CTLA-4 gene polymorphism in promoter and exon-1 regions in Chinese patients with systemic lupus erythematosus.

Cytotoxic T lymphocyte associated antigen 4 (CTLA-4), a structural homologue of CD28, has been reported to be an important negative regulator of autoimmune diseases. Recent studies showed that CTLA-4 gene polymorphism was associated with several kinds of human autoimmune diseases, suggesting that CTLA-4 gene is probably a general susceptibility gene to autoimmune disease. The present study was conducted in Chinese to determine whether there is any association of the CTLA-4 gene polymorphism with the development of systemic lupus erythematosus (SLE). CTLA-4 gene polymorphism in promoter and exon 1 was detected by polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) method in 81 patients with SLE and 81 normal controls. The results showed that there were no statistically significant differences in both exon 1 and promoter gene polymorphism between SLE patients and normal controls. The preliminary study does not suggest an association of the known polymorphism in exon 1 and promoter of CTLA-4 gene with Chinese SLE. However, SLE is a very heterogeneous syndrome and CTLA-4 gene polymorphism might correlate with some specific clinical features. To exploring this possibility, subgroup analysis in more patients needs to be performed.     

The A-G polymorphism in exon 1 of the CTLA-4 gene is not associated with systemic lupus erythematosus

OBJECTIVES: Factors contributing to the development of systemic lupus erythematosus (SLE) remain largely unknown although are likely to include both environmental and genetic components. Studies on murine lupus have indicated a role for an antibody that blocks binding of cytotoxic T lymphocyte associated-4 (CTLA-4) to B7 on antigen presenting cells in the treatment of disease, suggesting that CTLA-4 may play an important part in the disease process. This study, therefore, investigated the frequency of a previously described A-G polymorphism in exon 1 of the CTLA-4 gene, the G allele of which has shown to be associated with both Graves' disease and type I diabetes, to determine whether this polymorphism was playing a part in the development of SLE. METHODS: One hundred and twenty six SLE patients and 363 control subjects were genotyped for the A-G polymorphism in exon 1 of the CTLA-4 gene. Target DNA was amplified using the polymerase chain reaction and the resulting product was digested using the BbvI restriction enzyme. RESULTS: No differences in allele or genotype frequencies were observed between patients with SLE and control subjects. CONCLUSION: These data suggest that the A-G polymorphism in exon 1 of the CTLA-4 gene does not play a part in the genetic susceptibility to the development of SLE.     

Polymorphisms of the TAP2 transporter gene in systemic lupus erythematosus.

OBJECTIVES--To determine whether the TAP2 transporter gene, which lies between HLA-DP and HLA-DQ, is involved in determining susceptibility to systemic lupus erythematosus (SLE). METHODS--TAP2 types were determined by ARMS-PCR in 89 white patients with SLE and 156 control subjects. RESULTS--No particular TAP2 dimorphism or allele was associated with SLE or with any clinical/immunological subgroup of SLE. Furthermore, there was no evidence for significant linkage disequilibrium between TAP2 and HLA-DQ/DR in SLE. CONCLUSIONS--These data suggest that TAP2 is not a disease susceptibility gene for SLE and that the disease-predisposing haplotypes do not extend as far as TAP2. This indicates that any HLA-DP association with SLE must be independent of other class II (DQ/DR) associations.     

Polymorphisms of the interleukin-4 gene in chinese patients with systemic lupus erythematosus in Taiwan

We aimed to evaluate the relationship between two polymorphisms of the IL4 gene (-590T/C and intron 3) and systemic lupus erythematosus in Chinese patients in Taiwan. This study included 91 patients with systemic lupus erythematosus (SLE) and 163 unrelated, age matched healthy controls living in the same area. The typing of -590T/C and intron 3 VNTR (variable number of tandem repeats) polymorphisms were performed by PCR-RFLP and PCR, respectively. Allelic frequencies and carriage rates between SLE patients and controls were compared, and the relationship between allelic frequencies and clinical manifestations of SLE was evaluated. The genotype frequencies of IL-4 intron 3 were found to differ significantly between SLE patients with and without discoid rash (chi-square test, P = 0.03 5). The allelic frequency of intron 3 RP1 was significant different in the patients with discoid rash when compared to patients without this clinical feature (OR = 3.70, 95% CI 2.04-6.72, chi2 test, P = 0.029). The RP1/RP1 homozygous carriage was significantly associated with patients with discoid rash when compared to patients without this clinical feature (OR = 6.04, 95% CI 2.81-12.95, P = 0.01). The allelic frequency of -590T was significant different in the patients with discoid rash when compared to patients without this clinical feature (OR = 3.44, 95% CI 1.88-6.31, chi-square test, P=0.04). The T/T homozygous carriage was significantly associated with patients with discoid rash when compared to patients without this clinical feature (OR = 5.41, 95% CI 2.50-11.68, P = 0.02). We describe a novel association between RPI/RPI and T/T homozygous carriage and patients with discoid rash. The role of the intron 3 polymorphism of the IL4 gene in SLE remains unclear and further substantiation based on larger patient samples is needed.     

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.     

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.     

CTLA-4 gene polymorphisms and systemic lupus erythematosus in a population-based study of whites and African-Americans in the southeastern United States

Cytotoxic lymphocyte antigen-4 (CTLA-4) plays an important role in regulating T cell activation, and may help to limit T cell response under conditions of inflammation. Genetic variability in CTLA-4 has been implicated in the development of several autoimmune diseases. Some studies have described associations between CTLA-4 polymorphisms and systemic lupus erythematosus (SLE), but findings have been inconsistent. We examined polymorphisms in the CTLA-4 gene promoter region (-1722T/C, -1661 A/G, -318C/T) and exon I (+49G/A) with respect to SLE in a population-based case-control study in the southeastern US. Genotypes from 230 recently diagnosed cases and 276 controls were examined separately for African-Americans and whites. We observed no overall associations between SLE and the four CTLA-4 polymorphisms examined. Subgroup analyses revealed effect modification by age for the presence of the -1661G allele, yielding a significant positive association with SLE in younger (<35 years) African-Americans (OR = 3.3). CTLA-4 genotypes also interacted with HLA-DR2 and GM allotype to contribute to risk of SLE. These findings suggest allelic variation in this region of CTLA4 is not a major independent risk factor for SLE, but may contribute to risk of disease in younger African-Americans or in the presence of certain immunogenetic markers.     

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).     

中国汉族人群系统性红斑狼疮患者信号传导和转录激活子4基因多态性研究

目的 探讨信号传导和转录激活子4(STAT4)基因多态性与中国汉族人群系统性红斑狼疮(SLE)的相关性.方法 运用焦磷酸测序的方法对SLE患者与健康对照组DNA中存在的3个单核苷酸多态性位点进行分型,并作统计学分析.结果 STAT4基因的3个单核苷酸多态性(SNP)及其构成的单倍型在患者与健康对照组间差异均有统计学意义[rs11889341:P=012 02,0R(95%CI)=1.22(1.044～1.424);m7574865:P=0.003 454,OR(95%CI)=1.25(1.076～1.451);rs8179673:P=0.004 275,OR(95%CI)=1.274(1.079～1.505)].结论 STAT4基因上ra11889341、rs7574865和rs8179673与中国汉族人群SLE的发病有关联,且STAT4是-个多种族均存在的SLE相关基因.     

Polymorphisms of human glucocorticoid receptor gene in systemic lupus erythematosus: a single-centre result

Clinical Rheumatology - SLE is a systemic autoimmune disorder with multiple organ manifestations. Despite of the innovations glucocorticoids (GC) have still remained the first-line therapy in SLE....     

系统性红斑狼疮患者脱氧核糖核酸酶1基因多态性研究

目的：探讨脱氧核糖核酸酶1（DNASE1）基因单核苷酸多态性（SNP）与中国人系统性红斑狼疮（SLE）相关性。方法：验证文献报道的DNASE1基因3′端4个SNP，选取杂合度较高者对312个中国人群SLE家系以TaqManMGB等位基因识别技术在ABI7900HT序列测定仪上进行SNP基因分型，数据以SDS2．0软件收集，Genehunter进行统计处理并构建SNP单倍型。结果：中国人群中，DNASE1SNP3398，3737杂合度均接近0．5，4184亦有一定的杂合度。3398与3737的C－G单倍型优先传递给患病子代，3398、3737，4184的单位型C－G－G优先传递给患病子代（P＜0．05）。结论：在SLE患者中存在特定的SNP单倍型，部分SLE患者的发病与DNASE1基因相关联。     

Polymorphisms of DMA and DMB genes in Japanese systemic lupus erythematosus

Associations between polymorphisms of DMA and DMB alleles and systemic lupus erythematosus (SLE) were studied in 51 Japanese SLE patients and 77 normal subjects by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Phenotype frequencies of DMB*0101 tended to increase in SLE, but the difference was not significant (76.5% vs 70.1% in controls). The phenotype frequency of DMB*0103 was decreased in the SLE group, but the difference was not significant (49.0% vs 53.2%). Furthermore, there was no evidence of any association of either DMA or DMB alleles with HLA-DRB1*1501. The phenotype frequency of DMB*0101 was higher in the SLE group with anti- double-stranded DNA antibody (a-dsDNA) than in the SLE group without a- dsDNA, but the difference was not significant (P = 0.045, corrected P not significant). No other DMA or DMB alleles showed any associations in various immunological subgroups of SLE. These data suggest that neither the DMA nor the DMB gene determines susceptibility to SLE in Japanese.      

Polymorphisms in the promoter region of RANTES and the regulatory region of monocyte chemoattractant protein-1 among Chinese children with systemic lupus erythematosus

OBJECTIVE: Chemokines play an important role in the physiology and pathophysiology of acute and chronic inflammatory processes. We investigated whether chemokines such as RANTES (regulated upon activation, normally T cell expressed and secreted) promoter and monocyte chemoattractant protein-1 (MCP-1) regulatory polymorphisms were associated with systemic lupus erythematosus (SLE) in Chinese children. METHODS: Forty-six patients with SLE and 107 healthy children of comparable ages were studied for genotypes with polymerase chain reaction-based assays. RESULTS: The frequency and distribution of genotypes of the -28(C/G) RANTES gene polymorphism were significantly different between the 2 groups (p < 0.001), and the RANTES -28G allele was significantly more frequent in patients with SLE than in healthy controls (23.9% vs 11%; p = 0.006, OR 2.37, 95% CI 1.25-4.28). There was no significant difference in the frequency or in the distribution of genotypes of the -2518(A/G) MCP-1 and the -403(G/A) RANTES gene polymorphisms between patients and controls (p = 0.32 and p = 0.19, respectively). The RANTES -28G allele was also significantly associated with higher initial levels of antinuclear antibody, lower levels of C3, and higher incidences of central nervous system lupus. CONCLUSION: In the Chinese population, children with RANTES -28C/G polymorphisms have increased risk of developing SLE. Healthy controls with the C/G or G/G genotype were 2.37 times more likely to have SLE compared to those with the C/C genotype.     

Genetic variation in the interleukin-10 gene promoter in Polish patients with systemic lupus erythematosus

Identification of susceptibility genes in systemic lupus erythematosus (SLE) has recently become a topic of interest. The IL-10 promoter contains three single base-pair substitutions at −627C > A, −854C > T and −1117G > A. These single base-pair substitutions produce three different haplotypes, GCC, ACC and ATA, which affect IL-10 expression. We examined the distribution of −627C > A, −854C > T and −1117G > A IL-10 promoter polymorphisms in patients with SLE (n = 103, women only) and matched controls (n = 300). Despite the higher prevalence of the GCC/GCC, GCC/ATA and ATA/ATA genotypes in SLE patients than in controls, we observed that only GCC/GCC genotype frequency distribution was significant between these groups. We observed that women with the GCC/GCC genotype displayed an approximately twofold increased risk of SLE OR = 2.245 (95% CI = 1.354–3.721, P = 0.0022). We did not find any associations between various genotypes of IL-10 promoter haplotypes and clinical manifestations or autoantibody production in patients with SLE. Our observations indicate that the GCC/GCC promoter genotype may contribute to SLE incidence in Polish patients.     

Polymorphisms of the toll-like receptor 9 (TLR9) gene with systemic lupus erythematosus in Chinese

SIR, Systemic lupus erythematosus (SLE) patients and murinelupus models of SLE are characterized by the presence of autoantibodiesthat recognize DNA and nucleosomes. It has been shown that interactionof bacterial CpG DNA with toll-like receptor 9 (TLR9) expressedon B cells can stimulate production of antibodies [1]. In thelupus mouse model and SLE patients, DNA fragments isolated fromplasma are hypomethylated and they may mimic microbial DNA and