Association of <i>CTLA-4</i> Gene A-G Polymorphism (<i>IDDM12</i> Locus) With Acute-Onset and Insulin-Depleted IDDM as Well as Autoimmune Thyroid Disease (Graves' Disease and Hashimoto's Thyroiditis) in the Japanese Population

Awata, Takuya; Kurihara, Susumu; Iitaka, Makoto; Takei, Shinichiro; Inoue, Ituro; Ishii, Chikara; Negishi, Kiyohiko; Izumida, Taro; Yoshida, Yoko; Hagura, Ryoko; Kuzuya, Nobuaki; Kanazawa, Yasunori; Katayama, Shigehiro

doi:10.2337/diab.47.1.128

Cited by 142 publications

(95 citation statements)

References 11 publications

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“…3 These results were confirmed in other populations such as Asians, populations of European ancestry, and Mexican-Americans. [11][12][13][14][15][16] Nevertheless, in other studies with populations of European ancestry, no evidence of association was found. [17][18][19][20] Recently, an association with a novel polymorphism at position 159 has been found in West African populations, but not in Chinese.…”

Section: Introductionmentioning

confidence: 74%

“…This result is consistent with the absence of association of this marker with T1D in West Africans 21 and Asians. 11,13,19 The absence of association between different alleles of the dinucleotide (AT) repeat and the level of CTLA4 expression as well as the stability of CTLA4 mRNA has been reported. 25 Therefore, the differences of frequencies found for the smallest allele (allele 7) of the (AT) n repeat in our population and the previously observed association between T1D and longer alleles may be the result of LD between specific microsatellite alleles and the true etiological factor of susceptibility.…”

Section: Discussionmentioning

confidence: 99%

“…No association is found for the three other SNPs including CTLA4+49 that has been recurrently associated in other populations. 11,13,15,21 If we had just analyzed the CTLA4+49 marker in our sample set, we would have failed to find any association with T1D. Thus, a similar analysis of different SNPs would be required for other ethnic groups that have failed to show any association between the CTLA4 region and T1D.…”

Section: Discussionmentioning

confidence: 99%

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Association of the CTLA4 promoter region (−1661G allele) with type 1 diabetes in the South Moroccan population

et al. 2003

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The contribution of the candidate gene CTLA4 to type 1 diabetes is not well established. Although several polymorphisms have been repeatedly associated to the disease, several studies have not confirmed the association. The joint analysis of three SNPs in the CTLA4 promoter region (À1722, À1661, and À319), one SNP in the first exon (+49), and one dinucleotide repeat in the 3 0 untranslated region, in a case-control study in a North African population, shows a strong association of the CTLA4 region with the disease. The À1661G allele showed a significant association with an odds ratio of 2.13. Moreover, the internal structure of the dinucleotide repeat has been deeply analyzed. The present results reveal the importance of polymorphisms in the CTLA4 promoter region, their probable role in gene expression and, ultimately, their relation to the etiology of type 1 diabetes. Previous contradictory association studies might be due to the effect of linkage disequilibrium between the polymorphism analyzed and the alteration within the CTLA4 region. This alteration may be different depending on the genetic background of the population. The present work stresses the need to perform exhaustive analysis of the promoter region polymorphisms in order to detect association with the disease.

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Section: Introductionmentioning

confidence: 74%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Association of the CTLA4 promoter region (−1661G allele) with type 1 diabetes in the South Moroccan population

et al. 2003

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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%

“…Linkage and association of the CTLA-4 exon 1 polymorphism with GD, and to lesser extent with HT, has been found in several populations, although there seems to be some inconsistency, probably due to population heterogeneity [11,17,27,[30][31][32][33] (Table 1).…”

Section: Autoimmune Thyroid Diseasesmentioning

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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Molecular Genetics of Type 1 Diabetes

Kelly

Barnett

Bain

2003

International Textbook of Diabetes Mellitus

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Approximately one third of susceptibility to type 1 diabetes is determined by genetic factors. These factors are termed susceptibility genes as they modify the risk of diabetes but are neither necessary nor sufficient for disease to develop. More than 20 different regions in the human genome have been suggested to contain diabetes susceptibility genes. The IDDM1 locus, which encompasses the human leukocyte antigen (HLA) gene complex on chromosome 6p, is the major genetic risk factor, accounting for approximately 40% of inherited susceptibility. The HLA‐DQ genes within this region are thought to be primary risk determinants of IDDM1 , although other genes also contribute. The IDDM2 locus, which maps to a variable number of tandem repeats region close to the insulin gene on chromosome 11p, contributes approximately 10% of genetic predisposition. The precise location and identity of other diabetes susceptibility genes remain unknown. These loci, however, are likely to make much smaller contributions to disease risk. Further research is necessary to identify all the genetic susceptibility factors for type 1 diabetes and to determine how they interact, with each other and with environmental factors, to influence disease risk.

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Association of CTLA-4 Gene A-G Polymorphism (IDDM12 Locus) With Acute-Onset and Insulin-Depleted IDDM as Well as Autoimmune Thyroid Disease (Graves' Disease and Hashimoto's Thyroiditis) in the Japanese Population

Cited by 142 publications

References 11 publications

Association of the CTLA4 promoter region (−1661G allele) with type 1 diabetes in the South Moroccan population

Association of the CTLA4 promoter region (−1661G allele) with type 1 diabetes in the South Moroccan population

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

Molecular Genetics of Type 1 Diabetes

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