Cytotoxic T-lymphocyte Antigen-4 Gene Polymorphisms Research Articles

Association between cytotoxic T‐lymphocyte antigen 4 gene polymorphisms and primary biliary cirrhosis in Chinese population: data from a multicenter study

The cytotoxic T-lymphocyte antigen 4 (CTLA4) gene polymorphisms have been shown to be associated with the risk of primary biliary cirrhosis (PBC). The study aimed to confirm the associations of CTLA4 gene polymorphisms with risk of PBC and patients' quality of life in Chinese population. A total of 312 female PBC patients from Chinese Han population were included as case, and 375 age-matched female healthy volunteers were included as control. Four single nucleotide polymorphisms (SNPs) including rs231775, rs3087243, rs231725, and rs5742909 were genotyped. The differences of genotype and allele distributions between PBC patients and healthy controls were assessed. The relationship between CTLA4 gene polymorphisms and healthy status of PBC patients were then investigated through comparisons of the domain scores of PBC-40 questionnaire between different genotype categories of each single nucleotide polymorphism. The frequencies of G allele at rs231775 and A allele at rs231725 were both significantly increased in PBC patients when compared with normal controls (P < 0.001, odds ratio = 1.44, 95% confidence interval = 1.24-1.67 for rs231775; P < 0.001, odds ratio = 1.29, 95% confidence interval = 1.12-1.48 for rs231725). Besides, patients carrying A allele of rs3087243 had significantly lower score of fatigue domain than those carrying G allele (2.5 ± 0.8 vs 3.9 ± 1.3, P < 0.001). This study revealed that CTLA4 gene polymorphism might be associated with susceptibility of PBC. G allele of rs231775 and A allele of rs231725 were significantly associated with the risk of PBC. In addition, patients carrying A allele of rs3087243 could have significantly better quality of life than those carrying G allele.

Cytotoxic T-Lymphocyte Antigen-4 Genetic Variants and Risk of Ewing's Sarcoma

Despite the knowledge of many genetic alterations present in Ewing's sarcoma (ES), the complexity of this disease precludes placing its biology into a simple conceptual framework. Cytotoxic T-lymphocyte antigen-4 (CTLA-4) can decrease T-cell activation and attenuate antitumor responses. Polymorphisms in the CTLA-4 gene have been shown to be associated with different diseases. Here, we investigated the association of four CTLA-4 gene polymorphisms, -1661A/G (rs4553808), -318C/T (rs5742909), +49G/A (rs231775), and CT60A/G (rs3087243), with ES in the Chinese population. A total of 308 ES cases and 362 healthy controls were recruited and CTLA-4 polymorphisms were tested by polymerase chain reaction-restriction fragment length polymorphism. Results showed that frequencies of the CTLA-4 gene +49AA genotype, +49A allele, and GTAG haplotype were significantly increased in ES patients compared to healthy controls (odds ratio [OR]=2.42, 95% confidence interval [CI] 1.43-4.09, p<0.001; OR 1.38, 95% CI 1.11-1.73, p=0.005, and OR=1.46, 95% CI 1.06-2.02, p=0.020, respectively). We further compared CTLA-4 polymorphisms in ES patients based on different clinical parameters and data revealed that ES patients with metastasis had higher numbers of the +49AA genotype than those without metastasis (p=0.004). These results indicated that the CTLA-4 polymorphism could be a risk factor for ES and suggested a potential role of CTLA-4 in the metastasis of this malignancy.

758 Association of cytotoxic T-lymphocyte antigen-4 gene polymorphisms with increased likelihood of recurrence in non-muscle invasive bladder cancer

758 Association of cytotoxic T-lymphocyte antigen-4 gene polymorphisms with increased likelihood of recurrence in non-muscle invasive bladder cancer

Cytotoxic T-Lymphocyte Antigen-4 Polymorphisms and Susceptibility to Ewing's Sarcoma

The development of Ewing's sarcoma (ES) is a complex process, resulting from interplay between mutations in oncogenes and tumor suppressors, host susceptibility factors, and cellular context. Cytotoxic T-lymphocyte antigen-4 (CTLA-4) plays important roles in downregulating the T-cell activation. Polymorphisms in the CTLA-4 gene have been shown to be associated with different autoimmune diseases and cancers. The current study evaluated the association of two CTLA-4 gene polymorphisms, -318C/T (rs5742909) and +49G/A (rs231775) with ES in the Chinese population. CTLA-4 polymorphisms were detected by polymerase chain reaction-restriction fragment length polymorphism in 223 ES cases and 302 age-matched healthy controls. Data were analyzed using the chi-square test. Results showed that prevalence of the CTLA-4 gene +49AA genotype and +49A allele were significantly increased in ES patients compared to controls (odds ratio [OR]=2.03, 95% confidence interval [CI], 1.13-3.66, p=0.018; and OR=1.33, 95%CI, 1.03-1.72, p=0.027). Also, subjects with CA (-318, +49) haplotype had a 1.37-fold increased risk to develop ES (p=0.032). In addition, ES patients with metastasis had higher numbers of +49AA genotype than those with localized cases (OR=2.66, 95%CI, 1.14-6.22, p=0.022). These results indicate that the CTLA-4+49G/A polymorphism is a new risk factor for ES and may affect the prognosis of this cancer.

Influence of cytotoxic T lymphocyte antigen-4 (CTLA-4) gene polymorphisms in periodontitis

AimPersistent host inflammatory immune response against the pathogens results in the destruction of periodontal tissues. Cytotoxic T lymphocyte antigen 4 (CTLA-4) is a particularly important molecule in down-regulating T-cell expansion and cytokine production. This study aimed to assess three functional SNPs within CTLA-4 gene, −1722 T/C, −318 C/T, and +49 A/G in patients with aggressive or chronic periodontitis. Materials and methodsA total of 197 patients with periodontitis (71 aggressive and 126 chronic periodontitis) and 218 healthy controls were recruited. All samples were genotyped for CTLA-4 gene polymorphisms by polymerase chain reaction-amplification refractory mutation system (PCR-ARMS). ResultsThe allelic and genotype frequencies of only +49 A/G SNP were more prominence in patients with chronic periodontitis (CP) than that controls (0.0005 and 0.001, respectively). Multivariate logistic regression analysis was demonstrated that homozygosity in +49 G/G had profoundly increased susceptibility for CP, OR=3.7 (95% CI; 1.6–8.5, P=0.001). In addition, comparison of CTLA-4 SNPs between patients with CP and aggressive periodontitis (AgP) revealed that heterozygosity in −1722 T/C polymorphism of CTLA-4 gene had a significantly higher risk for CP compared with AgP with a calculated odds ratio of 2.18 (95% CI; 1.17–4.06, P=0.01). ConclusionThese results suggest that CTLA-4 gene variants might be associated to susceptibility to specific form of periodontitis and participate in the CP development.

A Pilot Study on Cytotoxic T Lymphocyte-4 Gene Polymorphisms in Urinary Schistosomiasis

Urinary schistosomiasis is caused by the digenetic trematode Schistosoma haematobium, characterized by accumulation of eggs in the genitourinary tract. Cytotoxic T-lymphocyte antigen 4 (CTLA-4) can play an important role in parasitic infection due to its major role as a negative regulator of T-cell activation and proliferation. This study was performed in patients with schistosomiasis and healthy controls to analyze the allele and genotype frequencies of four CTLA-4 gene polymorphisms. The CTLA-4 gene was amplified using Taqman real-time polymerase chain reaction, and allele and genotypes of 49 patients with schistosomiasis were analyzed using allelic discrimination analysis followed by subsequent direct sequencing. The results were compared with healthy control subjects. The frequencies of CTLA-4 rs733618 A allele at position -1722 (p=0.001), rs11571316 C allele at position -1577 (p<0.001), and rs231775 A allele at position +49 (p=0.002) in the patient group were significantly higher than the control group. The rs733618 AA genotype (p=0.001), rs11571316 CC genotype (p<0.001), and rs231775 AA genotype (p=0.007) were also significantly overrepresented. Meanwhile, rs733618 AG genotype (p=0.001), rs11571316 CT genotype (p=0.02), and rs231775 GG genotype (p=0.029) were significantly decreased in the patients with schistosomiasis, as compared with the controls. No significant difference was observed in both allele and genotype of rs16841252. The results of this study suggest that the rs733618, rs11571316, and rs231775 polymorphisms in the CTLA-4 gene may influence susceptibility to schistosomiasis infection in the Gabonese children.

Association of CTLA-4 gene polymorphisms with sporadic breast cancer risk and clinical features in Han women of Northeast China

Cytotoxic T lymphocyte antigen-4 (CTLA-4) is an inhibitory molecule that plays a pivotal role in downregulating T-cell mediated immune responses. To determine the role of CTLA-4 in tumor immunity, and to validate previous results as well, we investigated four tag single nucleotide polymorphisms (SNPs) of CTLA-4 in a relatively large Chinese Han cohort from northeastern China. Genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in 581 patients and 566 age-matched controls. Our data indicated that compared with the common genotype and allele of each SNP, the -1722 CC genotype and C allele showed an increased risk of breast cancer (P = 0.030, odds ratio (OR) = 1.457, 95% confidence internal (CI) 1.036-2.051; P = 0.024, OR = 1.214, 95% CI 1.026-1.436, respectively). The -1661 GG genotype and G allele were also associated with an increased risk of breast cancer (P = 0.018, OR = 1.396, 95% CI 1.058-1.843; P = 0.013, OR = 1.353, 95% CI 1.066-1.717, respectively). In the haplotype analysis, the CAAA haplotype showed a higher frequency in cases (P = 0.004), and this association remained significant after correcting the P value for multiple testing. Associations were shown between the SNPs of CTLA-4 and lymph node metastasis, estrogen receptor (ER), progesterone receptor (PR) and P53 statuses. These results indicate that some SNPs in the CTLA-4 gene may affect the risk of breast cancer and show that some SNPs are associated with breast cancer characteristics in Han women in northeastern China.

CTLA-4 gene polymorphisms and their influence on predisposition to autoimmune thyroid diseases (Graves’ disease and Hashimoto’s thyroiditis)

IntroductionAutoimmune thyroid disease (AITD) is associated with both genetic and environmental factors which lead to the overactivity of immune system. Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) gene polymorphisms belong to the main genetic factors determining the susceptibility to AITD (Hashimoto's thyroiditis, HT and Graves' disease, GD) development. The aim of the study was to evaluate the relationship between CTLA-4 polymorphisms (A49G, 1822 C/T and CT60 A/G) and HT and/or GD in Polish patients.Material and methodsMolecular analysis involved AITD group, consisting of HT (n=28) and GD (n=14) patients, and a control group of healthy persons (n=20). Genomic DNA was isolated from peripheral blood and CTLA-4 polymorphisms were assessed by polymerase chain reaction-restriction fragment length polymorphism method, using three restriction enzymes: Fnu4HI (A49G), BsmAI (1822 C/T) and BsaAI (CT60 A/G).ResultsStatistical analysis (χ2 test) confirmed significant differences between the studied groups concerning CTLA-4 A49G genotypes. CTLA-4 A/G genotype was significantly more frequent in AITD group and OR analysis suggested that it might increase the susceptibility to HT. In GD patients, OR analysis revealed statistically significant relationship with the presence of G allele. In controls, CTLA-4 A/A genotype frequency was significantly increased suggesting a protective effect. There were no statistically significant differences regarding frequencies of other genotypes and polymorphic alleles of the CTLA-4 gene (1822 C/T and CT60 A/G) between the studied groups.Conclusions CTLA-4 A49G polymorphism seems to be an important genetic determinant of the risk of HT and GD in Polish patients.

Association of CTLA4 gene polymorphisms with lymphatic filariasis in an East Malaysian population

Lymphatic filariasis (LF) is a parasitic disease caused by threadlike worms of the Brugia and Wuchereria species that live in the human lymphatic system. Regulatory T cells (Tregs) may play a key role in the pathogenesis of LF, and cytotoxic T-lymphocyte antigen-4 (CTLA4) expressed by Tregs is a potential candidate gene because it modulates T-cell activation. A case–control study was performed to establish a potential association of 5 CTLA4 gene promoter single nucleotide polymorphisms (SNPs; rs733618, rs11571316, rs5742909, rs231775, and rs16840252) with the occurrence of LF in an East Malaysian population (320 LF-infected individuals and 150 healthy controls). Polymorphisms were evaluated using TaqMan real-time polymerase chain reaction followed by direct sequencing. LF carriers of the rs733618 AG genotypes ( p = 0.02) and those with combined minor allele G carriers (AG + GG; p = 0.01) exhibited a significantly decreased risk for LF. Among the asymptomatic amicrofilaremic cases, positive associations were reported for all genotypes and variants of rs733618 with odds ratios (ORs) ranging from 0.27 to 0.45. In the asymptomatic microfilaremic cases, marker rs231775 exhibited a significant decreased risk, with ORs ranging from 0.50 to 0.57. The study has identified SNPs in the CTLA4 promoter gene that may be functionally linked with susceptibility to LF.

Association of CTLA4, CD28 and ICOS gene polymorphisms with clinicopathologic characteristics of childhood IgA nephropathy in Korean population

Primary IgA nephropathy (IgAN) is the most common glomerular disease in children and adolescents who undergo renal biopsy because of isolated microscopic haematuria or haematuria associated with proteinuria (Coppo 2008). Some evidence suggests the importance of the abnormal T-cell response in the pathogenesis of IgAN, and co-stimulatory molecules such as cytotoxic T-lymphocyte antigen 4 (CTLA4), CD28 molecule and inducible costimulator (ICOS) have been found to be vital for naive T-cells to initiate and terminate immune responses (Carreno and Collins 2002; Carreno et al. 2005). In this study, we tested single nucleotide polymorphisms (SNPs) of CTLA4/CD28/ICOS genes, and they were found to be associated with pathophisipology of paediatric IgAN in Korean population. The best-characterized T-cell co-stimulatory pathway involves receptors such as the CD28 and CTLA4 (also known as CD152). In addition, the ICOS has been also defined recently as a new pathway (Keir and Sharpe 2005). The CD28/CTLA4/ICOS genes lie within the 300-kb region on human chromosome 2q33 and their expressions are differentially regulated; although CD28 is constitutively present on naive T-cells, whereas CTLA4 and ICOS are present only after activation (Collins et al. 2005). Moreover, all of these molecules were found to be expressed by regulatory T-cells for the development and maintenance (Keir and Sharpe 2005).

Cytotoxic T-Lymphocyte Antigen-4 +49G/A Polymorphism Is Associated with Increased Risk of Osteosarcoma

Cytotoxic T-lymphocyte antigen-4 (CTLA-4) is a potent immunoregulatory molecule that suppresses anti-tumor response by down-regulating T-cell activation. CTLA-4 gene +49G/A polymorphism (rs231775) has been reported to be associated with various cancers. The objective of this study is to investigate the association between CTLA-4 gene +49G/A polymorphism and the susceptibility to osteosarcoma in the Chinese population. The CTLA-4 variant +49G/A was detected by polymerase chain reaction-restriction fragment length polymorphism in 205 osteosarcoma cases and 216 age-matched healthy controls. Data were analyzed using the Chi-square test. Frequencies of the CTLA-4 +49AA genotype and the +49A allele were significantly increased in patients with osteosarcoma compared to healthy controls (OR 2.27, p=0.010, and OR 1.41, p=0.015). Our data suggest that the +49G/A polymorphism of CTLA-4 gene is associated with increased susceptibility to osteosarcoma.

Immunoregulatory gene polymorphisms in women with preeclampsia

The costimulatory molecules CD28, cytotoxic T-lymphocyte antigen-4 (CTLA-4) (cytotoxic T-lymphocyte-associated antigen-4) and inducible costimulator (ICOS) are believed to have a critical modulatory role in the immune response. However, few studies have been performed on the role of these immune regulatory molecules and their polymorphisms in women with preeclampsia (PE). The aim of our study was to evaluate the CTLA4 (+49 A/G) (rs 231775), CD28 (+17 T/C) (rs 3116496) and ICOS (-1564 T/C) (rs 4675378) gene polymorphisms in Brazilian women with PE. This case-control study included 130 patients with PE and 261 control women without any obstetric or systemic disorders. Genomic DNA was extracted from peripheral blood, and the polymorphism genotyping was performed by digesting the PCR products with the restriction endonucleases BbvI (CTLA-4), AfeI (CD28) and AluI (ICOS). Data were analyzed by χ(2) or Fisher's exact test; a P-value of <0.05 was considered as significant. There were significant differences in the ICOS genotype and allelic frequencies between the PE and control groups (P=0.01 and P=0.01, respectively). We found a significantly lower frequency of the ICOS (-1564) T allele in women with mild PE compared with the controls. There were no differences in the CTLA-4 (+49 A/G) and CD28 (+17 T/C) genotypes and allelic frequencies between the PE patients and controls. Our data suggest that PE is associated with ICOS, but is not associated with the CTLA-4 or CD28 gene polymorphisms.

CTLA-4 gene polymorphisms (-318C/T, +49A/G, +6230A/G) in Iranian patients with multiple sclerosis.

Multiple sclerosis (MS) is a disease of the central nervous system (CNS) characterized by multiple regions of demyelination and inflammation along axons with a T cell-mediated autoimmune etiology. While the cytotoxic T lymphocyte antigen 4 (CTLA-4) gene seems to be a strong candidate gene in autoimmune diseases, we investigated its association with a group of patients with MS. One hundred and thirty five patients with relapsing-remitting form of MS and 135 healthy subjects were enrolled in this study. Three single nucleotide polymorphisms (SNPs) (-318C/T, +49A/G, +6230A/G) of the CTLA-4 gene were assessed using PCR-RFLP method. The genotypes -318 CC (82.9% in patients vs. 76.2% in controls) and +49 AA (31.1% in patients vs. 28.1% in controls) were overrepresented in the patient group; however, these differences were not statistically significant. In spite of some previous reports, this study did not confirm any significant association with alleles and genotypes of SNPs of the CTLA4 in Iranian MS patients. Such disparity could be due to genetic background, ethnicity and different forms of the disease.

Association analysis of cytotoxic T-lymphocyte antigen 4 gene polymorphisms with primary biliary cirrhosis in Japanese patients

Primary biliary cirrhosis (PBC) is an organ-specific autoimmune disease of still unidentified genetic etiology that is characterized by chronic inflammation of the liver. Since cytotoxic T-lymphocyte antigen 4 (CTLA4) polymorphisms have recently been linked with PBC susceptibility in studies on Caucasians, we investigated the genetic association between CTLA4 polymorphisms and PBC in a Japanese population. Five single nucleotide polymorphisms (SNPs) in the CTLA4 gene (rs733618, rs5742909, rs231775, rs3087243, and rs231725) were genotyped in 308 patients with PBC and 268 healthy controls using a TaqMan assay. One CTLA4 gene SNP (rs231725) was significantly associated with susceptibility to anti-mitochondrial antibody (AMA)-positive PBC, but clinical significance disappeared after correction for multiple testing. Moreover, CTLA4 gene SNPs did not influence AMA development or disease progression to orthotopic liver transplantation in our Japanese cohort. In haplotype analyses, one haplotype [haplotype 1 (CGGA)] at rs5742909, rs231775, rs3087243, and rs231725, was significantly associated with susceptibility to both AMA-positive PBC and overall PBC. This study showed that CTLA4 gene polymorphisms had a modest, but significant association with susceptibility to PBC in the Japanese population. The connection between genetic variants and the function of the CTLA4 gene remains to be addressed in future investigations.

CTLA-4 +49A&gt;G polymorphism is associated with the risk but not with the progression of colorectal cancer in Chinese

Colorectal cancer (CRC) is one of the most common malignancies in the world and a multipathway disease. Cytotoxic T-lymphocyte antigen-4 (CTLA-4) is a potent immunoregulatory molecule that suppresses antitumor response by down-regulating T-cell activation. The most studied +49A>G polymorphism of CTLA-4 gene has been associated with several autoimmune or cancer diseases. Our aim was to investigate the association between this genetic variant and the risk as well as progression of colorectal cancer in Chinese. We conducted a case-control study of 124 colorectal cancer cases and 407 healthy controls. DNA was extracted from blood specimens, and +49A>G polymorphism in the CTLA-4 gene was genotyped by polymerase chain reaction-ligation detection reaction (PCR-LDR). In our study group, the frequency of AG or GG or carrying at least one G allele at position +49 was significantly different in colorectal cancer patients and the control group, indicating that the risk of CRC was significantly higher among subjects with the AG or GG genotype or carrying at least one G allele at position +49 than among the subjects with the AA genotype. However, we observed no association between CTLA-4 +49A>G polymorphism and the progression of CRC. Interestingly, the CTLA-4 +49A allele was in non-significantly higher numbers in CRC patients with distant metastasis. Our results suggested that CTLA-4 +49A>G polymorphism was associated with an increased risk of colorectal cancer, but this polymorphism did not play an important role in the progression of CRC in Chinese.

The CTLA‐4 gene polymorphisms are associated with CTLA‐4 protein expression levels in multiple sclerosis patients and with susceptibility to disease

Cytotoxic T-lymphocyte antigen-4 (CTLA-4) is an important molecule in the down-regulation of T-cell activation. A study was undertaken to evaluate the association of the CTLA-4 gene polymorphisms -319C/T, +49A/G, (AT)(n), CT60A/G and Jo31G/T with the levels of membrane CTLA-4 (mCTLA-4) and cytoplasmic CTLA-4 (cCTLA-4) in CD4(+) T lymphocytes from patients with multiple sclerosis (MS) and with susceptibility to MS, and the course of the disease. It was found that the Jo31GG and CT60GG genotypes were associated with decreased mean fluorescence intensity (MFI) of total CTLA-4 (mCTLA-4 + cCTLA-4) molecules in CD4(+) T cells from both relapsing-remitting (RR) and secondary progressive (SP) MS patients compared with others. Consequently, possessing the Jo31G allele and/or the CT60G allele were associated with susceptibility to MS. The percentages of cells expressing mCTLA-4 and cCTLA-4 in RR patients were higher in carriers of the alleles non-predisposing to MS (namely CT60A and Jo31T), but the percentages of corresponding cells were unexpectedly significantly lower in SP patients than in RR patients. Increased risk of paresthesia and pyramidal signs as a first manifestation of disease, and earlier transition to the SP form in those patients, was also noted. It is hypothesized that the decreasing frequencies of cells expressing immunosuppressive mCTLA-4 and cCTLA-4 in carriers of alleles non-predisposing to MS (i.e. CT60A and Jo31T) may lead to inadequate down-regulation of ongoing T-cell responses in these patients and, as a consequence, earlier progression of disease from the RR form to the SP form.

Cytotoxic T-lymphocyte antigen 4 gene polymorphisms are associated with latent autoimmune diabetes in adults

Background Cytotoxic T lymphocyte antigen-4 (CTLA-4) molecule is an important regulator of T cell activation involved in the down-regulation of immune response. Polymorphisms within the CTLA-4 gene have been suggested to confer susceptibility to autoimmune endocrine disorders. Methods In order to evaluate the impact of allelic variants of the CTLA-4 gene in latent autoimmune diabetes in adults (LADA), the CT60 A/G SNP and the CTBC217_1 C/T SNP were studied in a population of Estonian origin, including 61 LADA patients and 230 controls. Results It was found that the CT60 GG genotype ( p = 0.004) and the CTBC217_1 TT genotype ( p = 0.007) were significant associated with LADA. Conclusions Our investigation revealed that not only type 1 diabetes but also LADA is associated with CTLA-4 gene polymorphisms. The role of CTLA-4 gene in the pathogenesis of LADA is open and needs further investigations.

Functional polymorphism of CTLA-4 and ICOS genes in allogeneic hematopoietic stem cell transplantation

Background T cells play a critical role in alloimmune recognition and thus contribute to graft-versus-host disease (GVHD) and relapse prevention in hematopoietic stem cell transplantation (HSCT). Cytotoxic T lymphocyte antigen-4 (CTLA-4) and inducible costimulator (ICOS) are costimulatory molecules of T cell activation and their genetic variations can affect the capacity of T cells to become activated or inactivated. Methods We examined CTLA-4 (− 318 C/T and + 49 A/G) and ICOS ( c.602 A/C and c.1624 C/T) genotypes in 123 patients with HSCT and their HLA-matched sibling donors, and then evaluated the impacts of the genetic polymorphisms on GVHD, disease relapse, and survival. Results By multivariate analysis, the donor CTLA-4 − 318 TT genotype increased the risk of disease relapse (Hazard ratio [HR]: 5.91, 95% confidence interval [CI]: 1.17–29.79, P = 0.0313). Recipients who received a graft from a donor with ICOS c.602 CC genotype had worse disease-free survival (HR: 5.97, 95% CI: 1.49–23.87, P = 0.0115). Additionally, recipients with ICOS c.1624 TT genotype had worse overall survival (HR: 12.98, 95% CI: 2.58–65.35, P = 0.0019). Nevertheless, CTLA-4 and ICOS genotypes were not associated with acute and chronic GVHD. Conclusions Both donor and recipient CTLA-4 and ICOS gene polymorphisms might be of importance for the outcome of allogeneic HSCT.

Cytotoxic T lymphocyte antigen-4 promoter −658CT gene polymorphism is associated with ulcerative colitis in Chinese patients

Cytotoxic T lymphocyte antigen-4 (CTLA-4) plays a role in the downregulation of T cell activation. The present study aimed to examine an association between the CTLA-4 gene polymorphisms and ulcerative colitis (UC) in the Han Chinese in central China. One hundred seventeen patients with UC and 246 healthy controls were genotyped for CTLA-4 gene -658CT in the promoter and CT61 at the 3' untranslated region using a method of polymerase chain reaction-based restriction fragment length polymorphism and single-strand conformation polymorphism, respectively. The distributions of the genotypes and the allele frequencies of the CTLA-4 gene in UC patients and healthy controls were compared by chi-square test. The frequency of the T/T+C/T genotype at the CTLA-4 gene -658CT in the promoter was significantly higher in UC patients than in healthy controls (26.5% vs 15.4%, chi (2) = 6.287, P = 0.015, OR = 1.973, 95%CI = 1.153-3.375). The frequency of the T allele at the CTLA-4 -658CT was also significantly higher in UC patients than in the controls (13.2% vs 8.1%, chi (2) = 4.707, P = 0.033, OR = 1.726, 95%CI = 1.049-2.838). The frequency of the T/T genotype at the -658 locus was highly associated with extensive colitis in UC patients (P = 0.037, OR = 3.955, 95%CI = 1.068-14.647). The frequency of the T allele at the -658 locus was highly associated with extensive colitis in UC patients (P = 0.0067, OR = 3.05, 95%CI = 1.320-7.048). The T allele of CTLA-4 -658 polymorphism in the promoter of CTLA-4 gene was highly associated with UC in the Han Chinese in central China.

CTLA4 Gene Polymorphisms in Children and Adolescents with Autoimmune Thyroid Diseases

Two common forms of autoimmune thyroid diseases are Graves' disease and Hashimoto's thyroiditis. Cytotoxic T lymphocyte antigen 4 (CTLA4) encoded by the CTLA4 gene on chromosome 2q33 plays a role in susceptibility to Graves' disease and is probably important also for Hashimoto's thyroiditis as well as for the other endocrine autoimmune disorders. The CTLA4 locus is the only nonhuman leukocyte antigen locus that has been found in association with Graves' disease repeatedly. Particularly, association of three polymorphic markers of CTLA4 gene, namely, C(-318)T, A49G, and (AT)n dinucleotide repeat, with Graves' disease was demonstrated in most of the population-based investigations. On the other hand, there are few studies to reveal the association of these markers with Hashimoto's thyroiditis. A49G polymorphism was proposed to be associated with Hashimoto's thyroiditis, and C(-318)T was suggested to be not associated. The patient groups consisted of 88 patients (10 males and 78 females; mean age: 14.5 +/- 3.2 years [4.6-21.0 years]) with a previous diagnosis of Hashimoto's thyroiditis and 112 euthyroid volunteers (51 males and 61 females; mean age: 14.1 +/- 2.9 years [5.2-18 years]). The frequency of A/G (A49G) genotype was high and statistically significant in patients with Hashimoto's thyroiditis in comparison with the control group. Although the frequency of C/T [C(-318)T] genotype is not significantly high in children with Hashimoto's thyroiditis according to the control group, the risk of Hashimoto's thyroiditis in A/G genotype group was 4.66 times greater than the group with A/A genotype. In this study, we documented that the A49G polymorphism might increase the susceptibility for Hashimoto's thyroiditis.