CTLA-4 gene polymorphisms in systemic lupus erythematosus: a highly significant association with a determinant in the promoter region
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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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.07/2014; 4:20. DOI:10.1186/s12348-014-0020-1
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ABSTRACT: Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) is an important negative regulator of Tcell responses. The -1722TC polymorphism of the CTLA-4 gene may be associated with systemic lupus erythematosus (SLE) risk, but related results from previous studies have been inconsistent. We carried out a metaanalysis to assess this association more precisely. A systematic search through PubMed, Science Direct, and OVID, Iran doc, Iranmedex and SID (Scientific Information Database) databases was performed with the last search updated on December 30, 2011. The odds of ratio (OR) and its 95% confidence interval (95%CI) were used to assess the strength of the association. We evaluated both fixed and random effect models, depending on the presence of between-study heterogeneity. The analyses were conducted using STATA software, version 11.0. A total of 9 independent studies on the CTLA-4 gene -1722TC polymorphism and SLE, including 1422 cases and 1417 controls were used in this meta-analysis. In the present meta-analysis, we found a significant association between -1722TC polymorphism and SLE risk in the overall analysis (TT versus OR=1.18, 95%CI 0.84-1.66, p= 0.32; TT/TC versus CC: OR = 2.06, 95%CI 1.07-3.99, p= 0.03; TT versus CC: OR = 2.32, 95%CI 1.62-3.32, p< 0.001; TC versus CC: OR = 1.99, 95%CI 1.42-2.78, p<0.001; TT versus TC: OR = 1.2, 95%CI 0.86-1.66,p= 0.28; T versus C: OR = 1.22, 95%CI 0.91-1.64,p= 0.16). In the subgroup analysis by ethnicity, -1722TC polymorphism was significantly associated with SLE risk in Asian population. This meta-analysis suggests a significant association between -1722TC polymorphism and SLE susceptibility. Large-scale and well-designed case-control studies are necessary to validate the risk identified in the present meta-analysis.Medical journal of the Islamic Republic of Iran 01/2014; 28:132.