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.     

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。     

CTLA4 Gene Polymorphisms in Dutch and Chinese Patients with Inflammatory Bowel Disease

Background: Inflammatory bowel diseases (IBDs) are characterized by chronic intestinal inflammation as a result of an exaggerated T-cell response. CTLA4, a receptor of activated T cells, has an inhibitory function in regulating T-cell activation. Since CTLA4 gene polymorphisms have been associated with several autoimmune diseases, the aim was to study these gene polymorphisms in patients with IBD in two different populations. Methods: The C-318T polymorphism in the promoter region and A+49G polymorphism in exon 1 of the CTLA4 gene were investigated by a PCR-SSP method. We studied 139 unrelated patients with ulcerative colitis (UC), 163 patients with Crohn disease (CD) and 174 healthy controls of Dutch Caucasian origin as well as 35 patients with UC and 62 healthy controls from the Chinese Han population. Results: No significant differences in the distribution of allele, genotype and haplotype frequencies were observed between C-318T and A+49G gene polymorphisms and IBD in Dutch Caucasians and UC in the Chinese Han population. Although the haplotypes of the C-318T and A+49G polymorphisms were distributed differently between Dutch Caucasian and Chinese Han populations, there were no differences in the subgroups of patients with CD classified according to age, localization and behaviour in the Vienna classification and in those with UC classified according to age at onset, disease extension and presence of colectomy in the Dutch patients. However, the CTLA4-318 genotype CC was more frequent in patients with CD over 40 years (93%) than in younger patients (74%) ( P = 0.045). Conclusion: C-318T and A+49G CTLA4 gene polymorphisms and their haplotypes are not associated in Dutch Caucasian patients with IBD and in Chinese patients with UC.     

CTLA4 gene polymorphisms in Dutch and Chinese patients with inflammatory bowel disease

BACKGROUND: Inflammatory bowel diseases (IBDs) are characterized by chronic intestinal inflammation as a result of an exaggerated T-cell response. CTLA4, a receptor of activated T cells, has an inhibitory function in regulating T-cell activation. Since CTLA4 gene polymorphisms have been associated with several autoimmune diseases, the aim was to study these gene polymorphisms in patients with IBD in two different populations. METHODS: The C-318T polymorphism in the promoter region and A+49G polymorphism in exon I of the CTLA4 gene were investigated by a PCR-SSP method. We studied 139 unrelated patients with ulcerative colitis (UC), 163 patients with Crohn disease (CD) and 174 healthy controls of Dutch Caucasian origin as well as 35 patients with UC and 62 healthy controls from the Chinese Han population. RESULTS: No significant differences in the distribution of allele, genotype and haplotype frequencies were observed between C-318T and A+49G gene polymorphisms and IBD in Dutch Caucasians and UC in the Chinese Han population. Although the haplotypes of the C-318T and A+49G polymorphisms were distributed differently between Dutch Caucasian and Chinese Han populations, there were no differences in the subgroups of patients with CD classified according to age, localization and behaviour in the Vienna classification and in those with UC classified according to age at onset, disease extension and presence of colectomy in the Dutch patients. However, the CTLA4-318 genotype CC was more frequent in patients with CD over 40 years (93%) than in younger patients (74%) (P = 0.045). CONCLUSION: C-318T and A+49G CTLA4 gene polymorphisms and their haplotypes are not associated in Dutch Caucasian patients with IBD and in Chinese patients with UC.     

CTLA-4 gene promoter and exon 1 polymorphisms in Iranian patients with gastric and colorectal cancers

BACKGROUND AND AIM: Cytotoxic T-lymphocyte antigen-4 (CTLA-4) is a potent immunoregulatory molecule that suppresses antitumor response by down-regulating T-cell activation. Effects of several polymorphisms in CTLA-4 on CTLA-4 expression and function have been previously documented. The aim of this study was to investigate the putative effect of CTLA-4 polymorphisms on susceptibility to gastric and colorectal cancers in an Iranian population. METHODS: A total of 155 patients (109 with colorectal cancer and 46 with gastric cancer) and 190 age- and sex-matched healthy controls were evaluated. Genotyping of -1722T/C, -1661A/G, and +49A/G were performed by PCR restriction fragment length polymorphism methods and of -318C/T by a PCR amplification refractory mutation system technique. RESULTS: No statistically significant differences were found in the genotype distribution and allele frequencies among patients and controls. Haplotype analysis demonstrated that the TACG haplotype (-1722T, -1661A, -318C, +49G) frequency was significant increased in patients with colorectal cancer (P = 0.009) and gastric cancer (P = 0.006) in comparison to the control group. In contrast, the TACA haplotype frequency was significantly decreased in patients with colorectal cancer (P = 0.02) and not significantly decreased in patients with gastric cancer (P = 0.13) compared to the control group. CONCLUSION: A positive association between CTLA-4 TACG haplotype and gastric and colorectal cancers was found in an Iranian population. A protective role for TACA haplotype is postulated.     

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.     

Promoter polymorphism of transforming growth factor-β1 gene and ulcerative colitis

AIM： To elucidate the possible difference in two promoter polymorphisms of the transforming growth factor-β1 （TGF-β1） gene （-800G 〉 A, -509C 〉 T） between ulcerative colitis （UC） patients and normal subjects.
METHODS： A total of 155 patients with established ulcerative colitis and 139 normal subjects were selected as controls. Two single nucleotide polymorphisms within the promoter region of TGF-β1 gene （-509C 〉 T and -800G 〉 A） were genotyped using PCR-RFLP. RESULTS： There was a statistically significant difference in genotype and allele frequency distributions between UC patients and controls for the -800G 〉 A polymorphism of the TGF-β1 gene （P 〈 0.05）. The frequency of the TGF-β1 gene polymorphism at position -800 showed that the AA genotype and the allele A frequencies significantly differed between the patients and healthy controls （P 〈 0.05）. At position -509, there was no statically significant difference in genotype and allele frequency between the patients and control subjects.
CONCLUSION： The results of our study indicate that there is a significant difference in both allele and genotype frequency at position -800G 〉 A of TGF-β1 gene promoter between Iranian patients with UC and normal subjects.     

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.     

Association of CTLA-4 gene microsatellite polymorphism with ulcerative colitis in Chinese patients

Ulcerative colitis (UC) is characterized by chronic intestinal inflammation as a result of an exaggerated T cell response. Cytotoxic T lymphocyte associated antigen-4 (CTLA-4), expressed mainly in activated T cells, inhibits T cell activation and proliferation by combining B7 through competing CD28 and maintains immune homeostasis. Polymorphisms of the CTLA-4 gene are known to be associated with several autoimmune diseases. The aim of this study was to investigate the association between the CTLA-4 gene microsatellite polymorphism and UC in Chinese patients. Unrelated 100 Chinese patients with UC and 140 healthy controls were studied. The (AT) repeats in the 3' untranslated region of exon 4 of the CTLA-4 gene were amplified by allele-specific polymerase chain reaction (PCR). The amplified products were electrophoresed on a 12% polyacrylamide gel, followed by silver staining. Twenty alleles were found in Chinese patients and healthy controls. The 122-bp allele was increased in UC compared with healthy controls (9.5% vs 0.7%, P = 0.0001/Pc = 0.002, OR = 14.591, 95%CI 3.357-63.420). The frequency of the longer alleles (>or=118 bp) of UC was higher than that in healthy controls (26% vs 4%, P = 0.0001/Pc = 0.0002, OR = 7.644, 95%CI 3.950-14.792), but was not associated with location and severity of the disease. Furthermore, the longer alleles were not associated with haplotypes of C-318T/A+49G of the CTLA-4 gene in Chinese patients with UC. The longer alleles of the CTLA-4 gene microsatellite polymorphism were strongly associated with UC in Chinese patients.     

Promoter polymorphism of transforming growth factor-β1 gene and ulcerative colitis

AIM: To elucidate the possible difference in two promoter polymorphisms of the transforming growth factor-β1 (TGF-β1) gene (-800G > A, -509C > T)between ulcerative colitis (UC) patients and normal subjects.METHODS: A total of 155 patients with established ulcerative colitis and 139 normal subjects were selected as controls. Two single nucleotide polymorphisms within the promoter region of TGF-β1 gene (-509C > T and -800G > A) were genotyped using PCR-RFLP.RESULTS: There was a statistically significant difference in genotype and allele frequency distributions between UC patients and controls for the -800G > A polymorphism of the TGF-β1 gene (P < 0.05). The frequency of the TGF-β1 gene polymorphism at position -800 showed that the AA genotype and the allele A frequencies significantly differed between the patients and healthy controls (P <0.05). At position -509, there was no statically significant difference in genotype and allele frequency between the patients and control subjects.CONCLUSION: The results of our study indicate that there is a significant difference in both allele and genotype frequency at position -800G > A of TGF-β1 gene promoter between Iranian patients with UC and normal subjects.     

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.     

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.     

Enzyme-to-enzyme channeling in the early steps of glycolysis in rat pancreatic islets

+49 A/G polymorphism of CTLA-4 gene has been suggested to be associated with type 1 diabetes in some populations. However, a functional significance of the +49 A/G polymorphism is unknown, because it is believed the polymorphism does not affect the function of the CTLA-4 molecule. In this study, we examined the +49 A/G polymorphism of the CTLA-4 gene in 30 Japanese type 1 diabetic patients (14 type 1B and 16 type 1A) and 40 non-diabetic subjects in a case-control study, and stratified patients according to genotype of the polymorphism. The distribution of genotype frequencies differed between type 1 diabetic patients and controls (p<0.01). When the subjects were subdivided into type 1A and type 1B subgroups, a significant difference in G allele frequency was found only between type 1B patients and controls, whereas G allele frequency tended to be higher in type 1A diabetic patients than controls. Type 1B patients displayed more severe metabolic decompensation (higher plasma glucose concentration, lower urinary C-peptide levels, higher insulin requirement, and higher serum amylase levels), and were found to be more prone to diabetic ketoacidosis than type 1A patients. After stratification by genotype, differences in urinary C-peptide and serum amylase levels between type 1A and type 1B patients were found to be due to differences in the GG genotype subgroup, whereas in the AG subgroup those differences disappeared. In conclusion, the +49 A/G polymorphism of CTLA-4 gene was associated with the occurrence of type 1B diabetes in a Japanese population, and type 1B diabetics with a GG genotype were associated with more severe cell dysfunction than their type 1A counterparts.     

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.     

Association between CTLA-4 Gene Promoter (49 A/G) in Exon 1 Polymorphisms and Inflammatory Bowel Disease in the Tunisian Population

Background/Aim:

To investigate the possible association between the polymorphism of the CTLA-4 exon 1 +49 A/G and susceptibility to Crohn''s disease (CD) and ulcerative colitis (UC) in the Tunisian population.

Methods:

The +49 A/G dimorphism was analyzed in 119 patients with CD, 65 patients with UC, and 100 controls by the polymerase chain reaction–restriction fragment length polymorphism method.

Results:

Significantly higher frequencies of the CTLA-4 +49A allele and A/A homozygous individuals were observed in patients with CD when compared with controls (pc = 0.0023 and pc = 0.0003, respectively). Analysis of CTLA-4 A/G polymorphism with respect to sex in CD showed a significant difference in A/A genotypes between female patients and controls (pc = 0.0001 and pc = 0.038, respectively). There were no differences in the subgroups of patients with CD.

Conclusions:

Forty-nine A alleles and AA genotype are associated with CD susceptibility in Tunisians. Other genes involved in the T-cell regulation remain strong candidates for IBD susceptibility and require further investigation.     

No association of polymorphisms of the CTLA-4 exon 1(+49) and promoter(-318) genes with rheumatoid arthritis in the Korean population

The aim of this study is to investigate the significance of the polymorphisms of the cytotoxic T lymphocyte associated antigen-4 (CTLA-4) exon 1(+49) and promoter(-318) genes in rheumatoid arthritis (RA). Polymerase chain reaction of genomic DNA-restriction fragment length polymorphism was used to determine genotypes of the CTLA-4 exon 1(+49) and promoter(-318) in 86 RA patients and 86 healthy control subjects. There was no significant difference in genotype, allele and phenotype frequencies of the CTLA-4 exon 1(+49) and promoter(-318) genes between RA patients and control subjects. There was no significant difference in age at onset, severity, functional class (> or = 3), physician global assessment, ESR, CRP or RF titer in patients with RA according to the CTLA-4 polymorphisms. Our data show that the polymorphisms within the CTLA-4 exon 1(+49) and promoter(-318) genes are not associated with susceptibility to RA and its clinical/serological manifestations in the Korean population.     

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.     

Ethnic differences in cytotoxic T lymphocyte associated antigen 4 genotype associations with systemic sclerosis

OBJECTIVE: To determine the role of cytotoxic T lymphocyte associated antigen 4 (CTLA-4) genetic polymorphisms in susceptibility to systemic sclerosis (SSc, scleroderma). METHODS: The study population consisted of 293 African American and Caucasian patients with SSc and matched controls. Subjects were genotyped for allelic determinants at 4 polymorphic sites: 3 in the promoter region (positions -318, -1661, -1722) and one in the first exon (position +49) of the CTLA-4 gene, using polymerase chain reaction (PCR) restriction fragment length polymorphism (RFLP) methods. Genotype frequencies were compared using Pearson's chi-square or Fisher's exact test. RESULTS: In African American patients, the frequency of AG heterozygotes at position +49 was significantly higher than in controls (71% vs 36%, p = 0.003; OR = 4.37), while the frequency of AA homozygotes was significantly lower in patients than in controls (29% vs 61%, p = 0.007; OR = 0.26). The distribution of CTLA-4 alleles at other loci did not differ significantly between patients and controls. CTLA-4 genotypes were not associated with SSc in Caucasians. No differences in CTLA-4 genotype distributions were observed between patients with the limited and diffuse forms of the disease. CONCLUSION: Our data show that the exon 1 (+49) polymorphism of the CTLA-4 gene is associated with systemic sclerosis in African Americans.     

CTLA-4 gene A-G polymorphism and childhood Graves' disease

OBJECTIVE: Graves' disease is associated with a polymorphism at position 49 in exon 1 of the cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) gene in Caucasians and Japanese. A high incidence of childhood Graves' disease has been documented in Hong Kong Chinese. The aims of this study were to investigate the CTLA-4 gene A-G polymorphism association in Chinese children with Graves' disease. PATIENTS AND DESIGN: One hundred and twenty-three Chinese children with Graves' disease (104 girls and 19 boys) and 158 racially matched healthy controls were recruited for the study. Genomic DNA was extracted from venous blood samples. The dimorphism at position 49 A-G was analysed by polymerase chain reaction, single-strand conformation polymorphism and restriction fragment-length polymorphism analysis. RESULTS: The genotype distribution and allele frequencies of children with Graves' disease differed significantly from those of the controls (P = 0.0023 and P = 0.022, respectively). The presence of at least one G allele (GG or AG) was associated with an increased risk of Graves' disease (OR = 6.8, 95% CI = 2.0-36.1; P = 0.001). CONCLUSIONS: This study confirms that CTLA-4 49 A-G polymorphism is associated with Graves' disease in Chinese children. The CTLA-4 49 G allele confers an increased risk of childhood Graves' disease.