CTLA4 Alanine-17 Confers Genetic Susceptibility to Graves' Disease and to Type 1 Diabetes Mellitus

Donner, H.

doi:10.1210/jc.82.1.143

Cited by 271 publications

(265 citation statements)

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“…27 Indeed, CTLA-4 has been shown to be associated with other autoimmune diseases. 14,18 Genetic susceptibility to the production of thyroid antibodies was first suggested by Hall et al 35 Their studies of first-degree relatives of probands with AITDs indicated proportions of affected relatives similar to the theoretical expectation for dominant inheritance. More recent family studies have shown that up to 50% of the siblings of AITD patients were TAb positive, 8,32 in contrast to a TAb population prevalence of 7-15%.…”

Section: Discussionmentioning

confidence: 88%

“…8 There have been several reports demonstrating an association between the cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) gene and the AITDs 6,9-25 ( Table 1). The association between GD and a CTLA-4 3 0 untranslated region (3 0 UTR) microsatellite (AT repeat) and an A/G single-nucleotide polymorphism (SNP) at position 49 in the CTLA-4 leader peptide (A/G 49 ) has been consistent across populations of different ethnic backgrounds, such as Caucasians, 6,9,10,[14][15][16][17] Chinese, 11 Japanese, 13,22 and Koreans. 23 The association of CTLA-4 and GD has also been confirmed in a family-based study using transmission disequilibrium test (TDT) analysis.…”

Section: Introductionmentioning

confidence: 97%

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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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Section: Discussionmentioning

confidence: 88%

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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“…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: 76%

“…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%

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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“…Again, there was marked population heterogeneity for this association: Italian, Spanish, French, Mexican, and Korean samples showed significantly increased transmission of the G allele to diabetics, while British, Sardinian, Chinese, and European-Americans showed little or no increased transmission of this allele. Significant increases of the G allele in diabetics have also been observed in case-control studies of Germans (p = 0.0001) [78] and Poles (p = 0.002) [79]. There is also evidence that diabetes predisposition is associated with homozygosity for long alleles at a CA-repeat microsatellite in the 3¢ untranslated region of CTLA4 [120].…”

Section: Is Positional Candidate Mapping Feasible?mentioning

confidence: 82%

Genetic linkage and association studies of Type I diabetes: challenges and rewards

Field

2002

Diabetologia

104

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Type I diabetes (formerly called insulin-dependent diabetes mellitus) results from the autoimmune destruction of the insulin-producing beta cells of the pancreas. It is now known that Type I diabetes is a genetically complex disease, i. e. a disease caused by multiple genes interacting with non-genetic (environmental and stochastic) factors. Family studies have clearly shown a genetic basis but inheritance of the disease does not follow a simple mendelian single-locus pattern. Population and family studies also suggest that most (perhaps all) affected individuals are genetically predisposed to Type I diabetes, particularly through HLA region genes. However, non-genetic factors appear to be required to precipitate the disease in these genetically susceptible persons because in monozygote (MZ) twin pairs in which one twin has Type I diabetes the MZ twin concordance rate is less than 100 %. It is not clear whether there are any purely genetic cases of Type I Diabetologia (2002) AbstractFamily and twin studies have shown clearly that Type I (insulin-dependent) diabetes mellitus has a genetic basis. However, only within the past decade has it been possible to systematically attempt to identify the genes that increase susceptibility to this disorder using linkage and association analysis of genetic markers distributed across the genome. More than 20 putative diabetes-predisposing genes have been localised in addition to HLA region susceptibility genes detected more than 25 years ago. Unfortunately, the effects of most diabetes-predisposing genes are weak, with the exception of HLA region susceptibility genes (which contribute about half of the genetic risk). The overall effects of diabetes-predisposing genes could be weak because the susceptibility gene occurs in only a small proportion of diabetic patients or the susceptibility gene (although it might be common) produces only a modest increase in risk, probably by acting in concert with other such genes to cause disease. The weak effects of these genes have made them difficult to locate, difficult to confirm in independent studies and difficult to isolate by genetic procedures. This paper summarizes the major challenges that have faced geneticists in mapping Type I diabetes genes, and reviews the progress achieved to date. The rewards of the genetic studies will be twofold: increased understanding of the causes of Type I diabetes, facilitating creation of preventative therapies, and enabling clinicians in the future to use genetic information to predict which children are predisposed to diabetes in order to target them for preventative therapies. [Diabetologia (2002) 45: 21±35]

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CTLA4 Alanine-17 Confers Genetic Susceptibility to Graves' Disease and to Type 1 Diabetes Mellitus

Cited by 271 publications

References 0 publications

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

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

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

Genetic linkage and association studies of Type I diabetes: challenges and rewards

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