CTLA-4 Gene Polymorphisms Research Articles

Clinical and Genetic Characteristics of Autoimmune Polyglandular Syndrome Type 3 Variant in the Japanese Population

Type 1 diabetes (T1D) is commonly associated with autoimmune thyroid disease (AITD), and the occurrence of both T1D and AITD in a patient is defined as autoimmune polyglandular syndrome type 3 variant (APS3v). We aimed to clarify the differences in the clinical and genetic characteristics of APS3v patients and T1D patients without AITD [T1D/AITD(-)] in the Japanese population. Our subjects were 54 APS3v patients and 143 T1D/AITD(-) patients who were consecutively diagnosed at Nagasaki University Hospital from 1983 to the present. A remarkable female predominance, a slow and older age onset of T1D, and a higher prevalence of glutamic acid decarboxylase autoantibodies were observed in APS3v patients compared to T1D/AITD(-) patients. The older onset age of T1D in APS3v patients was associated with a higher proportion of slow-onset T1D. Among the two major susceptible human leukocyte antigen (HLA) class II haplotypes in Japanese T1D, DRB1*0405-DQB1*0401, but not DRB1*0901-DQB1*0303, was associated with APS3v patients. Furthermore, DRB1*0803-DQB1*0601 was not protective in patients with APS3v. The frequencies of the GG genotype in +49G>A and +6230G>A polymorphism in the CTLA4 gene were significantly higher in T1D/AITD(-) patients, but not in APS3v patients, compared to control subjects. In conclusion, we found notable differences in the clinical and genetic characteristics of APS3v patients and T1D/AITD(-) patients in the Japanese population, and the differences in the clinical characteristics between the two groups may reflect distinct genetic backgrounds including the HLA DRB1-DQB1 haplotypes and CTLA4 gene polymorphisms.

The impact of rs231775 (+49AG) CTLA4 gene polymorphism on transplanted kidney function

CTLA4 is expressed on the surface of T helper cells and has a suppressive role in the lymphocytes' activation process. It transmits an inhibitory signal to T cells. Studies suggest that the rate of CTLA4 synthesis has a genetic background. There are several polymorphisms of the CTLA4 gene that can influence the expression of this molecule and may therefore affect immune response and allograft function after kidney transplantation. The aim of this study was to examine the impact of the rs231775 (+49AG) CTLA4 gene polymorphism on transplanted kidney function. The study enrolled 269 Caucasian renal transplant recipients (166 males, 103 females, mean age 47.63±12.96 years). Genotyping of the rs231775 (+49AG) CTLA4 gene polymorphism was performed using real-time PCR. The frequency of DGF was higher in the individuals with the G allele of the rs231775 (+49AG) CTLA4 gene polymorphism compared with the carriers of the A allele (GG+AG vs. AA, OR 1.80; 95% CI 1.02-3.18, p=0.05). In multivariate analysis, rs231775 CTLA4 gene polymorphism G allele was an independent factor associated with increased risk of DGF (p=0.03). Rs231775 (+49AG) CTLA4 gene polymorphism may be associated with increased risk of delayed graft function after kidney transplantation.

P-1233 - CTLA-4 and CD28 gene polymorphism with respect to frontal lobe functions in schizophrenia

Genetic factors that modulate the immune response have been implicated as risk factors both for schizophrenia as well as for cognitive impairments (endophenotypes of schizophrenia). Regulation of immune response is mediated by two related receptors: CD28 is a major co-stimulator, whereas CTLA-4 performs negative regulatory functions. Balance of immune response depends on the expression of these regulatory molecules due to their genes polymorphisms. The study was carried out to investigate the association between polymorphisms of two genes: CTLA-4 (49A/G, −319C/T, CT60 A/G) and CD28 (+17C/T) and frontal lobe functions in patients with schizophrenia. 118 patients diagnosed with schizophrenia (ICD-10) and 352 controls were included in the study. Frontal lobe functioning was assessed by Trail Making Test (TMT) and Stroop Test (SCWT). There was no significant difference in distribution of genotypes between patients and controls in the polymorphisms of CTLA-4 gene, but in polymorphism of CD28 gene (p = 0,0007). With respect to +17C/T CD28 gene polymorphism there was a trend level difference in performance on TMT: C allel carriers performed worse that T allel carriers (p = 0,054), suggesting weaker executive control function. Our data support a role of CD28 +17 C/T gene polymorphisms for the predisposition to schizophrenia. Among patients the distribution of genotypes of CD28 gene polymorphism is similar to that found in patients with autoimmune disorders such as: early onset type 1 diabetes and Behçet's disease. Additionally, +17C/T CD28 gene polymorphism might be considered as a risk factor for cognitive impairment in schizophrenia.

Association of CTLA4 gene polymorphism with ophthalmopathy of Graves´ disease in Spanish population

: Background: Graves’ disease (GD) is an autoimmune disease that develops as a result of a complex interaction between genetic and environmental factors. Numerous studies have demonstrated the important role of CTLA4 gene polymorphisms in the susceptibility to this disease. The CTLA4 gene is located on chromosome 2q33 and codes for the T-cell receptor, which negatively modulates the immune response by disabling T cells.Objectives: The aim of the present work was to determine whether A/G dimorphism at position +49 of exon 1 in the CTLA4 gene contributes to the severity and clinical manifestations of GD.Patients and Methods: We performed clinical and genetic studies on 100 Graves’ patients and 50 healthy controls. We determined the subjects’ genotypes for the +49 A/G polymorphism of the CTLA4 gene by PCR and an enzyme restriction test. Comparison of individual clinical and laboratory variables between genotypes was performed using SPSS 17. 0 (SPSS, Chicago, IL, USA).Results: We found a statistically significant relationship between CTLA4 gene polymorphism and ophthalmopathy in Graves’ patients.Conclusions: The +49A/G SNP of the CTLA4 gene is related to the development of Graves’ disease; however, more studies are necessary to clarify the role of the CTLA4 gene in influencing GD susceptibility and to explore other potential costimulation pathways in this disorder.

Recipient CTLA-4*CT60-AA genotype is a prognostic factor for acute graft-versus-host disease in hematopoietic stem cell transplantation for thalassemia

Polymorphisms of the cytotoxic T-lymphocyte antigen-4 gene (CTLA-4) have been associated with autoimmune diseases and it has recently been reported that donor genotypes correlate with the outcome of allogeneic hematopoietic stem cell transplantation in leukemia patients. With the aim of confirming this finding in thalassemia patients, we investigated the influence of genotype distribution of 3 CTLA-4 gene polymorphisms in 72 thalassemia patients and their unrelated donors. A significant association was observed for recipient CT60-AA genotype and onset of grade II–IV (63.2% vs 24.5%; p = 0.001) and grade III–IV (36.4% vs 7.6%; p = 0.005) acute graft-versus-host disease (aGVHD). The same association was observed for the 88-base-pair allele of the CTLA-4 (AT)n polymorphism, which was determined to be in complete linkage disequilibrium with the CT60 A allele. Multinomial Cox regression demonstrated that this association was independent of CT60 donor genotypes or other risk factors (p = 0.016; hazard ratio = 2.8). Our data confirm that the genetic variability in CTLA-4 is an important prognostic factor for aGVHD and suggest that some of the risk factors for this complication are generated by recipient cells that persist after the myeloablative conditioning regimen.

Donor CTLA-4 Gene Polymorphism Associations with Acute GvHD After Allogeneic Hematopoietic Stem Cell Transplantation

Abstract 2010Allogeneic hematopoietic stem cell transplantation (allo-HSCT) has been widely carried out as a therapy for several hematological malignances and non malignant disorders.Graft–versus -host disease is one of the major complications after allo-HSCT with main cause of morbidity and mortality. Donor T lymphocytes play the crucial role in alloimmune recognition and their ability to detect non –self antigens can lead to aGvHD.The effective recognition and activation of naïve T-cells requires two independent signals. The first, an antigen-specific signal, is sent via the T-cell receptor (TCR) on T-cells. The second signal, termed co-stimulation, is critical for allowing full activation, sustaining cell proliferation, preventing anergy and/or apoptosis, inducing differentiation to effector cells. CD28 is the primary T-cell co-stimulatory molecule. Cytotoxic T-cell antigen (CTLA-4) is a homologous molecule of CD28 which plays an inhibitory role in the early and late stages of T-cell activation. CTLA-4 ligation provides a negative signal for regulation of the cell cycle and inhibits the activity of the transcriptional factors: nuclear factor-kB (NF-kB), nuclear factor of activated T-cells (NF-AT), and activator protein 1 (AP-1). Moreover, CTLA-4 binds to CD28 ligands (CD80 and CD86) with higher affinity and avidity and in that way also inhibits T-cell activation. Since co-stimulatory and down regulatory molecules synthesis depend on the rate of gene transcription and/or translation, polymorphisms in the corresponding genes might result in abnormal expression, function as well as dysregulated trafficking of these molecules within cellular compartments. The human CTLA-4 gene is located on 2q33 which is susceptibility region for autoimmune diseases.The aim of this study is to investigate the associations between polymorphisms in CTLA-4 gene: CTLA-4c.49A>G (rs231775), CTLA-4g.319C>T (rs5742909), CTLA-4g6230G>A (CT60, rs3087243), CTLA-4g.10223G>T (Jo31, rs11571302) in donors of HSTC and occurrence of aGvH disease in recipients after allogeneic hematopoietic stem cell transplantation. Altogether 136 donors of HSCT (58- related donors, 88 haploidentical unrelated donors) were genotyped for all polymorphisms using allelic discrimination methods with the TaqManÒ SNP Genotyping Assay.In patients without aGvHD and in patients with aGvHD grade I-IV the similar distribution of alleles and genotypes for all investigated polymorphisms in donors was observed. However, we have noticed trend toward increased frequency of CT60 [G] donor allele among recipients with aGvHD I-IV (0.48 vs. 0.39, p=0.1, OR 1.49, 95% CI: 0.90–2.49) compared to recipients without aGvHD in whole group of patients. In patients transplanted from related donor also increased risk of aGvHD grade I-IV was observed for CT60 [G] donor allele (0.75 vs. 0.55, p=0.09, OR 2.11, 95%CI: 0.88–5.26). In contrary the frequencies of CT60 [G] donor allele in patients transplanted from unrelated donors are similar in recipients with and without aGvH symptoms. Haplotype estimation analysis indicated that donor haplotype CTLA-4c.49A>G[A], CTLA-4g.319C>T[C], CT60 [A], Jo31 [T] tended to be protective against aGvHD grade I-IV in whole studied group of patients (0.28 vs. 0.40, p=0.06, OR 0.60, 95% CI: 0.36–1.02) This association reach statistical significance in recipients of related transplantation (0.18 vs. 0.43, p=0.01, OR 0.29, 95% CI: 0.14–0.97)Our study indicated that donor CT60 polymorphism might be associated with occurrence of aGvHD, especially in recipients transplanted from HLA-identical sibling donors. Disclosures:No relevant conflicts of interest to declare.

Association between CTLA-4 gene polymorphism and susceptibility to cervical cancer

To investigate the association between CTLA-4 +49A/G polymorphisms and the risk of susceptibility to cervical cancer. A hospital-based case-control study was conducted. 314 cases with primary cervical cancer and 320 healthy controls were collected and genotyped by PCR-based RFLP for +49A/G polymorphisms in the CTLA-4 gene. The A allele and AA genotype of CTLA-4 gene were 32.5% and 9.6% in the patients, and 25.8% and 5.6% in the controls, respectively. Subjects with CTLA-4 +49AA genotype conferred a higher risk of cervical cancer (OR = 2.06, 95%CI: 1.10 - 3.85; P = 0.024). However, the correlation between AA genotype in CTLA-4 polymorphisms and clinicopathological characteristics was not significant. The results of this study suggest that CTLA4 gene is associated with cervical cancer risk and may be a susceptible gene of cervical cancer.

CTLA-4, CD28, and ICOS gene polymorphism associations with non-small-cell lung cancer

Polymorphisms in genes encoding CD28, ICOS, and CTLA-4 were demonstrated to be associated with susceptibility to malignancies. To the best of our knowledge, no study on this association has been performed in a Caucasian population for non-small-cell lung cancer (NSCLC). In the present work, we investigated the polymorphisms CTLA-4c.49 A> G (rs231775), CTLA-4g.319C> T (rs5742909), CTLA-4g. *642AT(8_33), CTLA- 4g.*6230G>A (CT60) (rs3087243), CTLA- 4g.*10223G>T (Jo31) (rs11571302), CD28c.17+3T> C (rs3116496), and ICOSc.1554+4GT(8_15) in 208 NSCLC patients and 326 controls. The distributions of the allele and genotype were similar in both groups for CTLA-4, CD28, and ICOS gene polymorphisms. However, we noted a tendency toward overrepresentation of individuals possessing the CTLA- 4c.49A>G[A] allele in NSCLC patients compared with controls (0.84 vs 0.79, p = 0.09). The association became significant compared with controls in women for the CTLA- 4c.49A>G[A] allele and CTLA- 4c.49A>G[AA] genotype (0.67 vs 0.54, p = 0.01, and 0.47 vs 0.30, p = 0.02; respectively). Moreover, the constellation of alleles C TLA- 4c.49A>G[A]/CT60[G]/ CD28c.17+3T>C[T]/ ICOSc.1554+4GT(8_15)[>10] increased the risk of NSCLC about 2-fold ( p = 0.002). The same constellation of alleles combined with smoking, CTLA-4g.319C> T[T], and ICOSc.1554+4GT(8_15)[>10] was associated with a decreased overall survival rate. In conclusion, the constellation of specific alleles in CTLA-4, CD28, and ICOS genes contributes to the susceptibility and clinical course of NSCLC.

Analysis of CTLA-4 gene polymorphisms in patients with advanced melanoma treated with anti-CTLA-4 therapy.

8588 Background: It has been suggested that specific CTLA-4 gene polymorphisms may have an important role in advanced melanoma patients (pts) receiving CTLA-4 blockade therapy (Breunis W. et al. J ...

CTLA4 exon1 A49G polymorphism in Slovak patients with rheumatoid arthritis and Hashimoto thyroiditis—results and the review of the literature

Autoimmune thyroid diseases frequently overlaps with rheumatoid arthritis (RA). Among genetic factors, the role of the HLA antigens and CTLA4 gene polymorphisms in the overlapping has been suggested. The aim of this study was to investigate the alleles and genotypes frequency of the CTLA4 exon1 A49G polymorphism in Slovak patients with RA, Hashimoto thyroiditis (HT), both (RA + HT) and in healthy controls. Fifty-seven unrelated adults with RA, 57 patients with HT, 34 patients with both (RA + HT), and 51 normal subjects were studied. All were ethnic Slovaks living in the same geographical area. The CTLA4 exon1 A49G polymorphism was genotyped by using small amplicon melting analysis after real-time PCR. The CTLA4 49GG genotype and G allele frequency in the group with RA was not significantly higher in comparison with controls (10.53% vs. 9.8%, p = 0.62, OR 1.39, 95% CI 0.35-5.74 and 39.47% vs. 34.31%, p = 0.43, OR 1.25, 95% CI 0.72-2.18). The frequency of GG genotype was slightly but not significantly higher in patients with HT as compared with control group (19.3% vs. 9.8%, p = 0.17, OR 2.27, 95% CI 0.67-8.45). However, the frequency of GG genotype and G allele in patients with both RA and HT was significantly higher than that in controls (29.41% vs. 9.8%, p = 0.02, OR 4.49, 95% CI 1.20-18.54 and 51.47% vs. 34.31%, p = 0.03, OR 2.02, 95% CI 1.08-3.81). The frequency of GG genotype of CTLA4 A49G gene polymorphism in Slovak patients with RA is not significantly higher in comparison to control group. However, carriers of GG genotype with RA may be susceptible to develop HT.

CTLA4 polymorphisms in primary biliary cirrhosis patients and first degree relatives of cretan origin

Introduction and backgroundCytotoxic T lymphocyte antigen 4 (CTLA4) encodes a coinhibitory immunoreceptor that is a key regulator of self tolerance with established genetic associations to multiple autoimmune diseases. Studies of...

Family Analysis of Linkage and Association of HLA-DRB1, CTLA4, TGFB1, IL4, CCR5, RANTES, MMP9 and TIMP1 Gene Polymorphisms with Multiple Sclerosis

Multiple sclerosis (MS) is a chronic inflammatory autoimmune disease of the central nervous system (CNS). Proteins of the immune system, as well as proteins that are involved in the infiltration of activated immune cells in the CNS, play an important role in the pathogenesis of MS. We investigated the association and linkage with MS of the following immune-system genes polymorphisms: HLA-DRB1,CTLA4,TGFB1,IL4,CCR5 andRANTES, as well as of the matrix metalloproteinase 9 (MMP9) and tissue inhibitor of metalloproteinase 1 (TIMP1) genes polymorphisms. For this purpose we used the transmission disequilibrium test (TDT). The group investigated was comprised of 100 nuclear families of Russian ethnicity, each consisting of an affected offspring and his nonaffected parents. It was found that HLA-DRB1*15alleleandMMP9*-1562C allele were transmitted from healthy heterozygous parents to affected children more frequently than alternative alleles (p = 0.02 andp = 0.04, respectively). Another family-based method, AFBAC (affected family-based control), showed MS association with HLA-DRB1*15, but not with theMMP9*-1562C allele.

Association of cytotoxic T lymphocyte-associated antigen 4 gene single nucleotide polymorphism with type 1 diabetes mellitus in Madurai population of Southern India

Type 1 diabetes mellitus formerly called juvenile diabetes, is an organ specific T-cell mediated autoimmune disease characterized by the progressive loss of function of the insulin producing beta–cells of the islets of Langerhans. Cytotoxic T lymphocyte-associated antigen 4 gene (CTLA-4) has been proposed as a candidate gene for conferring susceptibility to autoimmunity. Association of CTLA-4 gene polymorphism is well established in autoimmune endocrinopathies across world population. The present study was conducted to investigate the association of CTLA-4 exon 1 49A/G polymorphism with TIDM in Madurai, a city in Southern India. Fifty three clinically proven T1DM patients and 53 control subjects with no history of autoimmune disease were recruited for the study. Genomic DNA was extracted from peripheral blood. CTLA-4 exon 1 49 A/G polymorphism was assessed using PCR-RFLP methods. Our findings revealed a significant association of CTLA-4 exon 1 49 A/G polymorphism with T1DM in Madurai population.

ICOS Gene Polymorphism May Be Associated with Pemphigus

Pemphigus is an autoimmune blistering disease mediated by circulating IgG autoantibodies directed against desmogleins 3 and/or 1. As pemphigus is a T cell-mediated disease, one may assume that genetically determined disregulation of costimulatory signal may be involved in its pathogenesis. The aim of the present study was to evaluate the relationship between polymorphisms in genes encoding costimulatory receptors, CTLA4 and ICOS, and pemphigus in the Polish population. The study included 54 patients with pemphigus: 40 with pemphigus vulgaris (PV) and 14 with pemphigus foliaceus (PF). Additionally, 176 healthy unrelated blood donors served as controls. +49A/G CTLA4 and IVS1+173 ICOS polymorphisms were identified using a modified polymerase chain reaction-restriction fragment-length polymorphism. Analysis of the frequency of genotypes and alleles of +49A/G CTLA4 gene polymorphism showed no statistically significant differences between the PV and PF patients and the controls. The distribution of genotypes in IVS1+173 ICOS polymorphisms was significantly different in both PV (p < .01) and PF (p = .0004) patients when compared to controls. The carriers of the allele C were more frequent in PV or PF in comparison with the control group (p < .001 for both groups). Our results suggest that genetically determined abnormal function of costimulatory receptors in T cells may be associated with the pathogenesis of pemphigus.

CYTOTOXIC T LYMPHOCYTE ASSOCIATED MOLECULE -4 (CTLA-4) GENE POLYMORPHISMS IN OVARIAN CANCER PATIENTS

Background: Ovarian cancer is a relatively common cancer among postmenopausal women. Nowadays, there is controversy about immunotherapy of ovarian cancer patients with interleukins such as interferon to reach better out come in prognosis of patients under chemotherapy. CTLA-4 is a gene, which has an important role in homeostasis and regulation of immune response. Inhibitory nature of CTLA-4 is proved to be of significance in autoimmune diseases as well as in cancer. In this study we intend to find out the relationship between polymorphisms of this gene at the sites of +49 A/G and -318 C/T and ovarian cancer. Methods: The polymorphisms of the CTLA-4 gene at the sites of +49 A/G exon and -318 C/T promoter were investigated. Blood samples of 73 patients with ovarian cancer and 115 healthy subjects used for DNA extraction. Two groups genotypes and alleles were determined using PCR method and compared by statistical t-student test. Results: There was no statistically significant difference in genotypes and alleles prevalence of +49 A/G and -317 C/T between two groups (p>0.05). Conclusion: Further researches with larger sample size while paying attention to the relation between the gene polymorphism and stage and type of tumor is recommended

CTLA4 and CD86 gene polymorphisms and susceptibility to chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) may be related to chronic inflammation and immune-mediated conditions, and its pathogenesis involves T-cell activation and proliferation. Cytotoxic T-lymphocyte–associated protein 4 (CTLA-4) and costimulatory molecules ( CD80/CD86) genes are important mediators of T-cell activation in the immune response. The aim of this study was to investigate whether +2379G/C (rs17281995) and +1057G/A (rs1129055) in CD86 and −318C/T (rs5742909) and +49A/G (rs231775) in CTLA-4 genes single nucleotide polymorphisms (SNPs) are associated with COPD in a Chinese population. The four polymorphisms were identified in 396 COPD patients and 400 controls using polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP). The frequency of the T allele of the −318C/T in CTLA-4 and the A allele of the +1057G/A in CD86 polymorphisms showed significant association with COPD when compared with controls (T allele: p < 0.0001; A allele: p = 0.009). Comparison of genotype frequencies showed that −318CT, +1057GA, and +1057AA genotype was overrepresented in the COPD group, respectively (−318CT: 50.8% vs 28.5%, p < 0.0001; +1057GA: 58.6% vs 54.2%, p = 0.002; +1057AA: 30.1% vs 25.8%, p = 0.002). However, we failed to find any association between the four SNPs and COPD when cases were classified by smoking status or clinical stages ( p > 0.05). The results indicate that the polymorphisms of CTLA-4 (−318C/T) and CD86 (+1057G/A) may be important genetic factor associated with risk or protection for COPD in Chinese population.

Ctla-4 gene variations may influence cervical cancer susceptibility

Background CTLA-4 is the key player of the immune tolerance. Particular genotypes of ctla-4 have been reported to be associated with various diseases. Objective We aimed to evaluate the role of four single nucleotide polymorphisms (SNPs) of ctla-4 gene in cervical cancer. Methods 55 patients and 110 healthy controls were genotyped for four polymorphic loci, three in promoter region; − 1722(T/C), − 1661(A/G), − 318(C/T) and one in exon 1; + 49(A/G) using PCR-ARMS and -RFLP methods. Results At position − 1661 the frequency of A/A homozygote and A allele were lower in patients than in controls. (P = 0.01, P = 0.035; respectively), while at position − 318 the frequency of C/C homozygote and C allele were increased in patients (P = 0.021, P = 0.025; respectively). These significances, however, do not stand the Bonferroni correction suggesting that the effect of multiple comparisons should not be ignored. The haplotype analysis demonstrated 9 haplotypes, of which, 5 were observed in both groups with no significant different frequencies. The TGTA haplotype, however, was only observed in control group (9.54%, p = 0.002) and the TGCG haplotype was only occurred in cervical cancer patients (6.48%, p = 0.0003). The differences were still significant after Bonferroni correction. Conclusion As a conclusion TGTA haplotype as well as A allele at position − 1661 might imply a protective role whereas TGCG haplotype as well as C allele at locus − 318 might render susceptibility to cervical cancer. Investigation of ctla-4 gene variants in other ethnic populations will consolidate the findings of this study.

CTLA-4 gene polymorphism +49 A/G contributes to genetic susceptibility to two infection-related cancers—hepatocellular carcinoma and cervical cancer

Accumulated evidence suggested that cytotoxic T-lymphocyte antigen 4 (CTLA4) plays an important role in the negative regulation of T-cell proliferation and activation, and thus participates in antitumor immunity and cancer surveillance. Previously we reported that the CTLA4 49A/G (rs231775) single nucleotide polymorphism (SNP) was a candidate cancer susceptibility marker for breast, lung, esophageal, and gastric cancers. In the present study, we expanded our study to two infection-related cancers, namely, hepatocellular carcinoma (HCC) and cervical cancer. We genotyped rs231775 in two independent case-control studies of 864 HCC patients and 864 control subjects, and 719 cervical cancer patients and 719 control subjects. In the multivariate logistic regression models, CTLA4 +49 A/G variant genotype was associated with increased risk (AA vs GG) by 1.43-fold (95% CI = 0.94–2.17) for HCC, and 1.66-fold (95% CI = 1.13–2.44) for cervical cancer. Taken together, the results suggest that CTLA4 rs231775 may serve as a common cancer susceptibility marker.

The influence of CTLA-4 gene polymorphism on long-term kidney allograft function in Caucasian recipients

The aim of the study was to examine whether CTLA-4 (CD152) and CD28 gene polymorphisms affect the outcome of kidney transplantation (KTx). Polymorphisms of the CTLA-4 gene (− 318 C > T, + 49 A > G, and the microsatellite polymorphism in the 3′UTR of exon 4 (AT) n ) and a CD28 gene (IVS3 + 17 T > C) were investigated in 314 allograft recipients with a mean age of 41.9±12 years. The median time since KTx was 97.5 months. The genotypes of the SNPs were determined by SSP-PCR and (AT) n genotype by PCR and capillary electrophoresis (ABI Prism 310). In general, no relationship was found between the allele variants and acute rejection or graft function. Univariate and multivariate analyses showed no influence of CTLA-4 or CD28 polymorphism on graft/patient survival. In the individuals bearing the combination of the homozygous variant of low AT repeat number (82 bp) and the homozygous variant A (adenine) in CTLA-4 + 49 A > G, higher eGFR was observed at one year after KTx, which was also maintained at 10 years. In summary, 24.2% of the studied patients carrying the “favorable” CTLA-4 genotype exhibited significantly higher allograft function than the 16.9% recipients with the “unfavorable” genotype up to 10 years post transplantation.

CTLA-4 +49A&gt;G polymorphism of recipients of HLA-matched sibling allogeneic stem cell transplantation is associated with survival and relapse incidence

Conflicting observations have been reported about the role of CTLA-4 gene polymorphisms in the clinical outcome of allogeneic hematopoietic stem cell transplantation (HSCT). We have investigated three polymorphisms of the CTLA-4 gene (-318C>T, +49A>G, CT60G>A) in 133 donor/recipient pairs who underwent HLA-matched sibling donor HSCT for hematological malignancies. We found no association of the clinical outcome of the HSCT with either recipient or donor -318C>T and CT60G>A polymorphisms. At variance, we found a significant association of donor +49A>G G/G genotype with longer overall survival (OS; log-rank test, P = 0.04), and the number of +49A>G G-alleles in the recipient with longer OS (P = 0.027), longer disease-free survival (P = 0.036) and reduced relapse rate (P = 0.042). However, only recipient +49A>G polymorphism was retained as independent prognostic factor in a multivariate analysis, suggesting that the expression of CTLA-4 on the cells of recipient may be relevant for the clinical outcome of HSCT.