Cytotoxic T Lymphocyte-associated Antigen-4 Polymorphisms Research Articles

Correlation of CTLA-4 polymorphism and the risk of gastric cancer in a Chinese Bai population.

Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) is involved in the regulation of immune responses mediated by T cells. This study aimed to explore the correlation between CTLA-4 gene polymorphisms and the risk of gastric cancer (GC) in the Bai minority population of southwestern China. A total of 422 GC patients and 397 healthy controls (HC) were included in this case-control study. Four single nucleotide polymorphism sites of CTLA-4 gene (rs231775, rs733618, rs16840252 and rs3087243) were selected and analysed. The results showed a significant difference in the rs733618 loci between GC and HC groups. The frequency of the rs733618 polymorphism 'TC' genotype was significantly lower in GC group compared to the HC group [odds ratio (OR), 95% confidence interval (CI): .47 (.35-.63), p<.001]. GC cases with dominant genetic model 'TC+CC' had a 47% reduced risk of GC [OR, 95%CI: .53 (.40-.71), p<.001]. Subgroup analyses revealed that the rs733618 'TC+CC' genotype was associated with a lower risk of GC in male patients [OR, 95%CI: .42 (.31-.58), p<.001], those aged ≤60 years old [OR, 95%CI: .27 (.18-.42), p<.001], non-drinkers [OR, 95%CI: .21 (.13-.33), p<.001], non-smokers [OR, 95%CI: .38 (.25-.57), p<.001] and individuals without Helicobacter pylori infection [OR, 95%CI: .16 (.10-.26), p<.001]. Further multivariated analyses indicated that individuals with the 'TC+CC' rs733618 genotype who were aged ≤60 years old [OR, 95%CI: .42 (.29-.83), p=.032] and had no H. pylori infection [OR, 95%CI: .35 (.28-.76), p=.018] were found to have a protective effect against GC. Additionally, soluble CTLA-4 were significantly lower in GC patients with 'TC' and 'TC+CC' genotypes (all p<.05). Our findings suggest that the rs733618 polymorphism of CTLA-4 gene may play a critical role in the prevention of GC.

Reduced Number of Thymoma CTLA4-Positive Cells Is Associated With a Higher Probability of Developing Myasthenia Gravis.

Myasthenia gravis (MG) is an autoimmune disease associated with comorbid thymoma in 10%-15% of cases. Cytotoxic T lymphocyte-associated antigen 4 (CTLA4) expressed by T cells downregulates T-cell-mediated immune response. Polymorphisms in the CTLA4 gene have been associated with the development of MG. In this context, we aimed to determine whether CTLA4 expression in the thymoma differs between patients with and without MG and whether CTLA4 gene polymorphisms are associated with these differences. This is a retrospective study of all patients, with and without MG, surgically treated at our institution for thymoma between January 2010 and December 2020. Ten samples were obtained from normal thymuses as controls. The number of CTLA4-positive cells in paraffin-embedded thymoma samples was determined by immunohistochemistry. The presence of follicular-center and regulatory T-cell lymphocytes was determined by immunohistochemistry (B-cell lymphoma [BCL]-6 expression) and double immunofluorescence-based staining of CD4-FOXP3, respectively. We evaluated the association between thymic expression of CTLA4 and the development of MG. We also determined the association between CTLA4 expression and various clinical and prognostic characteristics of MG. We sequenced the CTLA4 gene and evaluated possible associations between CTLA4 polymorphisms and thymic CTLA4 expression. Finally, we assessed the potential association between these polymorphisms and the risk of MG. Forty-one patients with thymoma were included. Of them, 23 had comorbid MG (56.1%). On average, patients with MG had fewer CTLA4-positive cells in the thymoma than non-MG patients: 69.3 cells/mm2 (95% CIs: 39.6-99.1) vs 674.4 (276.0-1,024.0) cells/mm2; p = 0.001 and vs controls (200.74 [57.9-343.6] cells/mm2; p = 0.02). No between-group differences (MG vs non-MG) were observed in the number of cells positive for BCL6 or CD4-FOXP3. CTLA4 expression was not associated with differences in MG outcome or treatment refractoriness. Two polymorphisms were detected in the CTLA4 gene, rs231770 (n = 30 patients) and rs231775 (n = 17). MG was present in a similar proportion of patients for all genotypes. However, a nonsignificant trend toward a lower CTLA4-positive cell count was observed among carriers of the rs231775 polymorphism vs noncarriers: 77.9 cells/mm2 (95% CI: -51.5 to 207.5) vs 343.3 cells/mm2 (95% CI: 126.2-560.4). Reduced CTLA4 expression in thymoma may predispose to a higher risk of developing MG.

Association of CTLA-4 (+49A/G) polymorphism and susceptibility of developing rheumatoid arthritis in an Iraqi Arab population

BackgroundThe gene responsible for encoding the protein of cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) has been found to be associated with rheumatoid arthritis (RA) in different ethnic populations. But the association of +49A/G CTLA-4 polymorphism with susceptibility of RA among Iraqi Arab populations has not yet been determined. MethodsOne hundred and seventy-eight patients were examined, 67 of them were males (mean age 54.71 ± 10.4 years), while 167 were examined for the control group, of whom 64 were males and the rest were females. CTLA-4 DNA genotyping was carried on to determine the +49 A/G (rs231775) polymorphism using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Enzyme-linked immunosorbent assay (ELISA) was also applied here to measure the antibodies level for cyclic citrullinated peptides (anti-CCP) and Rheumatoid factor (RF). ResultsThe frequency of AG and GG genotypes in CTLA-4 + 49 were significantly higher among RA patients in comparing with controls (55.61% vs 42.51%, OR = 2.18, 95% CI = 1.62–3.79, P = 0.003) and (20.22% vs 10.77%, OR = 2.61, 95% CI = 1.31–6.46, P = 0.002) respectively. G allele frequency was also significantly higher among RA cases (52.24% vs. 31.73%, OR = 3.02; 95% CI = 1.61–7.39, P = 0.001). The frequencies of the AA genotype and A allele, however, were significantly lower in cases than controls (24.15% vs 46.70%, P = 0.001) and (47.75% vs 68.26%, P = 0.001) respectively. Moreover, the levels of Anti-CCP and RF were raised significantly among RA patients than controls (P = 0.0001), but none of these parameters were correlated with genotypes of CTLA-4. ConclusionsCarries of CTLA-4 + 49 AG and GG alleles were at a high risk of developing functional disability of RA, unlike the AA allele carriers.

Analysis of CTLA-4 -318C/T Polymorphism in Thalassemia Patients Transfused at the Casablanca Children's Hospital (Morocco)

Red blood cells (RBC) alloimmunization is a delayed adverse transfusion reaction in thalassemia patients. The mechanisms behind the inhibition or tolerance of red blood cells are still poorly understood. Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) molecule is expressed on Treg -lymphocyte membrane and is an inhibitory molecule which plays the mediator role of peripheral tolerance and maintains tolerance to self-antigens. Recent studies have reported that defect in the CTLA-4 gene expression could affect its function and be involved in the development of various pathologies as autoimmune diseases and the outcome after Allogenic hematopoietic stem cell transplantation; indeed, the objective of our study is the search for the association of the CTLA-4 polymorphism with the susceptibility to red blood cells alloimmunizations. In this study we looked for the polymorphism of the CTLA-4 gene at the -318 C/T position in 35 β-thalassemic patients (15alloimmunized and 20 non alloimunized) followed at the children's hospital in Casablanca, and 20 healthy controls, by PCR-RFLP and Sanger sequencing. In our cohort, none of the group cases revealed the mutation carried out by PCR RFLP. Indeed, this result was confirmed by Sanger sequencing. This study does not find an association of -318C/T SNPs in CTLA-4 gene and RBC alloimmunization among our cohort. Following these preliminary results, an investigation of the other exons of the CTLA-4 gene on a large cohort is necessary to complete this study.

CTLA-4 polymorphisms and predisposition to digestive system malignancies: a meta-analysis of 31 published studies

BackgroundThe results of genetic association studies regarding cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) polymorphisms and digestive system malignancies were controversial. The authors designed this meta-analysis to more precisely estimate relationships between CTLA-4 polymorphisms and digestive system malignancies by pooling the results of related studies.MethodsThe authors searched PubMed, Embase, Web of Science, and CNKI for eligible studies. Thirty-one eligible studies were pooled analyzed in this meta-analysis.ResultsThe pooled meta-analysis results showed that genetic distributions of rs231775, rs4553808, and rs733618 polymorphisms among patients with digestive system malignancies and controls differed significantly. Moreover, genotypic distribution differences were also observed for rs231775 polymorphism among patients with colorectal cancer/pancreatic cancer and controls, for rs4553808 and rs5742909 polymorphisms among patients with gastric cancer and controls, for rs3087243 polymorphism among patients with liver cancer and controls, and for rs733618 polymorphism among patients with colorectal cancer and controls in pooled meta-analyses.ConclusionsThis meta-analysis suggested that rs231775 polymorphism was associated with predisposition to colorectal cancer and pancreatic cancer, rs4553808 and rs5742909 polymorphisms were associated with predisposition to gastric cancer, rs3087243 polymorphism was associated with predisposition to liver cancer, and rs733618 polymorphism was associated with predisposition to colorectal cancer.

Estimation of associations between 10 common gene polymorphisms and gastric cancer: evidence from a meta-analysis

AimsAssociations between polymorphisms in cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4)/mannose-binding lectin (MBL)/interleukin-4 (IL-4)/interleukin-6 (IL-6)/phospholipase C ε−1 (PLCE1) and gastric cancer (GC) were already reported by many studies, yet the conclusions of...

PDCD1 and PDCD1LG1 polymorphisms affect the susceptibility to multiple myeloma.

Single-nucleotide polymorphisms (SNPs) of the programmed cell death protein-1 (PDCD1), programmed cell death protein-1 ligand-1 (PDCD1LG1), and cytotoxic T lymphocyte-associated antigen-4 (CTLA4) genes are implicated in the pathogenesis of some cancers. We investigated the role of PDCD1, PDCD1LG1, and CTLA4 SNPs in MM pathogenesis and the susceptibility to and clinical features of multiple myeloma (MM). We obtained genomic DNA from 124 patients with MM and 211 healthy controls and detected PDCD1 (rs36084323, rs41386349, and rs2227982), PDCD1LG1 (rs2297136 and rs4143815), and CTLA4 (rs733618, rs11571316, rs231775, and rs3087243) genotypes using the polymerase chain reaction-restriction fragment length polymorphism method or the TaqMan allelic discrimination real-time PCR method. The patients with MM had a significantly higher frequency of the PDCD1 GCC/GCC haplotype (rs36084323/rs41386349/rs2227982) compared with the healthy controls. PDCD1 rs2227982 CC genotype was associated significantly with a higher frequency of bone lesions. Patients with PDCD1LG1 rs2297136 TT and TC types (high-expression types) showed lower albumin level than those with CC genotype. In addition, the PDCD1LG1 rs4143815 CC and CG types (high-expression types) were associated significantly with higher frequency of patients who were treated with thalidomide and/or bortezomib. However, there was no statistical significance between CTLA4 polymorphisms and clinical variables of patients with MM. There were no significant differences between all the polymorphisms and OS. Our study indicates that the PDCD1 haplotype is associated with a susceptibility to MM. The PDCD1 rs2227982 and PDCD1LG1 rs2297136 affect the clinical features of multiple myeloma patients.

Relationship of genetic polymorphisms in CTLA-4 and IL-18 with viral hepatitis: evidence from a meta-analysis.

Relationship of genetic polymorphisms in cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and interleukin-18 (IL-18) with susceptibility to viral hepatitis was already investigated by many association studies. The aim of this study was to more comprehensively analyse associations between genetic polymorphisms in CTLA-4/IL-18 and viral hepatitis by combing the results of all relevant association studies. We searched Pubmed, Embase, Web of Science and CNKI for eligible studies. We used Review Manager to combine the results of eligible studies. Thirty-seven studies were finally included in this meta-analysis. Combined results demonstrated that CTLA-4 rs231775 (recessive comparison: OR 1.31, 95% CI 1.11-1.55), IL-18 rs1946518 (dominant comparison: OR 0.82, 95% CI 0.75-0.90; recessive comparison: OR 1.29, 95% CI 1.11-1.50; allele comparison: OR 0.76, 95% CI 0.68-0.86) and IL-18 rs187238 (dominant comparison: OR 1.25, 95% CI 1.03-1.52; allele comparison: OR 1.20, 95% CI 1.05-1.37) polymorphisms were all significantly associated with viral hepatitis in the general population. Further subgroup analyses revealed that CTLA-4 rs231775, IL-18 rs1946518 and IL-18 rs187238 polymorphisms were significantly associated with susceptibility to hepatitis B virus (HBV), especially among East Asians. Moreover, CTLA-4 rs5742909, IL-18 rs1946518 and IL-18 rs187238 polymorphisms were also significantly associated with susceptibility to hepatitis C virus (HCV), especially among South Asians. So to conclude, this meta-analysis demonstrated that CTLA-4 rs231775, IL-18 rs1946518 and IL-18 rs187238 polymorphisms may confer susceptibility to HBV in East Asians, while CTLA-4 rs5742909, IL-18 rs1946518 and IL-18 rs187238 polymorphisms may confer susceptibility to HCV in South Asians.

PTPN22 and CTLA-4 Polymorphisms Are Associated With Polyglandular Autoimmunity.

Single nucleotide polymorphisms (SNPs) of various genes increase susceptibility to monoglandular autoimmunity. Data on autoimmune polyglandular syndromes (APSs) are scarce. Evaluate potential associations of eight SNPs with APSs. Academic referral endocrine clinic. A total of 543 patients with APS and monoglandular autoimmunity and controls. The SNP protein tyrosine phosphatase nonreceptor type 22 (PTPN22) rs2476601 (+1858); cytotoxic T-lymphocyte‒associated antigen 4 (CTLA-4) rs3087243 (CT60) and rs231775 (AG49); vitamin D receptor (VDR) rs1544410 (Bsm I), rs7975232 (Apa I), rs731236 (Taq I); tumor necrosis factor α rs1800630 (-863); and interleukin-2 receptor alpha rs10795791 were tested by single-base extension in all subjects. The PTPN22 +1858 allele and genotype distribution were markedly different between APS, type 1 diabetes [T1D; odds ratio (OR): 2.67; 95% confidence interval (CI): 1.52 to 4.68; P = 0.001], Graves disease (GD; OR: 1.94; 95% CI: 1.16 to 3.25; P = 0.011), and controls (OR: 3.31, 95% CI: 1.82 to 6.02; P < 0.001). T-allele carriers' risk for APS was increased (OR: 3.76; 95% CI: 1.97 to 7.14; P < 0.001). T-allele frequency was higher among APS than controls (OR: 3.25; 95% CI: 1.82 to 5.82; P < 0.001), T1D (OR: 2.54; 95% CI: 1.48 to 4.36; P = 0.001), or GD (OR: 1.89; 95% CI: 1.15 to 3.11; P = 0.012). The SNP CTLA-4 CT60 G-allele carriers were more frequent in APS (85%) than controls (78%) (OR: 1.55; 95% CI: 0.81 to 2.99). Combined analysis of CTLA-4 AG49 and CT60 revealed OR 4.89; 95% CI: 1.86 to13.59; P = 0.00018 of the genotype combination AG/GG for APS vs controls. VDR polymorphisms Bsm I, Apa I, and Taq I did not, but the haplotypes differed between APS and controls (P = 0.0011). PTPN22 and CTLA-4 polymorphisms are associated with APS and differentiate between polyglandular and monoglandular autoimmunity.

CTLA-4 Polymorphisms in Patients with IgA Nephropathy Correlate with Proteinuria

Background/Aims: IgA nephropathy (IgAN) is the most common form of primary glomerulonephritis and still constitutes one of the most important causes of end-stage renal disease. Abnormal T cell responses may play a role in IgAN pathogenesis. Co-stimulatory molecules such as cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) are important for naive T cells to initiate and terminate immune responses. Single nucleotide polymorphisms (SNPs) in the CTLA4 gene locus are associated with several autoimmune diseases. Methods: We aimed to investigate the occurrence of the SNPs -318C/T, +49A/G and CT60 G/A within the CTLA4 locus in healthy blood donors (n=455) and IgAN patients (n=252) recruited from the recently published STOP-IgAN trial. The presence of these SNPs was then associated with baseline proteinuria in IgAN patients. Results: We observed a significantly increased frequency of the CTLA4 -318C/T genotype in IgAN patients as compared to controls (CC vs. CT+TT: OR 1.65, 95%-CI 1.03-2.65, p=0.035). No significant associations, neither with the +49A/G nor for the CT60 G/A SNP, were detected. However, when we stratified for proteinuria at time of inclusion into the STOP-IgAN trial (<1 g/day vs. >1 g/day), we observed significant differences in the frequencies of the CT60 G/A genotype, i.e. a significantly increased risk for higher proteinuria in patients carrying the G allele (OR 2.81, 95%-CI 1.03-7.64, p=0.042). Conclusion: The CTLA4 -318/C/T SNP was associated with an increased risk to develop IgAN, while the CT60 G/A genotype significantly associated with the risk for higher proteinuria suggesting a possible role for CTLA-4 in IgAN.

Distribution of Cytotoxic T Lymphocyte-Associated Antigen-4 Promoter Polymorphisms in Taiwanese Patients with Type 2 Diabetes Mellitus.

Type 2 diabetes mellitus (T2DM) is associated with chronic inflammation, suggesting the metabolic abnormalities are originated from or exacerbated by cytokine overproduction. Cytokines and counter-regulatory molecules are crucial in keeping the balance of immune responses and, therefore, are potential candidates involved in T2DM etiology, development and complications. Our previous reports identify several significant associations between the genotypes of cytokine genes and T2DM and/or the clinical lipid parameters, which strongly suggest the participation of immune-regulatory molecules in lipid metabolism. The aim of this study is to determine the distribution of gene encoding cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), a T-cell negative regulator, in T2DM patients and health subjects. Genomic DNA was extracted from 287 Taiwanese T2DM patients and 278 ethnic- and age- matched healthy subjects, and two CTLA-4 polymorphisms (-318 C/T and +49 A/G) were analyzed by polymerase chain reaction-restriction fragment length polymorphism. Intriguingly, CTLA-4 -318 genotype was associated with circulatory triglycerides in T2DM subjects (P=0.019) although no significant association between CTLA-4 -318 (P=0.119) and +49 (P=0.2) genotypes with T2DM was identified. In addition, CTLA-4 +49 genotype was significantly associated with the ratio between total cholesterol and high-density lipoprotein (P=0.004) in control subjects. Our results suggest that CTLA-4 may be involved in lipid metabolism and affect T2DM disease progression and/or the development of diabetic complications although this gene does not represent a major risk factor for T2DM.

&amp;lt;i&amp;gt;CTLA-4&amp;lt;/i&amp;gt; Gene Polymorphism in Women with Idiopathic Recurrent Pregnancy Loss

Cytotoxic T lymphocyte associated antigen-4 (CTLA-4) is considered as a negative regulator of T cell activation and its role in maintaining immune tolerance is well established. The present case-control study aimed to investigate the CTLA-4 +49 A/G, -1661 A/G, -318 C/T and -1722 T/C single nucleotide polymorphisms (SNPs) and predisposition to recurrent pregnancy loss (RPL) in Gaza Strip - Palestine. The study was performed on 200 women with a history of two or more pregnancy losses (case group) and 200 control women with at least two live births and without any previous history of abortion. PCR-based restriction fragment length polymorphism (RFLP-PCR) method was used for genotyping CTLA-4 polymorphisms. Study results revealed that there is no significant association between the allele/genotype frequencies of the four investigated CTLA-4 SNPs and RPL. This trend remained true under dominant, co-dominant and recessive models. The A\G genotype of -1661 A\G polymorphism was higher in patients (45%) as compared to controls (39.5%) but without statistical significance. The minor allele frequencies (MAFs) of the CTLA-4 gene polymorphisms in the patient/control group were as follows: +49A>G: 0.22/0.22, -318 C>T: 0.15/0.11, -1661 A>G: 0.30/0.26 and -1722 T>C: 0.08/0.08. The four investigated CTLA-4 polymorphisms do not contribute to the risk of RPL in the study population. Testing other CTLA-4 gene polymorphisms and the level of CTLA-4 expression in RPL patients is recommended.

The association between CTLA-4 (+49 A/G) polymorphism and susceptibility to ankylosing spondylitis: a meta-analysis.

The objective of the present meta-analysis was to investigate whether or not cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) polymorphisms are associated with ankylosing spondylitis (AS) susceptibility. A systematic search was conducted from the PubMed, ENBASE, and Springer link database up to April 2014. Odds ratios (ORs) with 95% confidence intervals (95% CIs) were used to assess the strength of association between CTLA-4 (+49 A/G) and AS risk. A subgroup analysis based on geographic region and a sensitivity analysis were also conducted. Five studies were eligible for meta-analysis, including 918 cases and 845 controls. The results showed that no significant association was found between AS and CTLA-4 (+49 A/G) for the additive model (G vs. A), dominant model (GG+AG vs. AA), co-dominant model (GG vs. AA, AG vs. AA) and recessive model (GG vs. AG+AA). The OR was 1.09 (95% CI, 0.87-1.38), 1.16 (95% CI, 0.89-1.51), 1.05 (95% CI, 0.75-1.46), 1.15 (95% CI, 0.86-1.52) and 0.99 (95% CI, 0.79-1.23), respectively. Although subgroup analysis demonstrated no association between CTLA-4 (+49 A/G) polymorphisms and susceptibility to AS in Europe and Taiwan, an association was found in Iran through both the co-dominant and dominant models. Exclusion of any individual study did not alter the significance of the final outcome, excepting the result by omitting the study by Huang etal. The present results suggest that the CTLA-4 may not be a major susceptibility locus in humans with AS. The relationship between them may be affected by different geographic populations.

HCV F protein amplifies the predictions of IL-28B and CTLA-4 polymorphisms about the susceptibility and outcomes of HCV infection in Southeast China

Cytotoxic T lymphocyte associated antigen-4(CTLA-4) is an inhibitory receptor with great value in the progression of hepatitis C virus (HCV) infection related diseases. To determine the potential associations of IL-28B rs12979860 and CTLA-4 rs231775, rs3087243 and rs5742909 polymorphisms with the generation of HCV F protein, susceptibility and outcomes of HCV infection, a total of 375 healthy controls, 219 HCV spontaneous recovered patients and 600 chronic HCV patients from Southeast China were recruited and genotyped in this study. And the relative mRNA levels of CTLA-4 in T cells were detected. Logistic regression analysis showed that rs231775 A allele was associated with significantly higher rate of spontaneous viral clearance in anti-HCV F antibody negative patients (adjusted OR=0.512, P=0.008), but allele A was related to higher mRNA level of CTLA-4 with the generation of HCV F protein. And rs5742909 T allele added up to the risk of HCV infection chronicity significantly in patients with the presence of HCV F protein (adjusted OR=2.698, P=0.003). Also, the rs5742909 CC genotype, along with the presence of HCV F protein, indicated a significantly higher CTLA-4 level than that in anti-HCV F antibody negative patients. The AG+AA genotype of rs3087243 significantly increased the susceptibility to HCV infection in subjects over 56years old (adjusted OR=1.595, P=0.011). Genotype–genotype interaction between IL-28B rs12979860 and CTLA-4 rs3087243 was found to be significantly associated with increased susceptibility to HCV infection (adjusted OR=1.509, P=0.005). Haplotype analysis in CTLA-4 also showed significant association with the generation of HCV F protein. All these results indicated the importance of IL-28B and CTLA-4 polymorphisms and their associations with HCV F protein in the risk and chronicity of HCV infection in Chinese Han population in Southeast China.

CTLA-4 polymorphisms and susceptibility to inflammatory bowel disease: A meta-analysis

ObjectiveThe aim of this study was to explore whether the cytotoxic T lymphocyte associated antigen-4 (CTLA-4) polymorphisms are associated with susceptibility to ulcerative colitis (UC) and Crohn’s disease (CD). MethodsThe authors conducted a meta-analysis on associations between CTLA-4 +49 A/G, −318 C/T, CT60 A/G polymorphisms, and (AT)n repeat in the 3′ untranslated region (UTR) and UC and CD susceptibility. ResultsA total of 15 comparison studies were considered in our meta-analysis. Meta-analysis revealed no association between UC and the CTLA-4 +49 G and CTLA-4 −318 T alleles in all subjects (OR=0.982, 95% CI=0.851–1.1339, p=0.804; OR=0.500, 95% CI=0.223–1.124, p=0.094). No association was found between UC and the CTLA-4 CT60 A/G polymorphism in Europeans. However, a significant association was observed between the longer allele (⩾118bp) of the (AT)n and UC in Asian population (OR=6.073, 95% CI=4.246–8.684, p=1.0×10−9). Meta-analysis of the CTLA-4 +49 A/G, −318 C/T, CT60 A/G polymorphisms showed no association with CD. ConclusionsThis meta-analysis demonstrates that the CTLA-4 (AT)n repeat in 3′ UTR may be associated with susceptibility to UC in Asians, while no association was found between the CTLA-4 +49 A/G, −318 C/T, and CD60 A/G polymorphism and susceptibility to UC and CD.

CTLA-4 polymorphisms (+49 A/G and -318 C/T) are important genetic determinants of AITD susceptibility and predisposition to high levels of thyroid autoantibodies in Polish children - preliminary study.

Autoimmune thyroid diseases (AITDs), including Hashimoto' s thyroiditis (HT) and Graves' disease (GD), are related to environmental and genetic factors. We analyzed the association of cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) gene two polymorphisms (+49 A/G, -318 C/T) with HT and GD development in Polish children, and correlated both polymorphisms with the production of thyroid autoantibodies (TPOAb and TgAb). The study involved 49 AITD patients (age 10-19) with HT (n=25) or GD (n=24) and 69 healthy controls. SNP genotyping was performed using genomic DNA and TaqMan® probes. The obtained results indicated that CTLA-4 +49 GG genotype was significantly more frequent in both HT and GD patients, whereas the AA genotype was more common in controls. CTLA-4-318 CT genotype was significantly more frequent in AITD, and the CC genotype more often occurred in controls. Significantly higher median TPOAb and TgAb values were associated with G allele in HT, and with T allele in GD patients. Concluding, both studied polymorphisms seem to be important genetic determinants of the risk of HT and GD, and appear to be associated with a predisposition to high levels of TAbs and clinical AITD. The obtained results give more information on the distribution of the CTLA-4 polymorphism in Polish AITD children, and further support the proposal that the CTLA-4 gene plays an important role in a TAb production.

The association between cytotoxic T lymphocyte-associated antigen-4 and cervical cancer

Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) gene polymorphisms have been associated with many autoimmune diseases and malignancy susceptibility, but the relationship between CTLA-4 and cervical cancer is still controversial. Hence, a meta-analysis of the published studies for the CTLA-4 gene polymorphisms and the risk of cervical cancer was performed to evaluate the association between them. Odds ratios (ORs) and 95% confidence intervals (CIs) for the codominant, dominant, and recessive genetic models were assessed. The fixed or random effect pooled measure was selected on the basis of the heterogeneity test among studies. The heterogeneity among studies was evaluated using the I (2). Eight studies with 2,835 cases and 2,560 controls were included. In seven studies for the CTLA-4 +49A/G polymorphism, a significant association was showed between the A allele and the increased risk of cervical cancer in the codominant (OR 1.16, 95% CI 1.05-1.29), dominant (OR 1.18, 95% CI 1.03-1.36), and recessive (OR 1.24, 95% CI 1.05-1.56) models. In five studies for the CTLA-4 -318C/T polymorphism, the meta-analysis showed a significant association of the C allele with the reduced risk of cervical cancer in the codominant (OR 0.79, 95% CI 0.66-0.94) and recessive (OR 0.76, 95% CI 0.63-0.93) models. This meta-analysis suggested that +49A/G and -318C/T polymorphisms of the CTLA-4 gene were significantly associated with the risk of cervical cancer. However, further studies are required to draw a solid conclusion on the relation between the CTLA-4 polymorphism and the risk of cervical cancer.

The CTLA4 +49A/G polymorphism is associated with an increased risk of Hashimoto’s thyroiditis in Asian but not Caucasian populations: an updated meta-analysis

The polymorphism +49A/G in the cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) gene has been implicated in susceptibility to Hashimoto's thyroiditis (HT), but the findings are not clear-cut. This study aimed to investigate the association between CTLA-4 polymorphisms and HT risk using an updated meta-analysis. A meta-analysis was carried out of 14 previous studies that investigated the CTLA-4 +49A/G polymorphism and HT risk. +49A/G was associated with a significantly increased HT risk in both allele analysis and all genetic models (allele analysis: G vs. A: P < 0.001, OR = 1.379, 95 % CI = 1.244-1.529). Subgroup analysis by ethnicity showed a significantly increased HT risk with the G allele and all other genetic models in the Asian subgroup (P < 0.001). In the Caucasian subgroup, no significant association was detected between the CTLA-4 +49 G allele and HT, or in the genetic model analysis (P = 0.05). This gene-based analysis indicates that the cumulative effect of the +49A/G polymorphism in CTLA-4 is associated with HT in Asians, but appears to have no effect on HT in Caucasians.

No evidence of association betweenCTLA-4polymorphisms and systemic lupus erythematosus in Iranian patients

Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) is an important negative regulator of T-cell responses. CTLA-4 polymorphisms have been confirmed to be associated with several autoimmune diseases such as systemic lupus erythematosus (SLE). We analyzed the role of CTLA-4 polymorphism at positions -1661 and -1722 in Iranian patients suffering from SLE. One hundred and eighty SLE patients and 304 ethnically and age-matched healthy controls were studied. Polymerase chain reaction restriction fragments length polymorphism (PCR-RFLP) was used to analyze the genotype and allele frequencies of these polymorphisms. There was no significant association between the studied genotypic and allelic frequencies between SLE patients and the controls. Although the TC genotype in 1722TC polymorphism was more common among the control group, the correlation was not statistically significant. Our results suggest that the -1661AG and -1722TC polymorphisms in the promoter region of the CTLA-4 gene does not play any role in genetic susceptibility to SLE. However, further studies on larger sample sizes are needed to approve our results.

Lack of association between CTLA-4 and PDCD1 polymorphisms and acute rejection in German liver transplant recipients

Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed cell-death 1 (PDCD1) are two genes encoding coinhibitory immunoreceptors that are involved in regulation transplant rejection and tolerance induction. Thus, CTLA-4 and PDCD1 may be good candidate genes to evaluate in liver transplant rejection. In this retrospective study, we investigated whether four functional single nucleotide polymorphisms (SNP) of the CTLA-4 gene and PDCD1 gene were associated with susceptibility to liver transplant rejection. The SNPs -1772T>C (rs733618), -1661A>G (rs4553808) of the CTLA-4 gene, and the SNPs 7146G>A (rs11568821), 7209C>T (rs41386349) of the PDCD1 gene were genotyped by polymerase chain reaction allele specific restriction enzyme analysis (PCR-ASRA) in 100 liver recipients with acute rejection, 104 liver transplant recipients without acute rejection and 100 healthy control individuals. For the selected SNPs we did not detect any significant difference in genotypic and allelic frequencies between liver transplant recipients with and without acute rejection. In conclusion, our results suggest that the tested SNPs may not be associated with susceptibility to acute liver transplant rejection in a Caucasian population.