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CTLA-4 gene polymorphisms in systemic lupus erythematosus: A highly significant association with a determinant in the promoter region

Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC 29425-2230, USA.
Human Genetics (Impact Factor: 4.52). 11/2002; 111(4-5):452-5. DOI: 10.1007/s00439-002-0807-2
Source: PubMed

ABSTRACT The cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4; CD 152) is a negative regulator of T-lymphocyte activation. Particular genotypes of the locus encoding the CTLA-4 glycoprotein have been associated with susceptibility to various autoimmune diseases. To determine their role in susceptibility to systemic lupus erythematosus (SLE), we genotyped 130 patients and 200 ethnically matched controls for allelic determinants at four polymorphic sites, viz., three in the promoter region at positions -1722 (T/C), -1661 (A/G), and -318 (C/T), and one within the first exon at position +49 (A/G), by restriction fragment length polymorphism methods. All genotype frequencies were in Hardy-Weinberg equilibrium. The genotypes at position -1722 were significantly associated with SLE. The frequency of T/T homozygotes was higher in patients than in controls (56% vs 33%, P=0.00003). Conversely, the frequencies of C/C homozygotes and C/T heterozygotes were higher in controls than in patients (15.5% vs 7%, P=0.019; 51.5% vs 37%, P=0.009). Genotypes at positions +49, -318, or -1661 were not significantly associated with SLE. These results show that allelic variation at the -1722 site influences susceptibility to SLE. This is the first report to our knowledge implicating CTLA-4 genotypes at the -1722 locus in susceptibility to any disease.

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    • "DNA from patients and controls was extracted from peripheral blood with DNA flash kit 2.0 (HaiGene Biotechnolgy Co., Ltd., Gentra Systems Corp.) according to the standard protocol from the manufacturer. The polymorphisms at positions −1661 and −1722 were analyzed by PCR-RFLP (polymerase chain reaction-restriction fragments length polymorphism) [13] "
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    ABSTRACT: Several variants of CTLA-4 have been reported to be associated with susceptibility systemic lupus erythematosus (SLE); however, findings have been inconsistent across different populations. Using a case-control study design, we have investigated the role of CTLA-4 polymorphism at positions -1661 and -1722 on SLE susceptibility in our Chinese SLE population in central China's Hubei province. Samples were collected from 148 SLE patients and 170 healthy controls. Polymerase chain reaction restriction fragments length polymorphism (PCR-RFLP) was used to analyze the genotypes of the two sites. Statistically significant difference was observed in genotypes for -1722, but not for -1661. The frequency of the T allele on the -1722 SNP was significantly increased in SLE patients: 57.8% versus 40.6% in controls (P < 0.001, OR = 2.002). While the detected C allele frequency in the controls was significantly elevated in comparison to that in the SLE patients (59.4% versus 42.2%). On the contrary, no association was found between SLE and CTLA-4 polymorphism at position -1661.
    BioMed Research International 09/2011; 2011:167395. DOI:10.1155/2011/167395 · 2.71 Impact Factor
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    • "Human genomic DNA was prepared from whole blood samples using a standard conventional method. The five markers at nucleotide position +49, –318, –1661, –1722 and +6230 were genotyped by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method as previously reported in other studies (Matsushita et al. 1999; Hudson et al. 2002; Takeuchi et al. 2003; Torres et al. 2004). "
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    ABSTRACT: In this study, we investigated the polymorphisms of the exon 1 (+49A/G), promoter sites (-1722T/C, -1661A/G, -318C/T), and 3'-untranslated region (3'-UTR) (+6230 A/G) of the CTLA-4 gene in systemic lupus erythematosus (SLE) affected patients. Polymerase chain reaction-restriction fragment length polymorphism was used to determine genotypes of these five markers in 130 SLE patients and 130 healthy controls. Of the five tested polymorphisms, there was no statistical significant difference between the genotypic and allelic frequencies of patients with SLE and controls. Hence, we propose that the CTLA-4 gene does not play a major role in the genetic susceptibility to the development of SLE in the Malaysian population.
    Annals of Human Biology 12/2009; 37(2):274-80. DOI:10.3109/03014460903325185 · 1.15 Impact Factor
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    • "Tel: + 90 242 247 67 21/ + 90 505 530 51 55; Fax: + 90 242 227 44 90; E-mail: ender2504@gmail.com 1999; Ahmed et al ., 2001; Lee et al ., 2001; Hudson et al ., 2002; Barreto et al ., 2004; Fernandez-Blanco et al ., 2004 "
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    ABSTRACT: Cytotoxic T lymphocyte-associated antigen-4 is a cell-surface molecule providing a negative signal for T cell activation. CTLA-4 gene polymorphisms are known to be related with genetic susceptibility to various autoimmune diseases, including systemic lupus erythematosus (SLE). However, the effects of this polymorphism on clinical features of SLE have not been defined. We analysed the CTLA-4 gene +49 A/G polymorphisms in patients with SLE by using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and investigated the effect of polymorphisms on clinical outcomes. Blood was collected from 47 unrelated Turkish SLE patients, all fulfilling the American College of Rheumatology criteria for SLE, and 100 ethnically matched healthy volunteers. The AA genotype was a predominant genotype in the Turkish population and genotype frequencies of CTLA-4 AA were significantly higher in SLE patients (70%) than healthy controls (47%) (P = 0.015). There was a statistically significant difference in the AA genotype [odds ratio (OR): 2.66, confidence interval (CI) 95%: 1.27-5.56, P = 0.014] distribution among patients and controls. There was also an increase in A allele frequency in SLE and controls, but the difference was not statistically significant (81% vs. 70%, P = 0.068, OR = 1.8, CI 95%: 0.99-3.28). Interestingly, mean age and mean age of onset disease was higher in AA homozygote SLE patients compared to non-AA (39.2 +/- 11.5 vs. 31.6 +/- 10.6, P = 0.044; 32.38 vs. 24.31, P = 0.046, respectively). There was no association between genotype and the other clinical features of SLE. Our results suggested that CTLA-4 +49 AA genotype might be a risk factor for the development of SLE in Turkish population and G allele might be involved in early development of SLE. No association with clinical features was found for polymorphism of the promoter region in CTLA-4 +49.
    International Journal of Immunogenetics 09/2009; 36(4):245-50. DOI:10.1111/j.1744-313X.2009.00856.x · 1.34 Impact Factor
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