Table 1 - uploaded by João Faro Viana
Content may be subject to copyright.
Allele frequencies, w 2 test and OR for the alleles and genotypes at the exon 1 SNP and 3 0 UTR microsatelite markers of CTLA4
Source publication
Several lines of evidence implicate the Cytotoxic T Lymphocyte Antigen 4 (CTLA4) gene in susceptibility to autoimmune disease. We have examined the association of systemic lupus erythematosus (SLE) with polymorhisms within the CTLA4 gene that were previously proposed to regulate CTLA-4 function: a single nucleotide polymorphism (SNP) in position +4...
Contexts in source publication
Context 1
... results obtained in the case -control association study of the CTLA4 3 0 UTR microsatelite marker with SLE, involving a total of 125 SLE patients and 185 healthy controls, are presented in Table 1. A total of 21 alleles and 46 different genotypes were found for this marker, many of which are very rare. ...
Context 2
... with a frequency lower than 1% were grouped for the analysis. A significant overall association of the CTLA4 3 0 UTR microsatelite marker with SLE was found (w 2 ¼ 24.190, P ¼ 0.001), with a particular allele of 106 bp showing a protective effect (w 2 ¼ 17.310, Po0.001) and another of 104 bp increasing susceptibility to SLE (w 2 ¼ 4.636, P ¼ 0.031) ( Table 1). The OR for each of the alleles confirms the protection conferred by the 106 bp allele (OR ¼ 0.28, 95% CI ¼ 0.15 -0.53). ...
Context 3
... that SLE affects primarily women, the male:female ratio is not equal in the case and control samples. Matching for sex did not change the overall association (w 2 ¼ 21.247, P ¼ 0.003) (Table 1). We confirmed the association of the 106 bp protective allele (w 2 ¼ 12.716, Po0.001; OR ¼ 0.27, 95% CI ¼ 0.055 -0.13) and of the 88/ 106 genotype (w 2 ¼ 15.206, Po0.001; OR ¼ 0.14, 95% CI ¼ 0.050 -0.39). ...
Context 4
... confirmed the association of the 106 bp protective allele (w 2 ¼ 12.716, Po0.001; OR ¼ 0.27, 95% CI ¼ 0.055 -0.13) and of the 88/ 106 genotype (w 2 ¼ 15.206, Po0.001; OR ¼ 0.14, 95% CI ¼ 0.050 -0.39). In this matched sample, we find that allele 104 and genotype 88/104 are more frequent among patients, although the difference in frequencies among patients and controls is not significant, likely due to loss of power given the much lower number of controls used in this analysis (Table 1). ...
Context 5
... and genotype distributions of the þ 49 exon 1 SNP did not differ significantly between patients and healthy control subjects (Table 1), even after matching the popula- tion for sex (data not shown). These results corroborate four previous reports of no association of this SNP with SLE, 9 -12 although three other studies did find evidence for association. 13 -15 Given the conflicting results obtained in these case -control studies that have examined the associa- tion between SLE and the CTLA4 exon 1 SNP, and because this polymorphism is thought to regulate the levels of membrane-bound CTLA4, we have performed a meta- analysis to clarify the involvement of this SNP in the etiology of SLE. ...
Citations
... There have been numerous studies linking polymorphisms in the CTLA-4 gene to autoimmune disorders such as diabetes mellitus type 1, Graves' disease, Hashimoto thyroiditis, and lupus [11][12][13][14], as well as the risk of developing cancer [15]. The link between multiple gene polymorphisms and polygenetic disorders such as diabetes, obesity, and various cancers is gaining traction [16] T cells and Natural Killer Cells (NK cells) play an important role in the fight against cancer [17]. ...
... The severity and disease progression of RA are governed by multiple factors including immune, genetic and environmental factors (1,2) . Multiple components of immunity and inflammation play a role in the onset and progression of the disease, including T and B lymphocytes, neutrophils, monocytes and the vascular endothelium. ...
Rheumatoid Arthritis (RA) is a chronic, destructive inflammatory poly-articular joint and systemic autoimmune disease. It typically results in warm, swollen, and painful joints, and stiffness often worsens followed by rest. The aim of treatment is to mitigate pain, contain inflammation and improve a person's overall day to day functioning. Despite tremendous development in synthetic drugs during recent years, the side effect still persists and hence is a matter of concern to develop less toxic drugs in the disease progress. It was thought, Rasa Mezhugu is one of the higher order herbo-mineral formulations in the Siddha System of medicine. Acute and Sub-Acute Toxicity studies confirmed the safety even at the higher dosage of 5000 mg/kg body weight. Also, Physico Chemical and other heavy metal analyses showed that the trial drug does not possess heavy metals at a hazardous level to harm the animals. 90-days-old Wistar male rats were used for the purpose and divided into four groups. They were treated with Saline, Palm Jaggary, Rasa Mezhugu and Indomethacin. Body weight, biochemical and hematological analysis were analyzed to evaluate the anti-arthritic effect. Rasa Mezhugu was found to significantly reduce the Arthritis effect induced by Complete Freund's Adjuvant (CFA)-induced arthritic rat.
... [4,6] Various single nucleotide polymorphisms (SNPs) in the CTLA4 gene have been implicated in susceptibility to autoimmune disorders including Graves disease, [7,8] type 1 diabetes mellitus, [9] celiac disease, [10][11][12] Addison's disease, [13] autoimmune thyroid disease, [14][15][16] rheumatoid arthritis [17] and SLE. [18,19] Mutations in CTLA4 have been found to be associated with extensive infiltration of CD4 T cells in various organs. [20] The important and fine function of CTLA-4 in inducing immune modulatory and hemostatic signals in the ongoing immune response poised this molecule under evolutionary pressure to go in the process of the point mutation in CTLA4 and polymorphism within the population and along the species. ...
... Therefore, this report indicated results contrary to those of previous sporadic publications with inconsistent results, demonstrating a clearly strong association of the CTLA4 gene at position +49A/G with SLE, particularly in Asian and with a lesser degree in the European population. [18,19] Another meta analysis published later again contradicted previous reports and concluded no association between the risk of SLE and CTLA polymorphism. [31] A previous study from India itself reported that CTLA4 +49 A/G polymorphism is a potential genetic risk factor for lupus susceptibility in South Indian Tamils. ...
Background:
Cytotoxic T lymphocyte-associated protein-4 (CTLA-4) or CD152 is an inhibitory receptor expressed constitutively on CD4+CD25+ T regulatory lymphocytes (Treg) and transiently on activated CD4+ and CD8+ T lymphocytes. Association of CTLA4 gene polymorphisms with Systemic Lupus Erythematosus (SLE) has been reported in south Indians, but not in north Indians. This study aims to investigate CTLA4 gene polymorphism and its association with the occurrence of SLE, its clinical manifestation and serological markers in north Indians.
Methods:
This cross sectional study was done in a tertiary health care centre in north India. Patients reporting to the hospital and diagnosed with systemic lupus erythematosus were included in study. +49 A/G (snp- rs231775) CTLA4 gene polymorphism was analysed in 41 SLE patients and 21 matched healthy controls by real time PCR method. ANA (Antinuclear Antibody), anti dsDNA, Interferon-γ (IFN- γ), TGF-β, IL-10 were measured by ELISA kits. Complement (C3 and C4) and immunoglobulins (IgA, IgG, IgM) estimation were done with the turbidometry method. Chi-square test was used for comparison between groups and odds ratio with 95% confidence interval was calculated to estimate the associated risk.
Results:
A/A genotype was most common (51.2%) followed by the A/G genotype (46.3%) and G/G genotype (2.4%, detected in only 1 patient). The frequency of A allele was 74.4%, while of G allele was only 25.6%. A/G genotype SLE patients showed a higher risk (odds ratio 37.5, 95% CI- 6.048-232.51) of developing edema compared to A/A genotype patients. There was no statistically significant association of various CTLA4 genotypes with the occurrence of SLE and serum markers.
Conclusions:
A/A was the most common CTLA4 genotype in both SLE patients and healthy controls of north India. Contrary to the previous report in south Indians, there was no statistically significant association between CTLA4 genotype and occurrence of SLE in north Indians. Only the presence of generalised edema was found significantly associated with the A/G genotype.
... contribute to autoimmune response (Ueda et al. 2003;Atabani et al. 2005). Previous studies have also indicated associations between CTLA-4 and multiple autoimmune diseases, such as T1DM (Westra et al. 2018), systemic lupus erythematosus (Barreto et al. 2004), and rheumatoid arthritis (Lee et al. 2003). The rs231775 polymorphism located in exon 1 of CTLA-4 and led to substitution of alanine with threonine. ...
Polymorphisms rs231775 and rs3087243 of cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) gene have been associated with risk of latent autoimmune diabetes in adults (LADA). However, the results were inconsistent. The purpose of this study was to quantitatively assess the relationship between polymorphisms rs231775 and rs3087243 of CTLA-4 and LADA in a larger pooled population by performing a meta-analysis. Systematic search for eligible studies was conducted in PubMed, Web of Science, and Embase. Case–control studies containing genotype frequencies of polymorphisms rs231775 or rs3087243 were selected, and pooled odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the associations between polymorphisms of CTLA-4 and LADA in allelic, dominant and recessive genetic model. A total of eleven studies, in which five studies reported rs231775, two studies reported rs3087342, and four studies reported both rs231775 and rs3087243, were identified. Among them, one study wasn’t included in the following meta-analysis because the distribution of genotypes in the control group didn’t comply with Hardy–Weinberg equilibrium. Significant associations with susceptibility to LADA were detected for rs231775 (785 cases and 3435 controls) and for rs3087243 (820 cases and 4824 controls) in overall population. Further subgroup analyses for ethnicity (Asian, Caucasian, and African) have also indicated the positive association between rs231775 and LADA. As for rs3087243, subgroup analyses detected the association between polymorphism and LADA in Caucasian population under recessive model. Polymorphisms rs231775 and rs3087243 of CTLA-4 gene are potential risk factors for LADA and may serve as novel genetic biomarkers of LADA.
... Genetic polymorphisms of the CTLA4 gene are associated with multiple autoimmune diseases including SLE. The CTLA4 rs231775 has been linked to SLE susceptibility in Asian populations (Iranian, Indian, and Japanese) (Barreto et al. 2004;Kailashiya et al. 2019;Lee et al. 2005). A haplotype of CTLA4 has also been linked to DLE (Järvinen et al. 2010). ...
Lupus erythematosus (LE) is a heterogeneous disease with a wide range of manifestations ranging from localized lesions in cutaneous lupus erythematosus (CLE) to severe disseminated disease in systemic lupus erythematosus (SLE).Lupus results from a complex interaction between genetic and epigenetic backgrounds and environmental triggers that cause loss of tolerance to self-antigens and the formation of autoantibodies. Genetic susceptibility plays a key role in the pathogenesis of lupus erythematosus. In most cases, multiple common alleles with modest effect sizes are combined to result in the polygenic inheritance of the disease but monogenic variants of lupus have also been described. Genes from the innate and adaptive immune system along with genes involved in apoptosis and immunoglobulin clearance have been linked to SLE. This chapter aims to explore the functions of these genes and their contribution to the pathogenesis of the disease.
... There have been numerous studies linking polymorphisms in the CTLA-4 gene to autoimmune disorders such as diabetes mellitus type 1, Graves' disease, Hashimoto thyroiditis, and lupus [11][12][13][14], as well as the risk of developing cancer [15]. The link between multiple gene polymorphisms and polygenetic disorders such as diabetes, obesity, and various cancers is gaining traction [16] T cells and Natural Killer Cells (NK cells) play an important role in the fight against cancer [17]. ...
... Indeed, an association between CTLA4 polymorphisms and lupus has been found in numerous studies worldwide. 45,46 In addition, in agreement with our results, increased CTLA4 expression has been shown in T cells from patients with SLE. 47 Similar to our work, another study demonstrated that regardless of the dramatically increased CTLA4 expression in T responder cells from patients with SLE compared with healthy controls, its ability to regulate lupus T-cell signaling and proliferation was impaired. ...
Introduction:
Elevated levels of interleukin 17A (IL-17A) have been found in systemic lupus erythematosus (SLE). Forkhead box protein P3 (FOXP3) activates T-regulation lymphocytes and is a master regulator cell function. The cytotoxic T-lymphocyte-associated protein 4 (CTLA4) gene plays a similar role. We investigated the role of these expressions in SLE patients with/without nephritis.
Methods:
The present study was a case-controlled study including 49 patients with SLE and 26 healthy controls. The genes expression of IL-17A, FOXP3, and CTLA4 were measured by quantitative Real-Time PCR. The relation between lupus nephritis and disease activity with IL-17A, FOXP3, and CTLA4 genes expression was evaluated.
Results:
IL-17A, FOXP3, and CTLA4 expressions in T-cells were significantly higher in SLE patients than controls (P < .0001). When comparing the nephritis group and no nephritis group to the control group individually, the expression of mentioned genes is also higher (P < .05). There was no significant difference regarding IL-17A, FOXP3, and CTLA4 genes expression in the nephritis group and no nephritis group (P > .05). But there was a low expression of FOXP3 and IL-17A in patients with the higher stage of nephritis (P < .05).
Conclusion:
Our findings elevated IL-17A, FOXP3, and CTLA4 expressions significantly contribute to SLE pathophysiology. This study provides new insight into the function of IL-17A, FOXP3, and CTLA4 in disease setting. The heterogeneity of SLE patients is reflected in the multiple abnormalities found in the immune system. Finding such variations can provide targets for better manipulation of the immune system.
... This is an important finding, since CTLA-4 (CD152) is an inhibitory cell-surface molecule that plays an important role in the promotion of anergy, immune regulation, and the prevention of autoimmunity. Abnormal function and susceptibility of CTLA-4 gene expression has been reported in SLE patients (50,51). Further, it was demonstrated that CTLA-4 modulates regulatory and follicular helper T cells, thus controlling humoral immunity (52)(53)(54). ...
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with widespread inflammation, immune dysregulation, and is associated with the generation of destructive anti-DNA autoantibodies. We have shown previously the immune modulatory properties of pCons peptide in the induction of both CD4⁺ and CD8⁺ regulatory T cells which can in turn suppress development of the autoimmune disease in (NZB/NZW) F1 (BWF1) mice, an established model of lupus. In the present study, we add novel protein information and further demonstrate the molecular and cellular phenotypes of pCons-induced CD4⁺ and CD8⁺ Treg subsets. Flow cytometry analyses revealed that pCons induced CD8⁺ Treg cells with the following cell surface molecules: CD25highCD28high and low subsets (shown earlier), CD62Lhigh, CD122low, PD1low, CTLA4low, CCR7low and 41BBhigh. Quantitative real-time PCR (qRT-PCR) gene expression analyses revealed that pCons-induced CD8⁺ Treg cells downregulated the following several genes: Regulator of G protein signaling (RGS2), RGS16, RGS17, BAX, GPT2, PDE3b, GADD45β and programmed cell death 1 (PD1). Further, we confirmed the down regulation of these genes by Western blot analyses at the protein level. To our translational significance, we showed herein that pCons significantly increased the percentage of CD8⁺FoxP3⁺ T cells and further increased the mean fluorescence intensity (MFI) of FoxP3 when healthy peripheral blood mononuclear cells (PBMCs) are treated with pCons (10 μg/ml, for 24-48 hours). In addition, we found that pCons reduced apoptosis in CD4⁺ and CD8⁺ T cells and B220⁺ B cells of BWF1 lupus mice. These data suggest that pCons stimulates cellular, immunological, and molecular changes in regulatory T cells which in turn protect against SLE autoimmunity.
... Therefore, dysfunction of CTLA-4 can increase self-reactivity of T lymphocyte and may contribute to autoimmune response (19,36). Previous studies have also indicated associations between CTLA-4 and multiple autoimmune diseases, such as T1DM (37), systemic lupus erythematosus (38), and rheumatoid arthritis (39). The rs231775 polymorphism located in exon 1 of CTLA-4 and led to substitution of alanine with threonine. ...
Background
Polymorphisms rs231775 and rs3087243 of cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) gene have been associated with risk of latent autoimmune diabetes in adults (LADA). However, the results were inconsistent. The purpose of this study was to quantitatively assess the relationship between polymorphisms rs231775 and rs3087243 of CTLA-4 and LADA in a larger pooled population by performing a meta-analysis. Methods
Systematic search for eligible studies was conducted in PubMed, Web of Science, and Embase. Case-control studies containing genotype frequencies of polymorphisms rs231775 or rs3087243 of CTLA-4 gene were selected, and pooled odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the associations between polymorphisms of CTLA-4 and LADA in allelic genetic model, dominant genetic model, and recessive genetic model. ResultsA total of eleven studies, in which five studies reported rs231775, two studies reported rs3087342, and four studies reported both rs231775 and rs3087243, were identified. Among them, one study wasn’t included in the following meta-analysis because the distribution of genotypes in the control group didn’t comply with Hardy-Weinberg equilibrium. Significant associations with susceptibility to LADA were detected for rs231775 (785 cases and 3435 controls, allelic genetic model OR 1.53, 95%CI 1.22-1.92; dominant genetic model OR 2.16, 95%CI 1.43-3.28; recessive genetic model OR 1.49, 95%CI 1.13-1.97) and for rs3087243 (820 cases and 4824 controls, allelic genetic model OR 1.26, 95%CI 1.03-1.55; dominant genetic model OR 1.11, 95%CI 0.88-1.40; recessive genetic model OR 1.41, 95%CI 1.07-1.86) in overall population. Further subgroup analyses for ethnicity (Asian, Caucasian, and African) have also indicated the positive association between rs231775 and LADA. As for rs3087243, subgroup analyses detected the association between polymorphism and LADA in Caucasian population under recessive model. Conclusions
Polymorphisms rs231775 and rs3087243 of CTLA-4 gene are potential risk factors for LADA and may serve as novel genetic biomarkers of LADA.
... 49 The relevance of the CTLA gene in the susceptibility to SLE is supported by evidence from different human populations with different polymorphisms. [50][51][52] Interestingly, SLE patients display increased expression of CTLA in isolated responder T cells (Foxp3 − ) compared to healthy controls and patients with other autoimmune rheumatic diseases (RA or psoriatic arthritis). 53 However, these T cells exhibit defective inhibition of T cell activation by CTLA-4 after CD3/CD28 costimulation. ...
In the last decade, approaches based on T cells and their immunomodulatory receptors have emerged as a solid improvement in treatments for various types of cancer. However, the roles of these molecules in the therapeutic context of autoimmune and cardiovascular diseases are still relatively unexplored. Here, we review the best known and most commonly used immunomodulatory T cell receptors in clinical practice (PD-1 and CTLA-4), along with the rest of the receptors with known functions in animal models, which have great potential as modulators in human pathologies in the medium term. Among these other receptors is the receptor CD69, which has recently been described to be expressed in mouse and human T cells in autoimmune and cardiovascular diseases and cancer. However, inhibition of these receptors individually or in combination by drugs or monoclonal antibodies generates a loss of immunological tolerance and can trigger multiple autoimmune disorders in different organs and immune-related adverse effects. In the coming decades, knowledge on the functions of different immunomodulatory receptors will be pivotal for the development of new and better therapies with less harmful side effects. In this review, we discuss the roles of these receptors in the control of immunity from a perspective focused on therapeutic potential in not only cancer but also autoimmune diseases, such as systemic lupus erythematosus, autoimmune diabetes and rheumatoid arthritis, and cardiovascular diseases, such as atherosclerosis, acute myocardial infarction, and myocarditis.
