Cytotoxic T-lymphocyte Antigen-4 Gene Polymorphisms Research Articles

Evidence of Association between CTLA-4 Gene Polymorphisms and Colorectal Cancers in Saudi Patients.

Cytotoxic T lymphocyte antigen-4 (CTLA-4) has been identified as an immunosuppressive molecule involved in the negative regulation of T cells. It is highly expressed in several types of autoimmune diseases and cancers including colorectal cancer (CRC). (1) Objective: To explore the association between CTLA-4 single nucleotide polymorphisms (SNP) and risk to (CRC) in the Saudi population. (2) Methods: In this case-control study, 100 patients with CRC and 100 matched healthy controls were genotyped for three CTLA-4 SNPs: rs11571317 (-658C > T), rs231775 (+49A > G) and rs3087243 (CT60 G > A), using TaqMan assay method. Associations were evaluated using odds ratios (ORs) and 95% confidence intervals (95% CIs) for five inheritance models (co-dominant, dominant, recessive, over-dominant and log-additive). Furthermore, CTLA-4 expression levels were evaluated using quantitative real-time PCR (Q-RT-PCR) in colon cancer and adjacent colon tissues. (3) Results: Our result showed a significant association of the G allele (OR = 2.337, p < 0.0001) and GG genotype of the missense SNP +49A > G with increased risk of developing CRC in codominant (OR = 8.93, p < 0.0001) and recessive (OR = 16.32, p < 0.0001) models. Inversely, the AG genotype was significantly associated with decreased risk to CRC in the codominant model (OR = 0.23, p < 0.0001). In addition, the CT60 G > A polymorphism exhibited a strong association with a high risk of developing CRC for the AA genotype in codominant (OR = 3.323, p = 0.0053) and in allele models (OR = 1.816, p = 0.005). No significant association was found between -658C > T and CRC. The haplotype analysis showed that the G-A-G haplotype of the rs11571317, rs231775 and rs3087243 was associated with high risk for CRC (OR = 57.66; p < 0.001). The CTLA-4 mRNA gene expression was found significantly higher in tumors compared to normal adjacent colon samples (p < 0.001). (4) Conclusions: Our findings support an association between the CTLA-4 rs231775 (+49A > G) and rs3087243 (CT60 G > A) polymorphisms and CRC risk in the Saudi population. Further validation in a larger cohort size is needed prior to utilizing these SNPs as a potential screening marker in the Saudi population.

Association of Cytotoxic T-Lymphocyte Antigen-4 Gene Polymorphism with Type 1 Diabetes Mellitus: In silico Analysis of Biological Features of CTLA-4 Protein on Ethiopian Population.

BackgroundT1DM is a chronic organ-specific T-cell-mediated autoimmune disease characterized by the selective destruction of β-cells in the islets of Langerhans, resulting in insulin deficiency and hyperglycemia. Genes for cytotoxic T lymphocyte-associated antigen 4 have been hypothesized as possible contender genes for T1DM vulnerability. However, it has not been studied in the Ethiopian population yet.ObjectiveThe aim of the study was to investigate CTLA-4 exon 1 was linked to A49G polymorphism with T1DM and its biological features of CTLA-4 among T1DM patients, in Ethiopia.MethodsA case–control study was done from December 2019 to March 2020 on 210 study participants (105 T1DM patients and 105 healthy controls). Polymerase Chain Reaction amplification with forward and reverse primers was followed by restriction fragment length polymorphism and gel electrophoresis to determine gene polymorphism. Bioinformatics data of SNP was retrieved from National Centers for Biotechnology Information databases. The chi-square test and logistic regression were used. Statistical significance was defined as a P-value of less than 0.05.ResultsThe CTLA-4 (+A49G) gene polymorphism was observed on 56 (26.7%) study participants, 39 (18.57%) of T1DM patients, and 17 (0.08%) were controls. In T1DM and controls, the frequency of the A allele was 73.3% and 89.5%, while the G allele was 26.7% and 10.5%, respectively. The G allele was found to be associated with T1DM (OR=3.1; 95% CI, 1.82 −5.32; P=0.001). Statistical analysis revealed an association between the likelihood of T1DM and GG genotype of the CTLA-4 (+A49G) gene polymorphism (OR=3.11; 95% CI, 1.37–10.90; P=0.01). Further in silico analyzed the SNP to assess its biological features.ConclusionThe study showed as CTLA-4 (+A49G) gene polymorphism is linked with T1DM in the Ethiopian population.

Association of CTLA-4 (+49 A/G) polymorphism with susceptibility to autoimmune diseases: A meta-analysis with trial sequential analysis

ObjectivesIn recent years, more and more studies have been focusing on the association between Cytotoxic T lymphocyte antigen-4 (CTLA-4) (+49 A/G) gene polymorphism and autoimmune diseases. However, the results of previous studies are still controversial. The meta-analysis is aiming at determining the association in CTLA-4 (+49 A/G) gene rs231775 polymorphism and ankylosing spondylitis (AS), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE). MethodsWe searched PubMed, Web of Science, Chinese National Knowledge Infrastructure (CNKI) and Chinese Biomedical Database (CBM) up to November 2020, use random or fixed-effect models to perform meta-analysis to compare alleles and other genetic models, including homozygous, heterozygous, recessive and dominant models. The odds ratio (OR) with a 95% confidence interval (95% CI) was used to assess the correlation between CTLA-4 (+49 A/G) gene polymorphism and the genetic affectability of AS, RA, and SLE. Meanwhile, we used sequential trial analysis (TSA) to analyze the reliability of the results. Finally, we searched the relevant data of genome-wide association studies (GWAS) to further verify the accuracy of the experimental results. Results47 studies with 11,893 cases and 12,032 healthy controls were included. The rs231775 G allele was relevant to high risk of autoimmune disease over all people (P < 0.05). The G allele of rs231775 was significantly related to RA susceptibility (P < 0.05), but not with AS or SLE. Subgroup analysis by ethnicity indicated that rs231775 G allele was closely related to RA in Caucasian populations and Mongolian populations (P < 0.05). A strong connection within rs231775 G allele and AS affectability was uncovered in Caucasian populations (P < 0.05). The analysis of the TSA shows that the meta-analysis can draw the conclusion. ConclusionCTLA-4 (+49 A/G) gene rs231775 G allele increases the risk of autoimmune diseases in Caucasian populations. And it also increases the risk of RA in Caucasian and Mongolian populations. More sample size and more elaborately designed studies are needed to elucidate the relationship in CTLA-4 (+49 A/G) gene rs231775 G allele and autoimmune diseases, especially AS, SLE.

Cytotoxic T-lymphocyte Antigen-4 (CTLA-4) Gene Polymorphism (rs3087243) Is Related to Risk and Survival in Patients With Colorectal Cancer.

Cytotoxic T-lymphocyte antigen-4 (CTLA-4), transiently expressed on T cells, plays a pivotal role in the negative feedback regulation of T-cell activation and proliferation. The aim of the present study was to examine the influence of CTLA-4 gene polymorphism rs3087243 on CRC susceptibility and long-term survival in Swedish patients with CRC. Genotypes of 491 patients and 433 healthy controls were determined, using TaqMan single nucleotide polymorphism (SNP) assays based on polymerase chain reaction. Patients carrying allele A were found to be at a higher risk of CRC and this allele was found to be more common in patients with disseminated disease compared to localized disease in the right colon. Kaplan-Meier analysis of cancer-specific survival showed that carriers of allele A had the highest risk of CRC-related death. The SNP rs3087243 of the CTLA-4 gene was associated with CRC risk and, therefore, it could be a prognostic marker for Swedish patients with CRC.

Determination the CTLA-4 and PTPN22 Gene Polymorphism in Graves’ Disease Patients

Graves’ disease (GD) is a multifactorial autoimmune disease with contribution from both genetic andepigenetic factors in its causation. Gene “protein tyrosine phosphatase non receptor 22” (PTPN22) is animportant immune regulatory gene preventing hyper responsiveness of T cells by negatively regulatingtheir signal transduction. Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) gene polymorphisms belong to themain genetic factors determining the susceptibility to development Graves’ disease. This study aimed toanalyze whether 1858 C/T SNP in PTPN22 and 1822 C/T SNP in CLTA-4 genes have any association withGD in Iraqi population. PCR-RFLP was performed for genotyping 1858 C/T SNP and 1822 C/T SNP withinPTPN22 and CLTA-4 respectively, in patients with GD and healthy controls. Among the patients with GD,the frequencies CLTA-4 CC, CT, and TT genotypes were 43.3%, 45%, and 11.6%, respectively, whereas inhealthy controls the frequencies of CC, CT genotypes were 60%, 30%, and 10%, respectively. While thereis no mutation recorded in PTPN22 1858 C/T SNP in both PCR-RFLP and DNA sequence analysis. Theseresults indicated that there is no significant association was found between PTPN22 1858 C/T SNP andCLTA-4 in patients with GD. It has been concluded that GD is not associated with PTPN22 1858 C/T SNPand 1822 C/T SNP of CLTA-4 in Iraqi population.

Identification of +49A/G polymorphism of cytotoxic T lymphocyte-associated protein-4 gene in type 1 diabetes patients in Kerbala province/Iraq

BackgroundType 1 diabetes mellitus (T1DM) is an insulin-dependent form of diabetes associated with progressively increasing morbidity and mortality across the globe. Cytotoxic T lymphocyte antigen-4 (CTLA-4) encoded by the CTLA-4 gene on chromosome 2q33 has an important role in homeostasis and negative regulation of immune responses. Therefore, CTLA-4 gene polymorphisms are considered to be a key element in the development of T1DM. Aim of the studyThe study aimed to elucidate the contribution of cytotoxic T-lymphocyte antigen-4 (+49 A/G) polymorphism of CTLA-4 gene to the susceptibility T1DM. MethodsA present case-control study was designed to include 120 Iraqi children with T1DM and 120 healthy children as a control group. The patients were diagnosed previously with T1DM by Al-Imam Al-Hassan center for endocrine and diabetes in Al-Imam Al-Hussein medical city in holy Kerbala province.Genotyping CTLA-4 (+49A/G) gene was performed using tetra-primer amplification refractory mutation system-polymerase chain reaction technique (T-ARMS-PCR). ResultsRisk factors of T1DM (Family history of diabetes mellitus, age at onset, gender) were found to be an independent risk factor for T1DM P value >0.05.The AG genotype significantly raised the risk of T1DM by more than six folds (OR = 6.7, 95% CI; 3.63–12.29, P < 0.05). While the G allele significantly raised the risk of T1DM by more than two folds (OR = 2.8, 95% CI; 1.88–4.15, P < 0.05). In addition to the GG genotype also was significantly (OR = 7.76, CI 95% = 2.16–27.88, P < 0.05) changed among the two groups. ConclusionOur case-control study suggests that the CTLA-4 (+49A/G) gene polymorphism is associated with T1DM in the Kerbala children.

The Association between (CT60) Cytotoxic T-lymphocyte Antigen-4 Gene Polymorphism with its Plasma Levels in Alpecia Areata Patients

The Association between (CT60) Cytotoxic T-lymphocyte Antigen-4 Gene Polymorphism with its Plasma Levels in Alpecia Areata Patients

Association of Cytotoxic T Lymphocyte Antigen-4 Gene Polymorphisms with Psoriasis Vulgaris: A Case-Control Study in Turkish Population.

Psoriasis is a common, chronic, and autoimmune skin disease in which dysregulation of immune cells, particularly T cells, is thought to play an important role in the pathogenesis. Cytotoxic T lymphocyte antigen-4 (CTLA-4) expressed only on activated T cells is an immunoregulatory molecule and plays a role in the pathogenesis of autoimmune disorders. We aimed to determine whether CTLA-4 gene polymorphisms are associated with development and/or clinical features of psoriasis vulgaris (Pv). Genotyping of SNPs (−318C>T, +49A>G, and CT60A>G) in CTLA-4 gene was performed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in 103 Pv patients and 102 controls. No statistically significant associations were detected in any of the investigated genetic models for the −318C>T polymorphism. The genotype distributions of +49A>G and CT60A>G were associated with Pv development. In haplotype analysis, while frequency of CAA haplotype was significantly higher in the control group, frequencies of CGG and CAG haplotype were significantly higher among the patients. However, all of CTLA-4 polymorphisms and haplotypes do not have an effect on severity and onset age of Pv. In conclusion, the +49A>G and CT60A>G polymorphisms may be risk factors for Pv development. Furthermore, CGG and CAG haplotypes may contribute to Pv development, while CAA haplotype may be protective against Pv.

Association Between Cytotoxic T-Lymphocyte Antigen 4 Gene Polymorphisms and Torque Teno Virus Infection After Hematopoietic Stem Cell Transplantation.

An association between costimulatory molecule gene polymorphisms and viral infection after hematopoietic stem cell transplantation may be related to clinical outcomes, especially acute graft-versus-host disease. Cytotoxic T-lymphocyte antigen 4 has been suggested as a crucial negative regulator of the immune system. In this study, our objective was to investigate the association between cytotoxic T-lymphocyte antigen-4 gene polymorphisms (including -1722 T/C, -1661 A/G, -318 C/T, and +49 A/G) and torque teno virus infection after hematopoietic stem cell transplantation in patients with and without acute graft-versus-host disease. Our study included 71 recipients. We evaluated cytotoxic T-lymphocyte antigen 4 gene polymorphisms using the polymerase chain reaction-restriction fragment length polymorphism method. Our results showed that the GG genotype of the cytotoxic T-lymphocyte antigen 4 +49 A/G was significantly more frequent in transplanted patients infected with torque teno virus, whereas the AG genotype was more common in transplanted patients who did not have this infection. In addition, the -1661 AA and GA genotypes and -318 TC genotypes were significantly more frequent in transplanted patients infected with the virus and who had low-grade (grades I and II) acute graft-versus-host disease. Among those with grade I graft-versus-host disease, the GG genotype of the cytotoxic T-lymphocyte antigen 4+49 A/G was more frequent in transplanted patients with torque teno virus infection, whereas the AG genotype was higher in transplanted patients who did not have this infection. This is the first report indicating that cytotoxic T-lymphocyte antigen 4 gene polymorphism may be implicated in prevalence of torque teno virus infection after stem cell transplant. Further larger studies and evaluation of other costimulatory molecules are suggested.

Association of CTLA-4 gene polymorphisms -318C/T and +49A/G and Hashimoto's thyroidits in Zahedan, Iran.

Hashimoto's thyroiditis (HT) is a chronic inflammation of the thyroid gland and is known as the most common autoimmune disease. Development of autoimmune destruction of thyroid cells is a multi-step process involving convergence of genetic and environmental factors. Cytotoxic T-lymphocyte antigen-4 (CTLA-4) has an important role in homeostasis and negative regulation of immune responses, and is therefore considered to be a key element in the development of autoimmune diseases. The present study evaluated the association of the CTLA-4 gene polymorphisms 318C/T (rs5742909) and +49A/G (rs231775) with HT in an Iranian population (including 82 patients with HT and 104 healthy controls who were referred for routine premarital blood screenings). Genotyping was performed using the tetra-primer amplification refractory mutation system polymerase chain reaction technique. No significant differences were observed in genotype and allele frequencies in the single nucleotide polymorphisms (SNPs) between cases and controls. In the cases as well as in the controls, the TT genotype in the -318C/T polymorphism was absent and the predominant genotype was CC, while the predominant genotype for the +49A/G SNP was AA. As only few studies in this field have assessed Iranian and even Middle Eastern populations, additional studies with a higher number of samples are recommended to further assess the impact of -318C/T (rs5742909) and +49A/G (rs231775) polymorphisms of CTLA-4 on HT.

Lack of association between cytotoxic T-lymphocyte antigen-4 gene polymorphisms and lymphoid malignancy risk: evidence from a meta-analysis.

Cytotoxic T-lymphocyte antigen-4 (CTLA-4) polymorphisms have been associated with susceptibility to lymphoid malignancies. However, results from the published single studies are inconsistent. Therefore, the present meta-analysis was conducted to get a more accurate estimation of the relationship between CTLA-4 gene polymorphisms and the lymphoid malignancy risk. We identified nine independent studies accounting for 3090 subjects up to January 30, 2016. Summary odds ratios (OR) and 95% confidence intervals (CI) were used to evaluate the risk of lymphoid malignancies. Overall, no significant association was found between +49A/G (rs231775), -318C/T (rs5742909), and +6230A/G (rs3087243) CTLA-4 gene polymorphisms and lymphoid malignancies. Furthermore, ethnicity (Asian and Caucasian) and histopathology subgroup analyses (non-Hodgkin's lymphoma) also failed to detect an association between the studied polymorphisms and lymphoid malignancy risk. Our study shows that common CTLA-4 gene polymorphisms may not contribute to lymphoid malignancy susceptibility based on the current evidence.

Association of CTLA-4 (+49A/G) gene polymorphism with type 1 diabetes mellitus in Egyptian children

Objective The aim of the study was to investigate the distribution of cytotoxic T-lymphocyte antigen-4 (CTLA-4) (+49A/G) gene variants and its association with type 1 diabetes (T1D) in Egyptian children. Background T1D is a complex autoimmune disease characterized by T-cell-mediated destruction of the pancreatic island. Human leukocyte antigen (HLAs) account for about 60% of genetic susceptibility for the disease. About 20 non-HLA loci contributing to disease susceptibility have been identified. One among these is the CTLA-4 gene. CTLA-4 polymorphisms are associated with T1D in some but not all populations. The aim of our study was to investigate the frequency of CTLA-4 49A/G polymorphism in Egyptian children, and its susceptibility for development of T1D. Materials and methods A case-control study was conducted on 40 Egyptian children with T1D diagnosed according to ADA (2010). Their ages ranged from 1 to 16 years, with a mean of 8.76 ± 4.70 years; 15 were male and 25 were female. In addition, 20 age and sex-matched healthy controls were included. CTLA-4 (+49A/G) gene polymorphism typing was done by PCR amplification, followed by restriction fragment length polymorphism. Results The frequency of CTLA-4 polymorphisms (AA, AG, and GG) in T1D patients was 42.5, 52.5, and 5% versus 60, 40, and 0% in controls, respectively, with predominance of the AG variant in diabetic patients. Distributions of the CTLA-4 gene polymorphism on the basis of sex showed a normal pattern. The AA genotype was present in 64.7% of female diabetic patients versus 35.3% of male patients, whereas the heterozygous AG genotype was seen in 57.1% of female patients versus 42.9% of male patients, and the homozygous GG genotype was present in two female patients (5%) and was not recognized in male patients; the female predominance can be explained by steroid hormone association. Conclusion In this study the overall pooled prevalence of the CTLA4 (+49A/G) polymorphism was recognized but still not a risk susceptibility factor for T1D in Egyptian children.

Association of polymorphisms -319 C/T and +49 A/G of CTLA-4 gene with Chronic Hepatitis C virus Infection in Mexican population

Association of polymorphisms -319 C/T and +49 A/G of CTLA-4 gene with Chronic Hepatitis C virus Infection in Mexican population

Comprehensive evaluation of the cytotoxic T-lymphocyte antigen-4 gene polymorphisms in risk of bone sarcoma.

Cytotoxic T-lymphocyte antigen-4 (CTLA-4) is a critical immunoregulatory molecule that attenuates the antitumor response by elevating the T-cell activation threshold, thus inducing occurrence of cancer. Several studies have reported the associations of CTLA-4 polymorphisms and bone sarcoma, but the findings remain to be further verified due to incomplete and limited evidence. The purpose of this study was to reevaluate the associations via a comprehensive meta-analysis. We searched Embase, Web of Knowledge, and PubMed and identified a total of four case-control studies fulfilling the inclusion criteria. Meta-analysis was conducted in all subjects without further stratified analyses. The associations were estimated by odds ratio (OR) along with 95% confidence interval (CI). Analysis showed a significant association for the +49G>A polymorphism. This association was more pronounced in the homozygous model (OR=1.85; 95% CI: 1.40, 2.46; p=0.998 for heterogeneity) and the recessive model (OR=1.85; 95% CI: 1.41, 2.42; p=0.959 for heterogeneity). The allele model also demonstrated statistical evidence, indicating a moderately increased risk of bone sarcoma in relation to the +49>A polymorphism (OR=1.21; 95% CI: 1.08, 1.36; p=0.996 for heterogeneity). Conversely, neither an increase or nor a decrease was observed in the genotypes of -318C>T polymorphism. Our meta-analysis provides evidence that support that the +49>A polymorphism, but not the -318C>T polymorphism, may be associated with elevated risk of bone sarcoma in Asians.

Association between CTLA-4 gene polymorphisms and the susceptibility to Graves' disease

Objective To determine whether the single nucleotide polymorphisms (SNPs) rs231775 and rs3087243 of the cytotoxic T lymphocyte antigen 4 (CTLA-4) gene are associated with susceptibility to Graves' disease (GD) in Chinese Han population.Methods Patients were enrolled from outpatient department and wards.Blood samples from each subject were collected to extract DNA,and the genotypes were determined by TagMan-MGB probe.Results The frequencies of allele G (OR =1.244,95％ CI 1.124-1.377,P＜0.01) and genotype GG (55.3 ％ vs 49.1％,OR =1.279,95 ％ CI 1.126-1.454,P＜0.01) of rs231775 in GD group were higher than those in control group.The frequencies of allele G (OR =1.303,95％ CI 1.166-1.457,P＜0.01) and genotype GG (76.8％ vs 71.8％,OR=1.302,95％ CI 1.143-1.484,P＜0.01) of rs3087243 in GD group were also higher.Conclusion GG genotypes in rs231775 and rs3087243 of CTLA-4 gene are related to the high risk of GD. Key words: Graves' disease ; Polymorphism, single nucleotide ; Cytotoxic T lymphocyte antigen 4

Cytotoxic T lymphocyte antigen 4 (CTLA4) gene polymorphism with bladder cancer risk in North Indian population

Cytotoxic T Lymphocyte antigen 4 (CTLA4) is a potent immunoregulatory molecule that suppresses antitumor response by down-regulating T cell activation. We examined candidate disease-susceptibility single nucleotide polymorphism (SNPs) of CTLA4 at +49A/G, CT60A/G and -318C/T genes in bladder cancer (BC) patients of North Indian population. Histopathologically confirmed 200 patients of BC and 200 unrelated, healthy controls of similar ethnicity were genotyped by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) and amplification refractory mutation specific (PCR-ARMS) methods. In present study SNP CTLA4 +49A/G, variant genotype showed 3.74-fold risks for BC. While looking at G allele carrier level, risk for BC was high (OR=1.54). The risk for BC was also evident in case G allele (OR=1.58). CTLA4 CT60A/G gene polymorphism variant genotype showed 1.36-fold risks for BC. While at G allele carrier and with variant G allele it showed significantly reduced risk for BC. CTLA4 +49A/G genotype exhibited 1.57-fold risks with smoking in BC patients in homozygous mutant condition. In silico analysis further supports the results of SNP at CTLA4 +49A/G and CTLA4 CT60A/G. None of the above SNPs of CTLA4 demonstrated association with tumor stage/grade for BC severity and progression. BCG immunotherapy had no impact on CTLA4 gene polymorphism revealing no significant association. Haplotype GAC showed high risk for BC while other haplotype AGT showed reduced risk for BC. Our results indicated that genetic variations in CTLA4 gene (+49A/G, CT60A/G) play role in susceptibility to BC. Haplotype GAC showed high risk for BC. An association study utilizing a larger sample size and different ethnicity warrant further investigation through replication and advance techniques.

Cytotoxic T-lymphocyte antigen-4 gene polymorphisms in hepatocellular carcinoma patients in Egypt

ObjectiveOur objective is to examine the genotypes at rs231775 in the cytotoxic T-lymphocyte antigen 4 gene (CTLA4) in an Egyptian population to detect the association between this single-nucleotide polymorphism (SNP) and susceptibility to hepatocellular carcinoma (HCC).BackgroundCTLA-4 is an important negative regulator in immune response. Its polymorphism +49G>A (dbSNP: rs231775) has been linked to an increased risk of T-cell-mediated autoimmune diseases, infectious diseases, and even carcinomas.MethodsThis study included 30 HCC patients (26 men and four women) and 20 healthy controls (18 men and two women). Laboratory investigations including complete blood picture, liver function tests, serum a-fetoprotein, and hepatitis viral markers (HBsAg, anti-HCV-Ab) were performed for all participants. The CTLA4 polymorphism at rs231775 was genotyped using the TaqMan allelic discrimination Assay technique.ResultsThe data showed a higher frequency of the A/A genotype (40 vs. 10%) and the A allele (55 vs. 27.5%) in patient groups (HCC) compared with the healthy controls. Our results also indicated a statistically significant difference in CTLA4 rs231775 between HCC patients and healthy controls in the AA genotype and the A allele (P = 0.04, 0.012), respectively.ConclusionOur results suggested that the A/A genotype and the A allele of rs231775 increase the risk of developing HCC in an Egyptian population, whereas the G allele appeared to have a protective effect in developing HCC.

Cytotoxic T lymphocyte antigen-4 gene polymorphism in systemic lupus erythematosus Egyptian patients

The human cytotoxic T lymphocyte antigen-4 (CTLA-4) gene has been confirmed to be associated with several autoimmune diseases. In this study, we investigated the CTLA-4 gene polymorphism in systemic lupus erythematosus (SLE) Egyptian patients. A polymerase chain reaction was conducted to amplify CTLA-4 gene, followed by restriction fragment length polymorphism (RFLP) assay to detect candidate genetic polymorphism at positions -1722 T/C and -1661 A/G. Sixty SLE patients (55 females and 5 males) with mean age 28.5 ± 7 years and 40 healthy controls (31 females and 9 males) with mean age 27.8 ± 6.2 years were included in this study. The genotypic distribution at position -1661 of CTLA-4 gene was GG (11.7 %), AA (70 %), and AG (18.3 %) in SLE patients versus GG (20 %), AA (65 %), and AG (15 %) in the control (P value 0.508); regarding the position -1772 of CTLA-4 gene, the distribution was TT (83.3 %) and TC (16.7 %) in SLE patients versus TT (77.5 %) and TC (22.5 %) in the controls (P value 0.466). On studying the clinicopathological impact of the studied single nucleotide polymorphism (SNPs) with the disease severity, there is a statistical significance (P = 0.011) for the presence of AA genotype and severity of disease at -1661 genotype. AA genotype at -1661 was protective against discoid rash (P = 0.005), TC genotype at -1772 site is protective against serositis (P = 0.05), and serositis occurs more commonly with the AG genotype at -1661 site (P = 0.038). In our study, we concluded that the studied SNPs at positions -1772 and -1661 of CTLA-4 gene were not associated with SLE risk in Egyptian population.

Genetic variations in cytotoxic T-lymphocyte antigen-4 and susceptibility to cervical cancer

Cytotoxic T-lymphocyte antigen-4 (CTLA-4), a molecule expressed predominantly on activated T cells, plays an important role in the down-regulation of T-cell activation. To evaluate the potential effects of CTLA-4 gene polymorphisms on susceptibility to cervical cancer, we genotyped polymorphisms in CTLA-4 (- 318 T/C, CT60 G/A,+49 G/A, - 658 T/C, and - 1661 G/A) and calculated odds ratios for the genotype and allele distributions between patients and controls. We then examined the functional relevance of the polymorphisms using enzyme-linked immunosorbent assays (ELISAs), in vitro lymphocyte proliferation assay, and cytotoxic assay. The CTLA-4 - 318 CC, CT60 AA, and+49 GG genotype frequencies were lower in patients than in controls (p <0.05). The frequencies of CTLA-4 - 318 T allele and CT60G allele carriers were significantly higher in patients than in controls (p <0.05). Upon stimulation, peripheral blood mononuclear cells (PBMCs) carrying the - 318TT and CT60GG genotypes exhibited significantly lower proliferation, IL-2, and IL-4 levels; fewer cytolytic activities; and higher TGF-β levels compared with PBMCs carrying the - 318 CC/CT or CT60 AA/AG genotypes. We also found that CTLA-4 - 318 T/C and CT60 G/A single nucleotide polymorphisms were associated with the severity of cervical cancer. These results indicate that CTLA-4 - 318 T/C and CT60 G/A can affect cervical cancer susceptibility by altering the immune status of an individual.

The impact of CTLA4 and PTPN22 genes polymorphisms on long-term renal allograft function and transplant outcomes

Cytotoxic T-Lymphocyte Antigen 4 (CTLA4) downregulates the immune system. Lymphoid tyrosine phosphatase (Lyp)—PTPN22 protein—is suggested to be negative regulator of T-cell reaction. There are several polymorphisms in the CTLA4 and PTPN22 genes, which can influence the immune response and allograft function after kidney transplantation. The aim of this study was to examine the impact of CTLA4 and PTPN22 genes polymorphisms on the long-term renal transplant function and recipients’ outcomes during a 5-year follow-up observation. The study enrolled 268 Caucasian renal transplant recipients. Genotyping of the rs231775 (+49AG) CTLA4 gene polymorphism was performed using real-time PCR and rs2476601 (C1858T) PTPN22 gene polymorphism using PCR-RFLP method. The 5-year graft survival rate was 81.7%. Dialysis was necessary in 22 (8%) patients, 7 (2.6%) patients died and 20 (7.4%) switched to another transplantation center. We found no association between studied polymorphisms and graft loss/dialysis. Comparison of the distribution of the +49AG CTLA4 and C1858T PTPN22 genes polymorphisms genotypes among dead and living patients showed no statistically significant differences. Above results suggest that the rs231775 (+49AG) CTLA4 and rs2476601 (C1858T) PTPN22 genes polymorphisms are not associated with long-term allograft failure, graft loss and mortality after transplantation.