The Relationship Between CTLA-4 (-318 C/T) Polymorphism and Urothelial Cancer Carcinogenesis in Japanese Patients.

Background Urothelial cancer is one of the most common types of urinary system cancer and there are several factors that can influence its growth. One of the most prominent factors among these is genetics. The Cytotoxic T-Lymphocyte Antigen-4 (CTLA-4) gene is suspected to be a susceptibility gene in urothelial carcinoma. The aim of this study is to investigate polymorphism in the CTLA-4 gene (CTLA-4 -318 C/T) and whether it is associated with urothelial cancer. Methods The study population consisted of 253 cases and 272 controls. In this case-control study, DNA was extracted from peripheral blood cells, and the CTLA-4 -318C/T genotypes were detected using polymerase chain reaction-restriction fragment length polymorphism. Results C/T (adjusted OR (aOR) 3.37; 95%CI: 1.98-5.74) genotype, C/T + T/T (aOR 3.25; 95%CI: 1.96-5.39) genotype, and T allele (aOR 2.94 95%CI: 1.87-4.62) all indicated they are significant risk factors for urothelial cancer, with the effects of polymorphism being higher in the nonsmoker group than in the smoker group. Furthermore, the association between polymorphism and urothelial cancer carcinogenesis was similar among men and women. Conclusions This is the first study examining the association between CTLA-4 -318C/T polymorphism and urothelial carcinoma in Japanese patients. A significant association between CTLA-4 -318C/T polymorphism and urothelial cancer among Japanese patients was detected in this study. This supports the development of research on polymorphisms in urothelial cancer and is an important root of immunoreactions in cancer. We believe this study will be beneficial to clarify the relationship between CTLA-4 polymorphism and urothelial cancer.

Association of CTLA-4 and CD28 Gene Polymorphisms with Type 1 Diabetes in South Indian Population.

Each functional gene illustrates the complexity of genetic predisposition to disease; however, it is difficult to bring out these traits with reference to autoimmune diseases like type 1 diabetes (T1D). To find out the genetic contribution of CTLA-4 + 49A/G, CTLA-4 -318C/T and CD28 + 17T/C polymorphisms toward T1D, the present study was performed with 124 T1D patients, 54 siblings and 125 parents including 39 trios in South Indian population. The association and linkage of CTLA-4 + 49A/G, CTLA-4 -318C/T and CD28 + 17T/C polymorphisms with T1D were analyzed and transmission disequilibrium test was performed. CTLA-4 G allele carrying genotypes (GG+AG) showed a higher risk association and can be considered as susceptible to develop T1D among patients with age at diagnosis from 0 to 10 years as compared to siblings (OR = 2.9; pc = 0.047) and parents (OR = 2.7; pc = 0.036). On the other hand, a strong protection against the disease (age at diagnosis; 0-10 years) was observed with CTLA-4 + 49AA genotype (OR = 0.37; pc = 0.036) and combined AA/CC genotype (OR = 0.31; pc = 0.034) of CTLA-4 + 49A/G and CTLA-4 -318C/T polymorphisms. However, a significant association was not observed between CTLA-4 -318C/T and CD28 + 17T/C polymorphisms and T1D. This family-based study reports a strong association between possible genotypes of CTLA-4 gene polymorphism and T1D in South Indian population, particularly in younger individuals.

Correlations of CTLA-4 exon-1 49 A/G and promoter region 318C/T polymorphisms with the therapeutic efficacy of 131 I radionuclide in graves' disease in Chinese Han population.

Graves' disease is an autoimmune process in which the thyroid gland is triggered by autoantibodies, resulting in hyperthyroidism. The purpose of the present study is to elucidate whether exon-1 49 A/G and promoter region 318C/T polymorphisms in the CTLA-4 gene. This study consisted of 653 eligible patients with Graves' disease. After receiving 131I radionuclide therapy, these patients were classified into the remission and non-remission groups. A logistic regression-based model was used to analyze independent factors affecting the patient response to 131I radionuclide therapy. The results showed that CTLA-4 49 A/G was closely related to the efficacy of 131 I treatment for Graves' disease (AG + GG vs. AA: OR = 6.543, 95%CI = 2.611 ∼ 16.40, P < 0.001; G vs. A: OR = 3.482, 95%CI = 2.457 ∼ 4.934, P < 0.001). Moreover, the findings revealed that haplotype A-C (P < 0.001, OR = 3.592, 95%CI: 2.451 ∼ 5.262) and G-C (P < 0.001, OR = 0.282, 95%CI: 0.204 ∼ 0.391) were associated with the efficacy of 131 I therapy in treating Graves' disease. Logistic regression analysis indicated that thyroid weight (OR = 0.963, 95%CI = 0.944 ∼ 0.982, P < 0.001) and CTLA-4 exon-1 49 A/G polymorphism (OR = 0.334, 95%CI = 0.233 ∼ 0.478, P < 0.001) independently affect the efficacy of 131 I therapy in Graves' disease. These data indicated that CTLA-4 exon-1 49 A/G polymorphism may be associated with patient response to radionuclide 131 I therapy in Graves' disease.

Relationship between cytotoxic T-lymphocyte antigen 4 -318C/T (rs5742909) gene polymorphism and the risk of acute rejection in renal transplantation.

Results on the relationship between CTLA4 -318C/T (rs5742909) gene polymorphism and risk of acute rejection in renal transplantation are still conflicting. This meta-analysis was performed to update the association between CTLA4 -318C/T and risk of acute rejection in renal transplantation. The association investigations were identified from PubMed and Cochrane Library, and eligible studies were included and synthesized using meta-analysis method. Twelve reports were included in this meta-analysis for the association of CTLA4 -318C/T gene polymorphism with acute rejection risk in renal transplantation, consisting of 728 acute rejection patients and 1628 non-acute rejection controls. The association between CTLA4 -318C/T gene polymorphism and acute rejection risk in renal transplantation for overall populations was not found in this meta-analysis (T allele: OR=0.96, 95% CI: 0.60-1.54, P=.88; TT genotype: OR=0.90, 95% CI: 0.47-1.71, P=.74; CC genotype: OR=1.00, 95% CI: 0.62-1.59, P=.98). Interestingly, T allele was associated with the risk of acute rejection in renal transplantation in African population. In conclusion, CTLA4 -318C/T gene polymorphism is not associated with the risk of acute rejection in renal transplantation in overall populations.

CTLA-4 gene polymorphisms associate with efficacy of postoperative radioiodine-131 for differentiated thyroid carcinoma.

AIM: To investigate the association of CTLA-4 polymorphisms with efficacy of postoperative radioiodine-131 (I-131) treatment for differentiated thyroid carcinoma (DTC). METHODS: A total of 324 DTC patients and 350 healthy individuals were enrolled in our study. Patients received I-131 remnant ablation following surgical resection. Based on the treatment efficacy, patients were divided into the effective (n = 183) and ineffective groups (n = 141). CTLA-4 polymorphisms (+49A>G, CT60A>G and -318C>T) were genotyped by polymerase chain reaction-restriction fragment length polymorphism. RESULTS: AG + AA genotype distribution and A allele frequency of +49A>G and CT60A>G polymorphisms were higher in the effective group than the ineffective group. CONCLUSION: +49A>G and CT60A>G polymorphisms were associated with the efficacy of postoperative I-131 treatment for DTC; and they might be bioindicators related to the prognosis of I-131 treatment.

Association between 318C/T polymorphism of the CTLA-4 gene and systemic lupus erythematosus in Iranian patients.

BACKGROUND: Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) is an important negative regulator of T-cell response. It is a functional candidate gene connected with susceptibility to systemic lupus erythematosus (SLE). We analyzed the role of -318C/T polymorphism in the promoter region of the CTLA-4 gene in Iranian patients suffering from SLE. METHODS: A total of 180 SLE patients and 304 healthy ethnically matched controls were enrolled in the study. DNA was extracted from blood samples according to the standard procedure. Polymerase chain reaction restriction fragments length polymorphism (PCR-RFLP) was used to analyze the genotype and allele frequencies of these polymorphisms. RESULTS: The CC genotype was observed in 170 (94.5%) of the SLE patients, which was significantly different compared to the controls (251 [82.4%]; P = 0.0001, OR = 3.51 95%CI = 1.77-7.53). T allele was significantly more common in the controls (9.2%) compared to SLE patients 2.8% (P = 0.0001, OR = 0.26, 95%CI = 0.13-0.53). There was no significant correlation between different genotypes and age, gender or family history of SLE in the studied population. CONCLUSION: It can be concluded that -318C/T polymorphism of CTLA-4 gene might play a significant role in the development of SLE in the Iranian patients.

Association of CTLA4 and CD28 Gene Variants and Circulating Levels of Their Proteins in Patients with Breast Cancer.

BACKGROUND/AIM: Breast cancer is one of the most common and lethal types of cancer among women. We focused on the importance of the immune system in the etiology of breast cancer by investigating critical polymorphisms of cytotoxic T-lymphocyte-associated protein 4 (CTLA4) and cluster of differentiation 28 (CD28) gene, and circulating levels of these proteins. MATERIALS AND METHODS: A total of 79 patients with breast cancer and 76 healthy controls were enrolled. Molecular assessment of CTLA4 (rs231775&rs5742909) and CD28 (rs3116496) variants were determined with polymerase chain reaction restriction fragment length polymorphism techniques. Circulating levels of soluble forms of CTLA4 and CD28 were analyzed by ELISA. RESULTS: Although no significant association was found between study groups, CTLA4 +49AA genotypic frequency, and sCTLA4 and sCD28 levels were higher in patients. Some clinicopathological features were also related with CTLA4 and CD28 variants and blood levels. CONCLUSION: While CTLA4 +49AA genotype is increased in patients with breast cancer, the CTLA4 -318T allele may have a prognostic value. In addition, sCTLA4 and sCD28 can be used for diagnostic purposes in patients with breast cancer.

Association between CTLA-4 gene polymorphism and ankylosing spondylitis: a case-control study.

AIMS: The aim of our study was to evaluate the association between CTLA-4 polymorphisms (+49A/G, -318C/T and CT60A/G) and ankylosing spondylitis (AS) susceptibility. METHODS: A total of 120 AS cases and healthy controls, matched on the age and gender, were enrolled in the study. Polymerase chain reaction-restriction fragment length polymorphisms (PCR-RFLP) were used to determine the gentypes of +49A/G, -318C/T and CT60A/G polymorphisms. Genotype distribution in control group was assessed by Hardy Weinberg Equilibrium (HWE) test. Odds ratio (OR) with 95% confidence interval (95% CI) were adopted to evaluate the relationship of CTLA-4 polymorphisms and AS susceptibility. RESULTS: In our study, genotype distribution of the three polymorphisms in control group was consistent with the HWE (P > 0.05). The genotype analysis showed that AA genotype of + 49A/G polymorphism could increase the risk for AS (OR=2.357, 95% CI=1.127-4.930). Moreover, the frequency of A allele was also presented as a risk factor for AS. Additionally, AA genotype and A allele of CT60A/G appeared to be related with AS susceptibility (OR=2.610, 95% CI=1.047-6.510; OR=1.751, 95% CI=1.160-2.641). However, the T allele of -318C/T appeared to be a protective factor for AS (OR=0.383, 95% CI=0.228-0.643). CONCLUSION: In summary, there existed significant association between CTLA-4 gene polymorphisms and increased or decreased risk for AS.

The influence of CTLA-4 single nucleotide polymorphisms on acute kidney allograft rejection in Turkish patients.

Cytotoxic T-lymphocyte antigen-4 (CTLA-4) is a cell surface protein, which down-regulates the immune response at CTLA-4/CD28/B7 pathway. We aimed to investigate the influence of the -318 C/T, +49 A/G, -1661 A/G and CT60A/G, and CTLA-4 gene polymorphisms on acute rejection of kidney allograft in Turkish patients. The study design was a case-control study that consists of three groups: Group 1 (n = 34) represented the kidney transplant (Ktx) recipients who experienced acute rejection, Group 2 (n = 47) was randomly assigned Ktx recipients without acute rejection, and Group 3 (n = 50) consisting of healthy volunteers to evaluate the normal genomic distribution. The polymerase chain reaction-restriction fragment length polymorphism technique was used to determine the polymorphisms. Genotype and allele frequencies among three groups denoted similar distributions for +49 A/G, -1661 A/G, and CT60A/G. Conversely, -318 C/T genotype was three times more frequent in the acute rejection group than in the non-rejection group (OR = 3.45; 95%CI = 1.18-10.1, p = 0.015) and two times more frequent than the healthy control group (OR = 2.45; 95% CI = 0.98 - 6.11, p = 0.047). Additionally, having a T allele at -318 position was significantly associated with acute rejection (0.147 vs. 0.043, OR = 3.45; 95% CI = 1.13-10.56, p = 0.02). 318C/T gene polymorphism and T allelic variant were found to be associated with increased acute rejection risk in Turkish kidney allograft recipients.