for systemic lupus erythematosus. Eur J Hum Genet, 12:620-626.

Bettinotti

et al. 1993. Polymorphism of the tumor necrosis factor beta gene in systemic lupus erythematosus: TNFB-MHC haplotypes. Immunogenetics, 37:449-454.

Brix

et al. 2001. Evidence for a major role of heredity in Graves' disease: a population-based study of two Danish twin cohorts. J Clin Endocrinol Metab, 86:930-934.

Brunet

et al. 1987. A new member of the immunoglobulin superfamily-CTLA-4. Nature, 328:267-270.

Chistiakov

, Turakulov

. 2003. CTLA-4 and its role in autoimmune thyroid disease. J Mol Endocrinol, 31:21-36.

Chua

et al. 2010. Study of the CTLA-4 gene polymorphisms in systemic lupus erythematosus (SLE) samples from Malaysia. Ann Hum Biol, 37:274-280.

Colhoun

et al. 2003. Problems of reporting genetic associations with complex outcomes. Lancet, 361:865-872.

10.

D'Alfonso

et al. 2000. Systemic lupus erythematosus candidate genes in the Italian population: evidence for a significant association with interleukin-10. Arthritis Rheum, 43:120-128.

11.

Deapen

et al. 1992. A revised estimate of twin concordance in systemic lupus erythematosus. Arthritis Rheum, 35:311-318.

12.

Einarsdottir

et al. 2003. The CTLA4 region as a general autoimmunity factor: an extended pedigree provides evidence for synergy with the HLA locus in the etiology of type 1 diabetes mellitus, Hashimoto's thyroiditis and Graves' disease. Eur J Hum Genet, 11:81-84.

13.

Finck

et al. 1994. Treatment of murine lupus with CTLA4Ig. Science, 265:1225-1227.

14.

Gaffney

et al. 1998. A genome-wide search for susceptibility genes in human systemic lupus erythematosus sibpair families. Proc Natl Acad Sci U S A, 95:14875-14879.

15.

Gateva

et al. 2009. A large-scale replication study identifies TNIP1, PRDM1, JAZF1, UHRF1BP1 and IL10 as risk loci for systemic lupus erythematosus. Nat Genet, 41:1228-1233.

16.

Gribben

et al. 1995. CTLA4 mediates antigen-specific apoptosis of human T cells. Proc Natl Acad Sci U S A, 92:811-815.

17.

Heward

et al. 1999. The A-G polymorphism in exon 1 of the CTLA-4 gene is not associated with systemic lupus erythematosus. Ann Rheum Dis, 58:193-195.

18.

Hudson

et al. 2002. CTLA-4 gene polymorphisms in systemic lupus erythematosus: a highly significant association with a determinant in the promoter region. Hum Genet, 111:452-455.

19.

Kavvoura

, Ioannidis

. 2005. CTLA-4 gene polymorphisms and susceptibility to type 1 diabetes mellitus: a HuGE Review and meta-analysis. Am J Epidemiol, 162:3-16.

20.

Kimkong

et al. 2011. Association between CTLA-4 polymorphisms and the susceptibility to systemic lupus erythematosus and Graves' disease in Thai population. Asian Pac J Allergy Immunol, 29:229-235.

21.

Kristiansen

et al. 2000. CTLA-4 in autoimmune diseases: a general susceptibility gene to autoimmunity? Genes Immun, 1:170-184.

22.

Kucharska

et al. 2009. Expression of CD152 (CTLA-4) in children with autoimmune thyroiditis and +49 A/G polymorphism of exon 1 of the CTLA-4 gene. J Physiol Pharmacol, 60:77-80.

23.

Lee

et al. 2001. Polymorphisms of the CTLA-4 exon 1 and promoter gene in systemic lupus erythematosus. Lupus, 10:601-605.

24.

Lee

et al. 2006. Meta-analysis of TNF-alpha promoter −308 A/G polymorphism and SLE susceptibility. Eur J Hum Genet, 14:364-371.

25.

Liu

et al. 2001. CTLA-4 gene polymorphism in promoter and exon-1 regions in Chinese patients with systemic lupus erythematosus. Lupus, 10:647-649.

26.

Matsushita

et al. 1999. Lack of a strong association of CTLA-4 exon 1 polymorphism with the susceptibility to rheumatoid arthritis and systemic lupus erythematosus in Japanese: an association study using a novel variation screening method. Tissue Antigens, 54:578-584.

27.

Nath

et al. 2005. Polymorphisms of complement receptor 1 and interleukin-10 genes and systemic lupus erythematosus: a meta-analysis. Hum Genet, 118:225-234.

28.

Parks

et al. 2004. CTLA-4 gene polymorphisms and systemic lupus erythematosus in a population-based study of whites and African-Americans in the southeastern United States. Lupus, 13:784-791.

29.

Pickering

et al. 2000. Systemic lupus erythematosus, complement deficiency, and apoptosis. Adv Immunol, 76:227-324.

30.

Pullmann

Jr.

et al. 1999. Cytotoxic T lymphocyte antigen 4 (CTLA-4) dimorphism in patients with systemic lupus erythematosus. Clin Exp Rheumatol, 17:725-729.

31.

Quintero-del-Rio

et al. 2002. The genetics of systemic lupus erythematosus stratified by renal disease: linkage at 10q22.3 (SLEN1), 2q34-35 (SLEN2), and 11p15.6 (SLEN3) Genes Immun Suppl, 1:S57-S62.

32.

Quintero-del-Rio

et al. 2004. SLEN2 (2q34-35) and SLEN1 (10q22.3) replication in systemic lupus erythematosus stratified by nephritis. Am J Hum Genet, 75:346-348.

33.

Scalapino

, Daikh

. 2008. CTLA-4: a key regulatory point in the control of autoimmune disease. Immunol Rev, 223:143-155.

34.

Takahashi

, Kimura

. 2010. HLA and CTLA4 polymorphisms may confer a synergistic risk in the susceptibility to Graves' disease. J Hum Genet, 55:323-326.

35.

Torres

et al. 2004. Association of the CT60 marker of the CTLA4 gene with systemic lupus erythematosus. Arthritis Rheum, 50:2211-2215.

36.

Ueda

et al. 2003. Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease. Nature, 423:506-511.

37.

Ulker

et al. 2009. CTLA-4 gene polymorphism of exon 1(+49 A/G) in Turkish systemic lupus erythematosus patients. Int J Immunogenet, 36:245-250.

38.

Vaidya

, Pearce

. 2004. The emerging role of the CTLA-4 gene in autoimmune endocrinopathies. Eur J Endocrinol, 150:619-626.

39.

Walport

et al. 1998. C1q and systemic lupus erythematosus. Immunobiology, 199:265-285.

40.

Waterhouse

et al. 1995. Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4. Science, 270:985-988.

Supplementary Material

Please find the following supplemental material available below.

For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.

For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.

0.00 MB

0.23 MB