Article

CTLA-4 gene polymorphisms and systemic lupus erythematosus in a population-based study of whites and African-Americans in the southeastern United States.

Epidemiology Branch, A3-05, NIEHS, NIH, DHHS, PO Box 12233, Durham, North Carolina 27709-12233, USA.
Lupus (Impact Factor: 2.78). 01/2004; 13(10):784-91. DOI: 10.1191/0961203304lu1085oa
Source: PubMed

ABSTRACT Cytotoxic lymphocyte antigen-4 (CTLA-4) plays an important role in regulating T cell activation, and may help to limit T cell response under conditions of inflammation. Genetic variability in CTLA-4 has been implicated in the development of several autoimmune diseases. Some studies have described associations between CTLA-4 polymorphisms and systemic lupus erythematosus (SLE), but findings have been inconsistent. We examined polymorphisms in the CTLA-4 gene promoter region (-1722T/C, -1661 A/G, -318C/T) and exon I (+49G/A) with respect to SLE in a population-based case-control study in the southeastern US. Genotypes from 230 recently diagnosed cases and 276 controls were examined separately for African-Americans and whites. We observed no overall associations between SLE and the four CTLA-4 polymorphisms examined. Subgroup analyses revealed effect modification by age for the presence of the -1661G allele, yielding a significant positive association with SLE in younger (<35 years) African-Americans (OR = 3.3). CTLA-4 genotypes also interacted with HLA-DR2 and GM allotype to contribute to risk of SLE. These findings suggest allelic variation in this region of CTLA4 is not a major independent risk factor for SLE, but may contribute to risk of disease in younger African-Americans or in the presence of certain immunogenetic markers.

0 Bookmarks
 · 
46 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Aim: To explore the potential genetic association of CTLA-4 Exon1 +49A/G and 3'UTR (AT)n to susceptibility to systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and overlapping (OP) autoimmunity; affected with more than one autoimmune disease. Expression of two major CTLA-4 isoforms; full length (mCTLA-4) and soluble (sCTLA-4) were explored in all subjects. A total of 680-age/gender/ethnically matched Kuwaitis were recruited and polymerase chain reaction (PCR)-fragment analysis was employed for genotyping both markers. mCTLA-4 and sCTLA-4 mRNA expression were analyzed using quantitative real time-PCR. The enzyme-linked immunosorbent assay (ELISA) was used to screen sCTLA-4 in all subjects' sera. Results: Only two CTLA-4 3'UTR (AT)n allelotypes; (AT)15 and (AT)6 were detected. The heterozygous (AT)15/6 genotype confers protectivity rather than susceptibility to SLE (p=0.01, odds ratio=0.43, and confidence interval=0.21-0.86). No significant association was observed between Exon 1 +49A/G and any of the tested diseases. A consistently high serum sCTLA-4 level was observed in RA (6.8 ng/mL, p=0.005), SLE (6.34 ng/mL, p=0.007), and OP (8.75 ng/mL, p=0.012) compared to healthy control. A significant increase in the expression of sCTLA-4 mRNA was observed in OP (p=0.05) and SLE (p=0.047), while a significant increase in the expression of mCTLA-4 (p=0.01) was observed only in OP. Conclusion: The present study is the first to report a statistically significant association between OP and serum sCTLA-4. The novelty of our study is the significance of CTLA-4 in the pathogenesis of OP besides SLE and RA.
    Genetic Testing and Molecular Biomarkers 02/2013; · 1.44 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The protective immune response against Brucella involves T cell-mediated immunity. T lymphocyte receptors, CD28 and Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), bind the same ligands, CD80 (B7-1) and CD86 (B7-2) on antigen-presenting cells (APCs) and regulate T cell activation. CD28 delivers stimulatory while CTLA-4 provides inhibitory signals for T cell activation. Here, we investigated the association of four polymorphisms in CTLA4 (+49A/G (rs231775) and -318 C/T (rs5742909)) and its ligand CD86 (+1057 G/A (rs1129055) and +2379G/C (rs17281995)) with brucellosis infection. The study included 153 Iranian patients with active brucellosis and 128 healthy individuals as the control group. Genotyping for the CTLA4 and CD86 variants were performed using tetra amplification refractory mutation system-polymerase chain reaction (T-ARMS-PCR) and PCR-restriction fragment length polymorphism (RFLP) analysis, respectively. The present study showed that the CTLA4 -318 CT genotype and T allele with a higher frequency in cases compared to controls were associated with an elevated risk for brucellosis (-318 TT genotype, OR = 2.544, p = 0.002) Likewise, the CD86 +1057 GA and AA genotypes and A allele were associated with an increased risk of brucellosis (+1057 AA genotype: OR = 3.81, p = 0.001). However, no statistically significant difference in the allele and genotype distributions of CTLA4, +49A/G (p = 0.859) and CD86, +2379G/C (p = 0.476) between brucellosis patients and controls was observed. In conclusion, we suggest that CTLA4 -318 CT genotype and T allele and the CD86 +1057 GA and AA genotypes and A allele play roles as risk factors for developing brucellosis infection in our population.
    Microbiology and Immunology 12/2013; · 1.55 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Systemic lupus erythematosus (SLE) is a prototype autoimmune disease with complex etiology. Loss of immune tolerance and synthesis of autoantibodies against nuclear antigens contributes to the disease. Genetic aberrations disrupting the functions of immune regulatory receptors may facilitate the development of autoimmune diseases. Cytotoxic T-lymphocyte antigen 4 (CTLA4) is an inhibitory receptor for T cells and this study was carried out to analyze the influence of CTLA4 +49A/G (rs231775) polymorphism on susceptibility to SLE in ethnic Tamils. Three hundred SLE patients and 460 age and sex similar, ethnicity-matched controls were screened for the +49 A/G polymorphism by real time polymerase chain reaction (PCR). The wild allele (A) frequency in controls and cases was 63% and 47%, respectively. The presence of heterozygous (AG) and homozygous mutant (GG) genotype was associated with a significant risk to develop SLE (P = 0.0001, OR-2.29, 95% confidence interval (CI), 1.6–3.3) and (P = 0.0001, OR-4.3, 95% CI, 2.8–6.99). The frequency of mutant allele (G) in patients was also significantly associated with SLE (P = 0.0001, OR-1.9, 95% CI, 1.5–2.4). However, this polymorphism did not influence the clinical or serological phenotypes in our study. Therefore the CTLA4 +49 A/G polymorphism is a potential genetic risk factor for lupus susceptibility in South Indian Tamils, but does not appear to influence either the clinical or serological phenotype.
    Tissue Antigens 04/2014; · 2.93 Impact Factor