Association between the Polymorphism A/G at Position 49 of Exon 1 of the CTLA-4 Gene and Antithyroid Antibody Production in Children with Hashimoto's Thyroiditis

CTLA-4 gene is considered to be one of the strongest factors determining the predisposition to antithyroid antibody (Ab) production. The aim of the study was to evaluate the association of the polymorphism A/G of exon 1 of CTLA-4 gene and antithyroid Ab level in children with Hashimoto's thyroiditis (HT). Material and Methods: 45 children with HT (aged 14.9 ± 2, range 8.1-7.9) and 55 healthy controls (aged 14.8 ± 2.34, range 8.0-17.4) were enrolled. Controls were euthyroid and free from any autoimmune disease. CTLA-4 gene (+49)A/G polymorphism was evaluated by a single-strand conformation polymorphism method and restriction fragment-length polymorphism. Results: The frequency of GG genotype in HT children was significantly higher than in controls: 31 vs. 14.5% respectively (p < 0.04, OR = 2.65, CI = 0.99-7.06). Anti-Tg Ab titers were higher in patients homozygous for G allele than with AA genotype. The GG genotype seemed to be protective from hypothyroidism at the moment of HT diagnosis, but this observation was not statistically confirmed. Conclusions: Our study provides the evidence supporting the association between CTLA-4 gene (+49)A/G polymorphism and the susceptibility to HT in Polish children and confirms the existence of a link between (+49)A/G polymorphism and anti-Tg Ab level.     

慢性HBV感染者外周血单个核细胞CTLA-4基因多态性与病情转归的关联研究

目的初步探讨慢性HBV感染者外周血细胞毒性T淋巴细胞相关抗原-4（CTLA-4）基因第1外显子区49位基因单核苷酸多态性（single nucleotide polymorphism，SNP）与乙型肝炎病毒感染转归的关系。方法采用聚合酶链式反应-限制性片段长度多态性法检测190例慢性HBV感染者和93例既往HBV感染者外周血CTLA-4基因49位点的多态性。结果慢性HBV感染者CTLA-4基因49位点A／G基因型分布与对照组比较差异有显著性（P=0．034），慢性感染者G等位基因频率明显低于对照组（0．561对0．677，P=0．008，OR=0．607）。结论CTLA-4第1外显子49位基因多态性可能与乙型肝炎病毒感染慢性化相关。     

Polymorphism in the promoter and exon 1 of the cytotoxic T lymphocyte antigen-4 gene associated with autoimmune thyroid disease in Koreans.

The objective of this study was to examine the polymorphism in the cytotoxic T lymphocyte antigen-4 (CTLA-4) gene and its relationship with autoimmune thyroid disease in Koreans. Polymorphism in the promoter and exon 1 of CTLA-4, clinical symptoms of disease and thyrotropin receptor antibody (TSHRAb) characteristics were analyzed. Polymorphism was detected using restriction fragment length polymorphism and polymerase chain reaction amplification of genomic DNA. All subjects were Korean (97 Graves' disease, 110 Hashimoto's thyroiditis, and 199 normal controls). Graves' patients had significantly more G allele in exon 1 and C allele in the promoter than controls. When the exon 1 genotype was GG, the frequency of CC genotype in the promoter was higher. Allele frequencies in CTLA-4 did not differ from controls in patients with Hashimoto's thyroiditis. In Graves' patients, there were significant differences between genotypic groups in serum triiodothyronine (T3) levels and the presence of ophthalmopathy. However, TSHRAbs and other clinical characteristics were not significantly different. In conclusion, the CTLA-4 G allele in exon 1 and C allele in the promoter may confer genetic susceptibility to Graves' disease in Koreans. These two polymorphisms are additional and dependent genetic risk markers that help to characterize risk alleles within CTLA-4 gene.     

Cytotoxic T lymphocyte associated antigen-4 gene polymorphisms confer susceptibility to primary biliary cirrhosis and autoimmune hepatitis in Chinese population

AIM: To investigate the association between Chinese patients with autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC) and the polymorphisms of cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) gene promoter (-318) and exon 1 (+49). METHODS: CTLA-4 promoter (-318 T/C) and exon1 (+49A/G) polymorphisms were genotyped via restriction fragment length polymorphism methods in 62 Chinese AIH patients, 77 Chinese PBC patients and 160 healthy controls. RESULTS: We found a significant association in CTLA-4 gene exon1 49 A/G polymorphism between PBC patients and controls (P = 0.006) and the frequency of G alleles was significantly increased in comparison with controls (P = 0.0046, OR = 1.8). We also found the frequency of C alleles in promoter -318 was significantly increased in AIH patients compared with controls (P = 0.02, OR = 0.41). Although the genotype distribution of the CTLA-4 exon 1-promoter gene was not significantly different between AIH and PBC patients and controls, the occurrence of GG-CC was increased in two groups of patients (AIH: 32.3%, PBC: 37.7%, control: 22.5%). CONCLUSION: Polymorphisms of CTLA-4 gene probably confer susceptibility to AIH and PBC in Chinese population.     

细胞毒T淋巴细胞相关抗原4基因多态性与汉族溃疡性结肠炎患者的相关性研究

目的　研究细胞毒T淋巴细胞相关抗原4(CTLA- 4)基因外显子1的49位点A/G和启动子- 318位点C/T多态性与溃疡性结肠炎(UC)的相关性。方法　采用序列特异性引物聚合酶链反应(PCR -SSP)方法,检测82例中国湖北汉族溃疡性结肠炎患者(UC)以及204 例健康对照者CTLA- 4 基因外显子1的49位点A/G和启动子-318位点C/T的基因型和单倍型。结果　UC患者CTLA -4 A+49G和C- 318T基因型与正常对照组间差异无统计学意义(P>0.05),且与性别无关。在单倍型分析中,UC患者CTLA -4单倍型2,3(C-318 G49/T-318 A49)显著低于正常人群(26%比41%,P<0.05,OR=0.4918,95%CI:0.2784~0.8688)。结论　UC患者CTLA- 4 基因A+49G和C -318T单倍型2,3 与UC呈负相关。     

CTLA-4 gene polymorphisms in Chinese patients with ulcerative colitis

BACKGROUND: Ulcerative colitis (UC) is characterized by chronic inflammation of the colon and rectum as a result of an exaggerated T-cell response. Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) is a T cell-restricted surface molecule induced with TCR or CD28 activation. There is evidence for genetic involvement of CTLA-4 in several autoimmune diseases, with the focus on the possible role of genetic variation of the CTLA-4 locus. The aim of this study was to investigate CTLA-4 gene polymorphisms in patients with UC in a Chinese population with Han nationality. METHODS: The C-318T polymorphism in the promoter region and A+49G polymorphism in exon 1 of the CTLA-4 gene were studied by a polymerase chain reaction-sequence-specific primer method. We studied 82 unrelated patients with UC and 204 healthy controls in a Chinese population with Han nationality. RESULTS: The frequency of the haplotype 2,3 (-318C+49G/-318T+49A) was 26% in patients with UC and 41% in healthy controls (Fisher exact test P = 0.0147, odds ratio = 0.4918, 95% confidence interval: 0.2784 - 0.8688), but this significance disappeared when Bonferoni correction was applied. No other significant differences in the distribution of allele and genotype frequencies were observed between C-318T and A+49G gene polymorphisms and UC in the Chinese Han population. CONCLUSION: The C-318T and A+49G polymorphisms of the CTLA-4 gene were not associated with UC in Chinese Han patients.     

Analysis of cytotoxic T lymphocyte associated antigen 4 gene polymorphisms in patients with ulcerative colitis

BACKGROUND AND AIM: Ulcerative colitis (UC) is a multifactorial disease associated with dysregulated immunity. Recently, cytotoxic T lymphocyte associated antigen 4 (CTLA-4) gene polymorphisms have been reported in association with several autoimmune diseases in several populations. In the present study, the possible implication of the CTLA-4 gene as a risk factor for UC in the Iranian population was investigated. METHODS: One hundred UC patients and 100 healthy subjects were studied. CTLA-4 exon 1 position 49 (A/G: codon 17: Thr/Ala) polymorphisms were investigated by polymerase chain reaction single strand confirmation polymorphism method. Four of the patients and one of the healthy controls were excluded from the study because of incomplete DNA extraction. RESULTS: The allele frequencies of A and G in 96 patients (A: 66.1%; G: 33.9%) were not significantly different from the 99 control subjects (A: 63.1%; G: 36.9%, P > 0.05). No significant differences in the distribution of genotype frequencies were observed between A + 49G gene polymorphisms and UC in the Iranian population (P > 0.05). CONCLUSION: CTLA-4 polymorphism is not associated with UC in the Iranian population.     

Association of asthma severity and bronchial hyperresponsiveness with a polymorphism in the cytotoxic T-lymphocyte antigen-4 gene

OBJECTIVES: Cytotoxic T-lymphocyte antigen (CTLA)-4 is a homolog of CD28, which is expressed only on activated T cells. It binds to accessory molecule B7 and mediates T-cell-dependent immune response. Signaling through CTLA-4 may down-regulate type 1 T-helper cell proliferation; moreover, some studies suggest that CTLA-4 might also deliver a positive signal to type 2 T-helper cell activation. Disruption of this delicate balance of immune regulation may lead to autoimmune diseases or atopic diseases. To evaluate the possible role of CTLA-4 polymorphisms in bronchial asthma, we investigated the association between polymorphisms (exon 1 +49 A/G, promoter -318 C/T) and atopy, asthma severity, and bronchial hyperresponsiveness in bronchial asthma patients and a group of healthy control subjects. PATIENTS: Eighty-eight asthmatic patients and 88 healthy control subjects were studied. MEASUREMENTS AND RESULTS: Asthma severity assessment, methacholine challenge, allergy skinprick test, and serum total IgE measurements were performed. The genotypes of the CTLA-4 promoter (-318 C/T) and exon 1 (+49 A/G) in all subjects were determined using the polymerase chain reaction and restriction fragment length polymorphism. The CTLA-4 promoter (-318 C/T) polymorphism was shown to be associated with asthma severity, but not with asthma, atopy, or bronchial hyperresponsiveness. A significant association was found between severe asthma and the T allele (p = 0.037). The CTLA-4 exon 1 (+49 A/G) polymorphism was shown to be associated with bronchial hyperresponsiveness, but not with asthma, atopy, or asthma severity. Asthmatic patients of the GG genotype had more hyperresponsive airways than those with the AG or AA genotype (p = 0.019). CONCLUSIONS: The CTLA-4 promoter (-318 C/T) T allele may serve as a clinically useful marker of severe asthma. The CTLA-4 exon 1 (+49 A/G) polymorphism may have a disease-modifying effect in asthmatic airways.     

HLA-DQB1 CAR1/CAR2, TNFa IR2/IR4 and CTLA-4 polymorphisms in Tunisian patients with rheumatoid arthritis and Sj?gren's syndrome.

OBJECTIVES: To evaluate the contribution of HLA class II region and the CTLA-4 gene in genetic susceptibility to rheumatoid arthritis (RA) and Sj?gren's syndrome (SS) in the Tunisian population. METHODS: The polymorphisms of a (CA)n microsatellite of HLA-DQB1 CAR1/CAR2, TNFa IR2/IR4 and an (AT)n microsatellite in the 3'-untranslated region of exon 3 of the CTLA-4 gene were analysed after specific polymerase chain reaction (PCR) amplification. Typing of CTLA-4 A/G exon 1 polymorphism was achieved by the PCR-restriction fragment length polymorphism method. RESULTS: Genomic DNA from 60 patients with RA, 58 patients with SS and 150 healthy individuals was genotyped. The distribution of HLA-DQ CAR1/CAR2 allele frequencies differed between patients and controls in both diseases (RA, P<10(-15); SS, P=7.6x10(-15); RA+SS, P<10(-15)). The analysis of TNFa IR2/IR4 and CTLA-4 A/G polymorphisms did not show any differences in allele or genotype frequencies between patients and control subjects in either disease. The distribution of CTLA-4 (AT)n allele frequencies differed between patients with RA and controls (P=10(-3)), whereas no significant difference was detected between patients with SS and controls. CONCLUSION: These data suggest the involvement of HLA-DQ CAR1/CAR2 polymorphisms in genetic susceptibility to RA and SS and the participation of the CTLA-4 gene, or a gene closely associated with it, in the development of RA.     

Relation of three polymorphisms of the CTLA-4 gene in patients with Graves' disease

Graves' disease is an autoimmune disease believed to be caused by a combination of environmental and genetic factors. One of the candidate genes is CTLA-4, a negative regulator of T cell activation. Three polymorphisms of the gene have been described, in the promoter at position -318, at position 49 in exon 1, and an (AT)n repeat within the 3'-untranslated region of exon 4. Many studies describe the association between a polymorphism of the CTLA-4 gene and autoimmune disease. To investigate the association of these CTLA-4 gene polymorphisms with each other, we analyzed the combined frequencies of each polymorphism and calculated the disequilibrium coefficients. We studied DNA samples from 120 Graves' disease (GD) patients and 80 healthy donors (NC). The exon 1 position 49 A/G polymorphism and promoter polymorphism at position -318, were typed using a PCR-restriction fragment length polymorphism method (PCR-RFLP). The polymorphic (AT)n repeat in exon 4 was determined by PCR amplification of genomic DNA, resolution of the amplified products on sequencing gels, and detection by autoradiography. There was a significant difference between GD and NC patients and occurrence of the polymorphism in exon 1 and exon 3, but not for the polymorphism in the promoter region. Furthermore, we found that the genotype with both the G allele in exon 1 and the 106 bp allele of the AT repeat in exon 4 occurred with much higher frequency in GD than NC (p<0.01), and that these polymorphisms are in linkage disequilibrium with each other. These results support the concept that CTLA-4 plays a critical role in the autoimmune process in GD, and that GD depends on multiple genetic susceptibility factors. Because the exon 1 and exon 4 polymorphisms are in strong linkage disequilibrium. It is not possible at this time to determine their unique relation to CTLA-4 function. Studies relating each polymorphism to CTLA4 function are required to determine whether one, or both, polymorphism(s) promote autoimmune disease.     

Cytotoxic T lymphocyte-associated antigen-4 gene polymorphisms confer susceptibility to atopic asthma in Korean children

Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) is a negative regulator of T lymphocyte activation. The gene encoding CTLA-4 is a candidate gene for conferring susceptibility to allergic disease. The purpose of this study was to evaluate the potential effects of CTLA-4 gene polymorphisms in Korean children on asthma. We genotyped 272 children with atopic asthma, 54 children with nonatopic asthma (NAA), and 254 control children for allelic determinants at two polymorphic sites in the region at positions promoter - 318 C > T and exon 1 + 49 G > A using restriction fragment length polymorphism methods. As a result, allele and genotype frequencies of the CTLA-4 exon 1 + 49 G > A polymorphism were different to some extent between the atopic asthma children and the controls with P<0.05, which did not reach statistical significance after the correction of multiple comparisons. In addition, CTLA-4 + 49 G > A polymorphism was significantly associated with elevated serum IgE levels (P=0.01). Of the four haplotype, haplotype 1 (C-G) was only associated with atopic asthma susceptibility after the correction of multiple comparisons (P=0.01, OR=0.702, 95% CI= 0.541-0.911). Polymorphisms in the CTLA-4 gene likely confer susceptibility to atopic asthma in Korean children.     

Association of CTLA-4 but not CD28 gene polymorphisms with systemic lupus erythematosus in the Japanese population.

OBJECTIVE: Systemic lupus erythematosus (SLE) in a multisystem autoimmune disorder characterized by multiorgan pathology and autoantibodies against a variety of autoantigens. The CD28 and CTLA-4 genes might be candidate genes for SLE, because costimulation signals from CD80/CD86 to CD28/CTLA-4 have been suggested to play an important role in the activation or inactivation of T lymphocytes. METHODS: We investigated three polymorphic regions within the CTLA-4 gene, a C/T base exchange in the promoter region -318 (CTLA-4 -318C/T), an A/G substitution in the exon 1 position 49 (CTLA-4 49A/G), an (AT)(n) repeat polymorphism in the 3' untranslated region of exon 4 [CTLA-4 3' (AT)(n)], and a CD28 gene polymorphism, a T/C substitution in the intron 3 position +17 (CD28 IVS3+17T/C), in SLE patients and controls. RESULTS: SLE patients had significantly higher frequencies of the CTLA-4 49G allele (P=0.003) and of the CTLA-4 (AT)(n) 106 bp allele (P=0.0008) than controls. We also found a strong linkage disequilibrium between the A allele of CTLA-4 49A/G and the 86 bp allele of CTLA-4 3' (AT)(n). On the contrary, no association was found between SLE and CTLA-4 -318C/T or CD28 IVS3 +17T/C. CONCLUSION: We conclude that the CTLA-4 gene appears to play a significant role in the development of SLE in the Japanese population.     

Cytotoxic T lymphocyte antigen 4 (CTLA-4) dimorphism in patients with systemic lupus erythematosus

OBJECTIVE: Genetic susceptibility to systemic lupus erythematosus (SLE) is conferred not only by various genes within the major histocompatibility complex (MHC) region, but also by several other non-MHC linked genes. The negatively signalling molecule CTLA-4 is involved in establishing and maintaining of peripheral T cell tolerance, which controls T cell activation and reactivity. Its attenuating action helps to prevent an inappropriate initiation of T cell responses to self antigens and to terminate ongoing T cell responses. We tested if there was an association between CTLA-4 and SLE, a disease with B and T cell hyperreactivity and impaired peripheral T cell tolerance. METHODS: Using the polymerase chain reaction--restriction fragment length polymorphism method with Bbv I digestion, we assessed an exon 1 transition dimorphism (49 A/G) of the CTLA-4 gene in 102 SLE patients and in 76 healthy controls. RESULTS: The distribution of CTLA-4 exon 1 genotypes in the SLE group was significantly different from that in the controls (chi 2 = 6.178, p < 0.05). 17.6% of the SLE patients were G/G homozygotes compared to 5.3% of the controls; 36.3% were A/G heterozygotes vs 40.8% of controls; and 46.1% were A/A homozygotes vs 53.9% of the controls. The frequency of the G allele was significantly higher in SLE patients (35.8%) than in controls (25.7%; chi 2 = 4.142, p = 0.042). CONCLUSION: Our results indicate that the non-MHC linked CTLA-4 gene could confer susceptibility in SLE, as it does in various other autoimmune diseases (Hashimoto thyroiditis, Graves' disease, IDDM).     

Genetic and epigenetic factors in autoimmune reactions toward cytochrome P4502E1 in alcoholic liver disease

Autoimmune reactions are often associated with alcoholic liver disease; however, the mechanisms responsible are largely unknown. This study investigates the potential role of the immune response against hydroxyethyl free radical (HER)-derived antigens and of polymorphisms in immunoregulatory genes in the development of anti-cytochrome P4502E1 (CYP2E1) autoantibodies in alcohol abusers. Immunoglobulin G (IgG) recognizing human CYP2E1 and HER-derived epitopes were measured by microplate immunosorbent assay in the sera of 90 patients with alcoholic fibrosis/cirrhosis (ALD), 37 heavy drinkers without liver disease or steatosis only (HD), and 59 healthy subjects. Single nucleotide polymorphisms in the interleukin 10 (IL-10) promoter and in exon 1 of the cytotoxic T-lymphocyte antigen-4 (CTLA-4) gene were genotyped by polymerase chain reaction-restriction fragment length polymorphism analysis. The titers and frequency of anti-CYP2E1 autoantibodies were significantly higher in ALD than in HD subjects or controls. ALD patients with anti-HER IgG had higher titers and a 4-fold increased risk (OR: 4.4 [1.8-10.9]) of developing anti-CYP2E1 autoantibodies than subjects without anti-HER antibodies. The mutant CTLA-4 G allele, but not the IL-10 polymorphism, was associated with an enhanced risk of developing anti-CYP2E1 IgG (OR: 3.8 [1.4-10.3]). CTLA-4 polymorphism did not influence antibody formation toward HER-antigens. ALD patients with concomitant anti-HER IgG and the CTLA-4 G allele had a 22-fold higher (OR: 22.9 [4.2-125.6]) risk of developing anti-CYP2E1 autoreactivity than subjects negative for these factors. In conclusion, antigenic stimulation by HER-modified CYP2E1 combined with an impaired control of T-cell proliferation by CTLA-4 mutation promotes the development of anti-CYP2E1 autoantibodies that might contribute to alcohol-induced liver injury.     

Interactions of HLA-DRB4 and CTLA-4 genes influence thyroid function in Hashimoto's thyroiditis in Japanese population

Hashimoto's thyroiditis (HT) is an autoimmune disease of the thyroid gland, and like many other autoimmune diseases, it is associated with the HLA and CTLA-4 gene. We have examined the distribution of the HLA DRB4*0101 allele and a CTLA-4 exon 1 A/G polymorphism in Japanese HT patients and controls and investigated possible interactions of these genes with thyroid function. Seventy Japanese HT patients and 105 controls were included in this study. HT was diagnosed on the basis of positivity for thyroid peroxidase (TPO) autoantibodies and the presence of a palpable diffuse goiter. Genotyping was performed by polymerase chain reaction (PCR)-based methods. CTLA-4-GG or -AG was more prevalent in the patients, and the odds ratio for the G allele was 4.95. The frequency of DRB4*0101-positive individuals was significantly higher in HT (odds ratio=2.17). The TSH values of HT patients at the time of diagnosis were compared to CTLA-4 genotype and HLA-DRB4*0101 positivity. They were slightly higher in the CTLA-4-AG group than in the -GG group and significantly higher in the HLA-DRB4*0101-positive group than in the -negative group (p<0.01). When the TSH values were compared in 4 groups based on positivity or negativity for HLA-DRB4*0101 and CTLA-4 GG or AG, they were found to be significantly higher in the CTLA-4-AG and HLA-DRB4*0101-positive group than in the 3 other groups (F=5.75, 3 degrees of freedom, p<0.01). These findings suggest that the interaction between the HLA-DRB4 and CTLA-4 genes determines the thyroid function of TPO-positive goitrous Japanese HT patients.     

细胞毒T淋巴细胞相关抗原4基因多态性与溃疡性结肠炎

目的炎症性肠病的发病与T细胞过度活化有关,细胞毒T淋巴细胞相关抗原4（CTLA-4）是重要的T细胞活化负性调节因子.本课题研究CTLA-4基因启动子区-1722位点（T/C）及-1661位点（A/G）多态性与中国汉族人群中溃疡性结肠炎（UC）的相关性.方法采用PCR-限制性片段长度多态性方法,对87例中国汉族UC患者和116例正常对照者进行CTLA-4基因-1722位点和-1661位点多态性检测.结果UC患者CTLA-4基因-1661位点A/G＋G/G基因型频率,-1661位点G等位基因频率显著高于正常对照组（34.5%比15.5%,P=0.002,OR=2.865,95%CI=1.467～5.596;19.0%比8.2%,P=0.002,OR=2.624,95%CI=1.435～4.796）;而在-1722位点的基因型频率、等位基因频率与对照组比较差异无统计学意义（P＞0.05）.结论CTLA-4基因启动子区-1661位点G等位基因与中国汉族UC存在显著相关性.     

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.     

Cytotoxic T-lymphocyte antigen-4 (CTLA-4) gene polymorphism and susceptibility to non-Hodgkin's lymphoma

The CTLA-4 molecule plays an important role in immune regulation by downregulating activation of T cells. Polymorphisms in the CTLA-4 gene have been shown to be associated to a number of autoimmune diseases including blood disorders. In this study, the intragenic polymorphisms of the CTLA-4 gene at position -318*C/T, +49*A/G, and the dinucleotide (AT)(n) repeat polymorphism in exon 3 were analyzed in patients with non-Hodgkin's lymphoma. Genotype and haplotype analysis showed that the exon 1+49*AA genotype was over-represented among patients with NHL (P = 0.002), whereas no difference was observed for the -318*C/T promoter and the (AT)(n) polymorphisms (P > 0.05). The data obtained indicate that the CTLA-4+49A/G polymorphism may have a role in genetic susceptibility to NHL.     

CTLA-4 +49 A/G polymorphism is associated with predisposition to type 1 diabetes in Iranians

CTLA-4 is a homeostatic regulator of T cell activation and is believed to play a critical role in peripheral tolerance. The contribution of CTLA-4 gene variants to type 1 diabetes has been analyzed in several ethnic groups. In this study, the association of CTLA-4 +49 A/G polymorphism with type 1 diabetes was investigated in Iranian patients. One hundred and nine patients and 331 healthy subjects formed the studied populations. CTLA-4 A/G polymorphism at position 49 in exon 1 was identified using PCR-SSCP and PCR-RFLP methods. Patient numbers with A/G, A/A and G/G genotypes were 78 (71.5%), 21 (19.3%) and 10 (9.2%) while in healthy controls, these were 149 (45%), 146 (44.2%) and 36 (10.8%), respectively. A significant decrease in the frequency of the A/A genotype was observed in the diabetes group (p = 0.000004). In diabetic subjects, the allele frequency of G was also higher than in controls (45% versus 33.4%, p = 0.00269). The differences in the genotypes and the alleles were greater in patients with younger age of diabetes onset (age < or = 15 years) compared with controls (p = 0.000001 and p = 0.000579, respectively). The distribution of the CTLA-4 polymorphism between patients did not show any significant difference according to diabetic ketoacidosis at onset. In conclusion, the result of this study in combination with the previous reports of other ethnic populations showed that CTLA-4 +49 A/G polymorphism confers genetic susceptibility to type 1 diabetes, particularly in younger individuals.     

CTLA-4 gene polymorphism in Japanese patients with rheumatoid arthritis

OBJECTIVE: To examine whether CTLA-4 gene confers susceptibility to rheumatoid arthritis (RA) in Japanese. METHODS: We investigated the distribution of a CTLA-4 gene polymorphism in 85 Japanese patients with RA and 200 controls. An A/G transition at position 49 of exon 1 was analyzed by the polymerase chain reaction (PCR)-restriction fragment length polymorphism method. The patients were also analyzed with respect to HLA-DR status. HLA-DR typing was performed by PCR sequence-specific oligonucleotide typing. RESULTS: The distribution of genotype frequencies differed between RA and controls (chi-squared 8.63, 2 df, p = 0.013). The CTLA-4 AG genotype occurred more frequently in patients with RA (59 vs 44%), and the presence of at least one G allele (GG or AG) conferred an odds ratio of 2.53 (95% CI 1.74-3.32). When the patients were analyzed with respect to HLA-DR status, this association was restricted to patients carrying the susceptible HLA allele (HLA-DRB1*0405). CONCLUSION: The CTLA-4 gene is associated with Japanese patients with RA carrying the susceptible HLA allele.