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: 4.82). 11/2002; 111(4-5):452-5. DOI: 10.1007/s00439-002-0807-2
Source: PubMed


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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    • "Cytotoxic T-lymphocyte antigen 4 (CTLA-4) gene is located on chromosome 2q33 and is expressed in activated T cells and inhibits T cell activation by CD28 [[44]]. Over 100 single-nucleotide polymorphisms (SNPs) have been identified in CTLA-4 gene regions, and some of these SNPs were found to be related to immune-mediated diseases including type 1 diabetes mellitus [[45]], multiple sclerosis [[46]], systemic lupus erythematosus (SLE) [[47]], rheumatoid arthritis [[48],[49]], Hashimoto's thyroiditis, and Graves' disease [[45]]. However, some of the studies showed conflicting results in the association of CTLA-4 gene polymorphisms and autoimmune diseases [[50]-[52]]. "
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    ABSTRACT: Vogt-Koyanagi-Harada (VKH) disease is a systemic autoimmune disorder against melanocytes. Recent studies have identified multiple genetic factors that might be associated with the pathogenesis of VKH disease. We performed an electronic database search of PubMed, MEDLINE, and EMBASE, and all relevant papers published up to 13 June 2014 were reviewed. A total of 1,031 publications including articles relevant to the genetics of VKH disease and the references of these articles were reviewed. The review identified a number of genetic factors which might be involved in the pathogenesis of VKH disease, some of which may alter the clinical course of VKH disease. Genes which might be involved in the pathogenesis of VKH disease included genes expressing HLA, complement factor H, interleukins, cytotoxic T-lymphocyte antigen 4 (CTLA-4), killer cell immunoglobulin-like receptors (KIR), programmed cell death 1 (PDCD1), protein tyrosine phosphatase non-receptor 22 (PTPN22), osteopontin, tumor necrosis factor alpha-induced protein 3 (TNFAIP3), macrophage migration inhibitory factor (MIF), and other immune response genes. Further studies to explore the correlation among different genotypes and phenotypes of VKH disease will be useful to shed light on the pathogenesis of uveitis in VKH disease and may facilitate the development of new treatment modalities of uveitis in VKH disease.
    Journal of Ophthalmic Inflammation and Infection 07/2014; 4(1):20. DOI:10.1186/s12348-014-0020-1
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    • "Polymorphisms in CTLA-4 influence the expression, transcription and translation of CTLA-4 and therefore affect its function. Particular polymorphisms such as SNPs in position +49, +106 and -1722 have been reported to influence the susceptibility to autoimmune diseases as Graves' disease, autoimmune hypothyroidism, multiple sclerosis and systemic lupus erythematosus 16, 19, 30, 31. And high incidence of CTLA-4 AA(CT60) polymorphism has been observed in renal cell cancer 32. "
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    ABSTRACT: Objective: Single-nucleotide polymorphisms (SNPs) in Cytotoxic T lymphocyte antigen 4 (CTLA-4) gene have been detected and proved to associate with the incidence of rejection after transplantation. However, previous studies gained inconsistent results about the association between CTLA-4 +49 single-nucleotide polymorphism and susceptibility of allograft rejection. Therefore we sought to clarify whether CTLA-4 +49 SNP influences the incidence of acute rejection after liver transplantation in Chinese population. Methods: Genomic DNA from 335 liver transplant recipients was genotyped for CTLA-4 +49 SNP by DNA sequencing. Acute rejection was confirmed by pathologic evidences. The association between CTLA-4 +49 SNP and incidence of acute rejection was then analyzed by dominant, recessive, codominant and overdominant models. Results: The incidence of acute rejection within the first 3 months was 11.9%. In acute rejectors, the frequency was 45% for G/G, 10% for A/A and 45% for A/G respectively, compared with 47.5% for G/G, 10.8% for A/A and 41.7% for A/G in non-acute rejectors. And no significant difference of allele distribution between these 2 groups was detected. Conclusions: This study suggests that CTLA-4 +49 SNP is not associated with acute rejection after liver transplantation in Chinese population.
    International journal of medical sciences 01/2013; 10(3):250-254. DOI:10.7150/ijms.5511 · 2.00 Impact Factor
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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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