CTLA‐4 promoter variants in patients with Graves' disease and Hashimoto's thyroiditis

Braun, J.; Donner, H.; Siegmund, Thorsten; Walfish, Paul G.; Usadel, K. H.; Badenhoop, Klaus

doi:10.1111/j.1399-0039.1998.tb02993.x

Cited by 128 publications

(73 citation statements)

References 11 publications

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“…The analysis of the CTLA-4 (AT) n polymorphism showed one common allele consisting of 8 AT repeats (AT) 8 and many uncommon alleles (frequency < 6%) ranging from (AT) 13 to (AT) 33 that we grouped as (AT) other . The (AT) 8 /(AT) other genotype was the most represented in both examined groups.…”

Section: Resultsmentioning

confidence: 93%

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

et al. 2004

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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 nonHodgkin'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. Am.

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Section: Resultsmentioning

confidence: 93%

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

et al. 2004

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“…Our results could explain the increased expression of CTLA-4 3 and the observed associations of the −318T allele to some diseases. 4 Homozygosity for −318/T in the promoter of Ctla-4 is rarely present in a Caucasian population. [4][5][6][7] In our previous study, the frequencies of individuals with genotypes −318C/C, C/T, and T/T were 86%, 17% and 0%, respectively, in healthy individuals (n = 122) and 69%, 31%, 0%, respectively, in patients with Wegener's granulomatosis (n = 32).…”

Section: Resultsmentioning

confidence: 99%

“…4 Homozygosity for −318/T in the promoter of Ctla-4 is rarely present in a Caucasian population. [4][5][6][7] In our previous study, the frequencies of individuals with genotypes −318C/C, C/T, and T/T were 86%, 17% and 0%, respectively, in healthy individuals (n = 122) and 69%, 31%, 0%, respectively, in patients with Wegener's granulomatosis (n = 32). When we considered the prevalence of longer (AT)n in the 3Ј-untranslated region together with the promoter single nucleotide polymorphism (SNP), we found that all patients carrying the −318T allele were homozygous for (AT)n Ͼ86 bp alleles.…”

Section: Resultsmentioning

confidence: 99%

A CTLA-4 gene polymorphism at position −318 in the promoter region affects the expression of protein

et al. 2002

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Sweden CTLA-4 is an important negative regulator of the immune system. The regulation of the CTLA-4 gene (Ctla-4) transcription is poorly understood. A single nucleotide polymorphism (SNP) at −318 in the Ctla-4 promoter region is associated with certain autoimmune diseases. Since the −318 SNP occurs in a potential regulatory region, it is conceivable that the CЈ T transition may affect the expression of In the present study, we show that the −318T allele is associated with a higher promoter activity than the −318C allele (8.13 ± 0.46 vs 6.87 ± 0.49 CTLA-4 plays an important role in the immune system as a T cell inhibitory factor. This inhibitory signal not only determines whether T cells become activated, but also affects the clonal representation in an immune response. CTLA-4 regulates cell cycle progression rather than directly the induction of apoptosis. 1 CTLA-4 Ig and anti-CTLA-4 have been applied for the treatment of both autoimmune diseases and cancers.Little is known about the regulatory mechanism for CTLA-4 expression. Polymorphisms in the Ctla-4 are associated with several autoimmune diseases, and polymorphisms at certain locations of the Ctla-4 might conceivably affect its expression. We have described a higher prevalence of thymine at position −318 of the Ctla-4 promoter (−318T) in patients with Wegener's granulomatosis. 2 Recently, Ligers and colleagues reported that individuals carrying −318T exhibited significantly increased expression both of cell-surface CTLA-4 in activated cells and of Ctla-4 mRNA in non-stimulated cells, 3 suggesting a potential role for the CЈ T transition in the regulation of expression. In the present study, we examined the effect of CЈ T switch at −318 on the Ctla-4 promoter activity. Our results demonstrated that the −318T allele was associated with a significantly higher promoter activity than the −318C allele. Results and discussionTo determine whether the CЈ T transition at position −318 transcriptionally regulates the Ctla-4 gene expression, we made two Ctla-4 promoter reporter constructs which contained C and T alleles, respectively. As shown in Figure 1, the −318T allele was associated with a higher promoter activity than the −318C allele (8.13 ± 0.46 vs 6.87 ± 0.49). This result was also confirmed in the THP-1 cell line transfected with these two reporter constructs, and stimulated with IFN-␥ (5 mg/ml) and PMA (10 ng/ml).Our allele-specific transcription data indicate that the −318T allele is associated with higher transcriptional activity than the −318C allele. The -318T allele could be considered as protective against autoimmune reactions. Our results could explain the increased expression of CTLA-4 3 and the observed associations of the −318T allele to some diseases. 4 Homozygosity for −318/T in the promoter of Ctla-4 is rarely present in a Caucasian population. [4][5][6][7] In our previous study, the frequencies of individuals with genotypes −318C/C, C/T, and T/T were 86%, 17% and 0%, respectively, in healthy individuals (n = 122) and 69%, 31%, 0%, respective...

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“…23 The association of CTLA-4 and GD has also been confirmed in a family-based study using transmission disequilibrium test (TDT) analysis. 16 In contrast, association studies using a C/T SNP in the promotor of CTLA-4 at position -318 (C/T À318 ) were less consistent with some showing association 25 and others not. 24 CTLA-4 was also reported to be associated with HT in various populations including Caucasians 10,20 and Japanese, 13 although some studies did not find this.…”

Section: Introductionmentioning

confidence: 97%

Analysis of the CTLA-4, CD28, and inducible costimulator (ICOS) genes in autoimmune thyroid disease

et al. 2003

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The cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) gene on 2q33 is associated with autoimmune thyroid diseases (AITDs). Our earlier study in 56 families showed linkage of 2q33 to the presence of thyroid antibodies (TAbs). The goals of this study were to confirm the linkage of the 2q33 region to TAbs, to fine map this region, and study the ICOS gene. We performed a linkage study in an expanded data set of 99 multiplex AITD-TAb families (529 individuals). The highest two-point LOD score of 2.9 was obtained for marker D2S325 on 2q33. To fine map this locus, we genotyped 238 Caucasian AITD patients and 137 controls for five additional markers in the linked locus, which contained the CTLA-4, CD28, and ICOS genes. The A/G singlenucleotide polymorphism at position 49 of CTLA-4 was associated with AITD (P¼0.01, OR¼1.5), while markers inside CD28 and ICOS were not. Functional studies have shown that the G allele was associated with reduced inhibition of T-cell proliferation by CTLA-4. We concluded that: (1) the AITD gene in the 2q33 locus is the CTLA-4 gene and not the CD28 or ICOS genes; and (2) the G allele is associated with decreased function of CTLA-4.

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CTLA‐4 promoter variants in patients with Graves' disease and Hashimoto's thyroiditis

Cited by 128 publications

References 11 publications

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

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

A CTLA-4 gene polymorphism at position −318 in the promoter region affects the expression of protein

Analysis of the CTLA-4, CD28, and inducible costimulator (ICOS) genes in autoimmune thyroid disease

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