Association of the CTLA-4 Gene 49 A/G Polymorphism With Type 1 Diabetes and Autoimmune Thyroid Disease in Japanese Children

Mochizuki, M.; Amemiya, Shin; Kobayashi, Kenichi; Kobayashi, Koji; Shimura, Yoshie; Ishihara, Tsukasa; Nakagomi, Yoshiko; Onigata, Kazumichi; Tamai, Shinya; Kasuga, Akira; Nanazawa, Shinpei

doi:10.2337/diacare.26.3.843

Cited by 55 publications

(42 citation statements)

References 34 publications

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“…Subsequently, the three known polymorphisms of the CTLA-4 gene were investigated for linkage and/or association in a large number of human autoimmune diseases. Of interest, some polymorphisms of the gene, such as those of exon 1 which alter CTLA-4 transcription, increase susceptibility to type 1 diabetes (T1D) and other autoimmune diseases [16][17][18][19].…”

Section: Autoimmunity and Ctla-4 Geneticsmentioning

confidence: 99%

The soluble CTLA-4 receptor and its role in autoimmune diseases: an update

Saverino

Simone

Bagnasco

et al. 2010

Autoimmun Highlights

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CTLA-4, initially described as a membranebound molecule, is a costimulatory receptor transducing a potent inhibitory signal. Increasing evidence shows the CTLA-4 gene to be an important susceptibility locus for autoimmune endocrinopathies and other autoimmune disorders. A soluble form of cytotoxic T-lymphocyte-associated antigen-4 (sCTLA-4) has been established and shown to possess CD80/CD86 binding activity and in vitro immunoregulatory functions. sCTLA-4 is generated by alternatively spliced mRNA. Whereas low levels of sCTLA-4 are detected in normal human serum, increased serum levels are observed in several autoimmune diseases (e.g. Graves’ disease, myasthenia gravis, systemic lupus erythematosus, type 1 diabetes, systemic sclerosis, coeliac disease, autoimmune pancreatitis and primary biliary cirrhosis). The biological significance of increased sCTLA-4 serum levels is not fully clarified yet. On the one hand, it can be envisaged that sCTLA-4 specifically inhibits early T-cell activation by blocking the interaction of CD80/CD86 with the costimulatory receptor CD28. On the other hand, higher levels of sCTLA-4 could compete for the binding of the membrane form of CTLA-4 with CD80/CD86 in the later phases of T-lymphocyte activation, causing a reduction in inhibitory signalling. This double-edged nature of sCTLA-4 to block the binding of CD28 to CD80/CD86 may result in different outcomes during the clinical course of an autoimmune disease.

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Section: Autoimmunity and Ctla-4 Geneticsmentioning

confidence: 99%

The soluble CTLA-4 receptor and its role in autoimmune diseases: an update

Saverino

Simone

Bagnasco

et al. 2010

Autoimmun Highlights

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“…An association was detected between the CTLA4 gene polymorphism and younger-onset type 1 diabetes with autoimmune thyroid disease (AITD) (Gough, et al, 2005).. The G variant was suggested to be genetically linked to AITD-associated type 1 diabetes of younger onset in this Japanese population (Mochizuk, et al, 2003). The defect in these patients presumably lies in a T-cell mediated autoimmune mechanism (Takara et al, 2000).…”

Section: Resultsmentioning

confidence: 95%

The codon 17 polymorphism of the CTLA4 gene in type 1 diabetes mellitus in the Baghdad population

Ahmed¹

2014

J. Med. Genet. Genomics

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The aim of this work was to study the polymorphism in CTLA4 gene in insulin-dependent diabetes mellitus (IDDM) type I patients in Baghdad population. To achieve this goal, blood samples were collected from 80 IDDM (40 males and 40 females) and 20 samples of healthy, DNA was isolated and the CTLA4 gene (A 152 bp fragment) were amplified by using specific primers for exon1 of this gene, and then found the sequence of this region. The DNA sequencing results of flank sense of CTLA4 gene from healthy patients was found to be compatible (100%) with wild type of Homo sapiens from the Gene Bank, while 99% compatibility were found for the gene from 70 IDDM cases patients with wild type of gene. The difference may be attributed to one transition mutations, A/G at position 49 of the CTLA4 gene (from AGC to AAC). It is a missense mutation that leads to changes in amino acid from serine (S) to asparagine (N). Our results showed that the incidence of A/G mutation at nucleotide position 49 and diabetes was highly significant (X 2 = 100, P < 0.01). In total, 12% of patients with IDDM (10 cases) had two transition mutation +49 A/G and +47 C/T single nucleotide polymorphism from total cases, 98% compatibility were found for that gene from 10 IDDM cases patients with wild type of gene. The +47 C/T SNP was silent mutation which resulted in change of codon from GGT to GGC but no changes translated to amino acid (glycine to glycine). However, there was no significant correlation between diabetes and incidence of C/T at nucleotide 47 (X 2 = 0.055, P > 0.05). In conclusion, our case study suggests that the +49 A/G SNP of the CTLA4 gene is strongly associated with genetic susceptibility to type 1 diabetes mellitus in the Baghdad/Iraqi population.

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“…The association of CTLA4 gene polymorphisms with the autoimmune diseases, including type 1 diabetes (19,24), GD (20)(21)(22)32), abdominal disease (33), systemic lupus erythematous disease (34), rheumatoid arthritis (35), autoimmune pancreatitis (36) and Addison's disease (37), have been investigated. The CTLA4 gene has multiple SNP loci and repeat sequences.…”

Section: Ctla4 (Cd152)mentioning

confidence: 99%

“…The most significant function of the CTLA4 gene is negative regulation of the human immune response. Several polymorphic sites in the CTLA4 gene are associated with thyroid diseases, such as -318C/T promoter and 49A/G exon 1, -224(AT)n dinucleotide repeat sequence single-nucleotide polymorphism (SNP), -1722C/T, -1661A/G, CT60 (rs3087243), CT61 (rs51157131), J031 (rsl1571302) and J027-1 (rsl1571297) (16)(17)(18)(19)(20)(21)(22). Several studies also show that the SNPs at the 3' untranslated region (UTR) are more associated with GD (23)(24)(25).…”

Section: Introductionmentioning

confidence: 99%

Association of the CTLA4 gene CT60/rs3087243 single-nucleotide polymorphisms with Graves' disease

Fang

Zhang

et al. 2015

Biomedical Reports

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Abstract. It has been widely reported that the CT60 single-nucleotide polymorphism (SNP), which is in the 3'-untranslated region of the cytotoxic T lymphocyte associated 4 (CTLA4) gene, is strongly correlated with certain immune-mediated diseases. The present case-control study aimed to investigate the genetic association between the CT60 SNP within the CTLA4 gene and Graves' disease (GD). A total of 288 patients with GD and 290 control subjects were recruited for the study. The CT60 SNP of the CTLA4 gene was detected by direct DNA sequencing. The results indicated that the frequencies of the GG genotype and G allele in the case group were evidently higher than that in the control group (P=4x10 , respectively). Furthermore, the G/G genotype of the CT60 SNP was associated with an increased risk for GD (odds ratio=2.223). In conclusion, these results suggested that the CT60 SNP is associated with susceptibility to GD. The frequency of the disease-susceptible G allele of CT60 was significantly associated with an increased risk of GD development. IntroductionGraves' Disease (GD), also known as toxic diffuse goiter, can increase the level of thyroid hormone, is one of the organ-specific autoimmune diseases and it accounts for 85% of all clinical hyperthyroidism (1,2). The disease often presents in patients aged from 20-40 years old, with a male to female ratio of ~1:8 and a significant familial tendency (3). The clinical performance of GD is not limited to the thyroid, but is a multi-system syndrome, including the high metabolic syndrome group, diffuse goiter, eye symptoms, lesions and thyroid extremity diseases (4-6). Immunologically, GD is characterized by increased circulating antibodies against thyroid-stimulating hormone receptor (TSHR), thyroglobulin (TG) and thyroid peroxidase (TPO). Although the precise pathogenesis involved in the process of GD is not completely understood, certain findings indicate that complex interactions between environmental, genetic, endogenous and local factors are involved in its pathogenesis (7-9). A study on the genetic susceptibility genes of GD has become of interest (10-13).Previous studies have demonstrated that a number of susceptibility genes are associated with the autoimmune thyroid diseases, including interleukin-21, TSHR, human leukocyte antigen class I and II, cluster of differentiation 40 (CD40) and cytotoxic T lymphocyte associated 4 (CTLA4) (10-15). Among them, CTLA4 as a key negative regulator of the T lymphocyte immune response has attracted an increasing focus on the susceptibility to autoimmune disease. CTLA4, which is expressed by activate T cells, is a type of transmembrane protein. The CTLA4 gene is located on human chromosome 2q33 (16). The most significant function of the CTLA4 gene is negative regulation of the human immune response. Several polymorphic sites in the CTLA4 gene are associated with thyroid diseases, such as -318C/T promoter and 49A/G exon 1, -224(AT)n dinucleotide repeat sequence single-nucleotide polymorphism (SNP), -1722C/T, -1661A/G, CT60 (...

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Association of the CTLA-4 Gene 49 A/G Polymorphism With Type 1 Diabetes and Autoimmune Thyroid Disease in Japanese Children

Cited by 55 publications

References 34 publications

The soluble CTLA-4 receptor and its role in autoimmune diseases: an update

The soluble CTLA-4 receptor and its role in autoimmune diseases: an update

The codon 17 polymorphism of the CTLA4 gene in type 1 diabetes mellitus in the Baghdad population

Association of the CTLA4 gene CT60/rs3087243 single-nucleotide polymorphisms with Graves' disease

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