CTLA-4基因49A/G多态性与Graves病复发相关

采用PCR-RFLP对120例Graves病(GD)复发患者(停药3年内复发85例,3年后复发35例),66例GD初发患者和100例健康对照的细胞毒性T淋巴细胞相关抗原4(CTLA-4)基因A/G多态性进行检测.结果 提示,CTLA-4第1外显子49位点A/G多态性在中国北方汉族人不仅与GD发生相关,而且影响GD停药后缓解的持续时间,与早期复发相关.     

CTLA-4 gene polymorphism is associated with predisposition to coeliac disease

BACKGROUND: Susceptibility to coeliac disease is strongly associated with particular HLA class II alleles. However, non-HLA genetic factors are likely to be required for the development of the disease. Among candidate genes is the CTLA-4 (cytotoxic T lymphocyte associated) gene located on chromosome 2q33 in humans, which encodes a cell surface molecule providing a negative signal for T cell activation. AIMS: To investigate CTLA-4 exon 1 polymorphism (position 49 A/G) in patients with coeliac disease. PATIENTS: 101 patients with coeliac disease and 130 healthy controls. METHODS: Allele specific hybridisation and restriction enzyme digestion of polymerase chain reaction amplified genomic DNA. RESULTS: The A allele of the CTLA-4 position 49 polymorphism was found on 82.2% of chromosomes in patients with coeliac disease compared with 65.8% in controls (p < 0.0001), mostly in the homozygous form (68.3% in patients versus 47.7% in controls; odds ratio (OR) 2.36, 95% confidence interval (CI) 1.37 to 4.06, p = 0.002). Four patients only had the G/G genotype compared with 21 controls (OR 0.21, CI 10.07 to 0.64, p = 0.002). These differences were maintained when subjects were stratified according to the HLA class II phenotype, in particular when patients and controls were matched for the presence of the predisposing HLA DQB1*02 (DQ2) allele or HLA-DQA1*0501/DQB1*02 heterodimer. CONCLUSION: The CTLA-4 gene polymorphism is a non-HLA determinant that predisposes to coeliac disease. Whether it directly contributes to disease susceptibility or represents a marker for a locus in linkage disequilibrium with CTLA-4 needs further investigation.     

CTLA-4基因外显子1A/G49多态性与1型糖尿病的相关性研究

目的 探讨细胞毒性T淋巴细胞相关抗原4（CTLA－4）基因外显子1的49位点A／G多态性与中国汉族人1型糖尿病（DM）的关系。方法 采用多聚酶链式反应限制性片段长度多态性（PCR－RFLP）技术对33例典型1型DM患者、57例成人晚发自身免疫性糖尿病患者（LADA)和84例健康对照者分析CTLA－4基因外显子1的49位点基因型。结果 1型DM患者的CTLA－4／G^49等位基因频率显著高于对照组（P=0.0005)，而典型1型DM和LADA两组间无显著性差异（P＝0.097)；ICA和GADAb阳性率与G^49无明显相关性（分别为P＝0.065,P=0.066)。结论 CTLA－4基因外显子1多态性与中国汉族人1型DM有关，G^49等位基因是1型DM的独立危险因素之一。     

CTLA-4 +49A/G gene polymorphism and type 1 diabetes mellitus in the Chinese population: a meta-analysis of 2238 subjects

Previous studies reported that cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) +49A/G gene polymorphism is correlated with type 1 diabetes mellitus (T1DM) risk. However, their results remain disputable. This study aims to discuss the relationship between CTLA-4 +49A/G gene polymorphism and T1DM in a Chinese population. The current meta-analysis involved 2238 participants from seven individual studies. The pooled odds ratio (OR) and its corresponding 95 % confidence interval (95 % CI) were assessed by the random- or fixed-effects model. A significant relationship between CTLA-4 +49A/G gene polymorphism and T1DM was detected under allelic (OR: 1.84, 95 % CI: 1.62–2.10, P?<?0.00001), dominant (OR: 1.152, 95 % CI: 1.062–1.249, P?=?0.001), recessive (OR: 1.631, 95 % CI: 1.443–1.844, P?<?0.00001), and additive (OR: 1.292, 95 % CI: 1.224–1.363, P?<?0.00001) genetic models. A significant relationship exists between CTLA-4 +49A/G gene polymorphism and increased T1DM risk in the Chinese population. Individuals having the G allele of CTLA-4 +49A/G gene polymorphism have a higher risk for T1DM in the Chinese population.     

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

Purpose  

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.     

Association of PTPN22 C1858T and CTLA-4 A49G polymorphisms with type 1 diabetes in Croatians

In this case–control study the association between the PTPN22 1858T and CTLA-4 49G gene variants and T1D in Croatian population was examined. We found that distribution of PTPN22 C1858T and CTLA-4 A49G genotypes between T1D patient (n = 102) and control (n = 193) groups differ significantly (p < 0.0001 and p = 0.012, respectively). Moreover, although the risk alleles of both SNPs are distributed more frequently in patients, the significant difference is observed only for PTPN22 1858T allele (p < 0.0001). This is therefore the first evidence that analyzed gene variants contribute to T1D pathogenesis in Croatian population.     

Association of PTPN22 C1858T and CTLA-4 A49G polymorphisms with type 1 diabetes in Croatians

In this case–control study the association between the PTPN22 1858T and CTLA-4 49G gene variants and T1D in Croatian population was examined. We found that distribution of PTPN22 C1858T and CTLA-4 A49G genotypes between T1D patient (n = 102) and control (n = 193) groups differ significantly (p < 0.0001 and p = 0.012, respectively). Moreover, although the risk alleles of both SNPs are distributed more frequently in patients, the significant difference is observed only for PTPN22 1858T allele (p < 0.0001). This is therefore the first evidence that analyzed gene variants contribute to T1D pathogenesis in Croatian population.     

CTLA-4 +49A>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.     

Increased frequency of the CTLA-4 49 A/G polymorphism in patients with acquired haemophilia A compared to healthy controls

Summary.  Acquired haemophilia (AH) is an autoimmune disorder characterized by autoantibodies against endogenous factor VIII (FVIII). Half of the patients present with an underlying disease known to cause the FVIII autoantibodies whereas in the other half the disease is of idiopathic nature. Recently, it has been shown that variants of the polymorphic cytotoxic T lymphocyte antigen-4 ( CTLA-4 ) gene are associated with autoimmune diseases and also represent a risk factor for inhibitor formation in inherited haemophilia A. In the present study, we investigated whether CTLA-4 variants also play a role in the pathogenesis of AH. Therefore, we analyzed three single nucleotide polymorphisms (SNPs) of the CTLA-4 gene (-318 C/T, +49 A/G and CT60 A/G) in 57 AH patients and 98 controls. The CTLA-4  +   49 G allele occurred with a significantly higher frequency in patients with AH compared with controls [odds ratio (OR) = 2.17, 95% confidence interval (CI): 1.36–3.48, P  = 0.001]. This effect was mainly caused by a higher frequency of the 49 G allele in female patients (OR = 5.1, 95% CI: 1.76–15.02, P = 0.002 ), whereas in males the frequencies were not significantly different (OR = 1.4, P  = 0.5). A higher frequency of the G allele was also observed in the subcohort with AH and underlying autoimmune disease (OR = 3.1, P  = 0.04). Our observations of a higher frequency of the CTLA-4  +   49 A/G SNP in AH patients are in concordance with findings in other autoimmune disorders. In conclusion, on the background of the CTLA-4 gene polymorphism, further genetic and/or environmental factors might contribute to and finally trigger the clinical manifestation of AH.     

Strong Association of CTLA-4 Variation (CT60A/G) and CTLA-4 Haplotypes with Predisposition of Iranians to Head and Neck Cancer

Background: Variations in Cytotoxic T Lymphocyte Antigen-4 (CTLA-4) affect the expression and function of this protein. Objective: We aimed to investigate the association of +49 A/G (rs231775), +1822 C/T (rs231779) and +6230 A/G (CT60, rs3087243) genetic variations, as well as the merged haplotypes in CTLA-4 gene with susceptibility to, or progression of head and neck cancer. Methods: Eighty patients with confirmed head and neck (HN) cancer (age 54.9 ± 16.1 years) and 85 healthy age/sexmatched controls (age 56.3 ± 12.4 years) were enrolled in the study. Genotypes were investigated by the PCR-RFLP method. Arlequin software package was used to check for Hardy-Weinberg equilibration, and to estimate the haplotypes. Results: At position +6230 A/G (CT60), AA genotype, as well as A allele was significantly decreased in patients with HN cancers than controls (18.8% vs. 40.7%, p=0.004; odds ratio=0.34, and 46.3% vs. 61.7, p=0.007; odds ratio=0.53%, respectively). Nearly the same results were obtained when we compared the subgroup of patients with squamous cell carcinoma of the HN (SCC-HN) with control subjects. The frequencies of genotypes and alleles at other positions were not significantly different between patients and controls, however ACG, GTA and GCA haplotypes emerged from three investigated loci occurred with significantly more frequencies in patients (p<0.0001), while ACA and GTG haplotypes were more frequent among controls (p<0.0001). Significant differences of haplotypes, genotypes and alleles frequencies resisted the Bonferroni correction. Conclusion: Our results suggest that CT60 A allele, as well as ACA and GTG haplotypes in CTLA-4 gene may have protective roles against HN cancer in Iranian population, while ACG, GTA and specially GCA haplotypes may render susceptibility.     

Cytotoxic T-lymphocyte antigen 4 gene +49A/G polymorphism significantly associated with susceptibility to primary biliary cirrhosis: a meta-analysis

OBJECTIVE: To evaluate comprehensively the association of cytotoxic T‐lymphocyte antigen 4 (CTLA‐4) +49A/G polymorphism with susceptibility to primary biliary cirrhosis (PBC). METHODS: PubMed was used to search for the relevant published articles. The risk of PBC association with the CTLA‐4+49A/G polymorphism was estimated for each study in a random‐effects model. Odds ratio (OR) and 95% confidence interval (CI) were estimated for each study. Risks to PBC were estimated by stratified analysis in patients with different ethnicity and antimitochondrial antibody (AMA) status, as well as histological stages. RESULTS: A total of 12 articles were included in the study. An association between PBC and CTLA‐4 G allele was found, overall OR = 1.20, 95% CI 1.03–1.41 (P = 0.02). However, stratification by ethnicity indicated a significant association between the G allele and PBC in Asians (OR = 1.36, 95% CI 1.12–1.65, P = 0.002), but not in Caucasians (OR = 1.15, 95% CI 0.95–1.39, P = 0.15). Moreover, AMA positive patients carrying G allele were more susceptible to PBC compared with AMA negative patients (OR = 1.23, 95% CI 1.06–1.43, P = 0.007; OR = 0.98, 95% CI 0.71–1.34, P = 0.88, respectively). CONCLUSIONS: Polymorphism in exon 1 of CTLA‐4 gene at position 49 may act as a candidate of susceptibility locus to PBC. However, larger studies with participants of varying ethnicity and stratified by clinical and laboratory characteristics are needed to validate our findings.     

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 of CTLA-4 polymorphism with positive anti-GAD antibody in Japanese subjects with type 1 diabetes mellitus

OBJECTIVE: CTLA-4, expressed on activated T cells, is thought to be a negative regulator of T cell function. Its gene (2q33) may confer genetic susceptibility to type 1 diabetes mellitus (IDDM12). The present study was undertaken to clarify the role of CTLA-4 gene polymorphism in Japanese subjects with type 1 diabetes and its effect on their clinical features. SUBJECTS AND METHODS: In 117 Japanese subjects with type 1 diabetes, the CTLA-4 exon 1 polymorphism (49 A/G) was defined by PCR-RFLP analysis. Anti-GAD antibodies (GAD-Ab) and fasting serum C-peptide were also determined. 141 healthy age- and sex-matched subjects served as controls. RESULTS: The frequency of each polymorphism was not different between the type 1 diabetic subjects and the controls; AA 21, AG 42 and GG 54 for the diabetic subjects, and AA 22, AG 47 and GG 72 for the controls. The frequency of the GG genotype was higher in the diabetic subjects with positive GAD-Ab (greater than 8 U/ml) (67%) than in the GAD-Ab negative subjects (39%) (P < 0.05). The prevalence of positive GAD-Ab declined with the duration of diabetes. In the diabetic subjects with disease duration of less than 5 years (n = 40), the frequency of the GG genotype was also higher in the GAD-Ab positive subjects (71%) (P < 0.05). In the analysis of all the diabetic subjects, there was a strong association between positive GAD-Ab and beta cell function (P < 0.0001). CONCLUSIONS: There was no evidence that the CTLA-4 exon 1 polymorphism (49 A/G) confers genetic susceptibility to type 1 diabetes mellitus in our case-control study in Japanese subjects. However, the frequency of positive GAD-Ab was higher in the GG subjects. CTLA-4 polymorphism might contribute to the clinical heterogeneity of type 1 diabetes mellitus in Japanese subjects.     

抗原肽运载体基因多态性与1型糖尿病关联性的初步探讨

目的　初步探讨抗原肽运载体 (TAP)基因在华南地区一组汉族人中的分布及其与 1型糖尿病的关联性。方法　采用扩增阻滞突变体系 (ARMS)检测TAP1及TAP2基因各多态性位点在 66例 1型糖尿病患者及 69例正常对照组中的分布。结果　TAP基因各多态性位点在本组华南地区健康汉族人中的分布与国内外其它组资料基本一致 ,但存在一定程度的差异 ,提示TAP1及TAP2基因型可能有民族、地区分布的差异。TAP1基因的单倍体型TAP1D和单倍体型TAP2A在正常人群中的分布频率显著高于 1型糖尿病组 (RR分别为 0 .1 7和 0 .31 ,P均 <0 .0 1 ) ;而TAP2基因TAP1A和TAP2F在正常人群中的分布频率显著低于 1型糖尿病组 (RR分别为 4 .1 0和 8.94,P分别 <0 .0 1和 <0 .0 5)。结论　TAP1D及TAP2A与 1型糖尿病的保护性相关 ,可能是 1型糖尿病的保护基因 ;TAP1A及TAP2F与 1型糖尿病的易感性相关 ,可能是 1型糖尿病的易感基因     

抗原肽运载体基因多态性与1型糖尿病

目的初步探讨抗原肽运载体(TAP)基因在华南地区一组汉族人中的分布及其与1型糖尿病的关联性.方法采用扩增阻滞突变体系(ARMS)检测TAP1及TAP2基因各多态性位点在66例1型糖尿病患者及69例正常对照组中的分布.结果 TAP基因各多态性位点在本组华南地区健康汉族人中的分布与国内外其它组资料基本一致,但存在一定程度的差异,提示TAP1及TAP2基因型可能有民族、地区分布的差异.TAP1基因的单倍体型TAP1D和单倍体型TAP2A在正常人群中的分布频率显著高于1型糖尿病组(RR分别为0.17和0.31,P均＜0.01);而TAP2基因TAP1A和TAP2F在正常人群中的分布频率显著低于1型糖尿病组(RR分别为4.10和8.94,P分别＜0.01和＜0.05).结论 TAP1D及TAP2A与1型糖尿病的保护性相关,可能是1型糖尿病的保护基因;TAP1A及TAP2F与1型糖尿病的易感性相关,可能是1型糖尿病的易感基因.