CTLA4 gene haplotypes cannot protect from IDDM in the presence of high-risk HLA DQ8 or DQ2 alleles in German families.

Donner, H.; Seidl, Christian; Braun, J.; Siegmund, Thorsten; Herwig, J.; Seifried, Erhard; Usadel, K. H.; Badenhoop, Klaus

doi:10.2337/diabetes.47.7.1158

Cited by 31 publications

(26 citation statements)

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“…A similar effect has been shown for CTLA-4 +642(AT) n by a study showing an association of longer microsatellite alleles with increased IL-2 expression and T-cell proliferation as well as an increased incidence of myasthenia gravis, suggesting a decreased regulatory effect of CTLA-4 (39,40). In addition, shorter microsatellite alleles have been associated with a decreased incidence of type I diabetes mellitus (41).…”

Section: Discussionmentioning

confidence: 51%

The Impact of Costimulatory Molecule Gene Polymorphisms on Clinical Outcomes in Liver Transplantation

Marder¹,

Schröppel²,

Lin³

et al. 2003

American Journal of Transplantation

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CTLA-4 and CD28 deliver opposing signals for T-cell proliferation. We examined single nucleotide polymorphisms (SNPs) CTLA-4 -318C/T and CD28 IVS3 +17T/C for associations with acute rejection in liver transplant recipients. These and two other polymorphisms in CTLA-4 [microsatellite polymorphism +642(AT) n and SNP +49 A/G] were also analyzed for influence on graft survival. Two hundred and eleven liver transplant recipient genotypes were determined by direct sequencing or restriction fragment length polymorphism analysis of PCR-amplified genomic DNA. Mean graft survival for patients with the GG genotype of CTLA-4 +49 A/G was 58.5 -6.0 months compared with 70.3 -4.0 months and 73.8 -2.8 months 2.8 months for the AA and AG genotypes, respectively (p = 0.0055). This is in support of previous studies suggesting decreased CTLA-4 function and increased incidence of autoimmune disease for this genotype. The 92-, 94-, and 100-bp alleles of CTLA-4 +642(AT) n occurred more often in African-American transplant recipients and were associated with decreased graft survival (p = 0.0001 and 0.007, respectively) but the independence of these variables could not be established. No associations with acute rejection or graft survival were found for CTLA-4 -318C/T or CD28 IVS3 +17T/C. The described associations between CTLA-4 gene polymorphisms and transplant outcomes provide the foundation for further investigations leading to genetic risk stratification for transplant recipients.

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Section: Discussionmentioning

confidence: 51%

The Impact of Costimulatory Molecule Gene Polymorphisms on Clinical Outcomes in Liver Transplantation

Marder¹,

Schröppel²,

Lin³

et al. 2003

American Journal of Transplantation

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“…170 There is a microsatellite marker in the 3ЈUTR of the CTLA4 sequence, and several polymorphisms have been detected at CTLA4. 39 These polymorphisms, in particular the exon 1 (49 GϾA) SNP, have been investigated by TDT analysis in several populations, 41,140,[171][172][173][174][175][176][177][178][179][180][181][182][183][184][185][186] and combined data sets from these large studies support linkage of the CTLA4 locus to T1D. 168,171,187 Interestingly, some evidence has also been produced to suggest that CTLA4 polymorphisms may influence gene expression.…”

Section: Iddm2-the Insulin Gene (Ins) Regionmentioning

confidence: 99%

Genetics of type 1 diabetes mellitus

2002

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“…Moreover, linkage disequilibrium between the CTLA4 polymorphisms has also been suggested in other studies (16,17).…”

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confidence: 91%

Technical Note: Linkage Disequilibrium and Disease-Associated CTLA4 Gene Polymorphisms

Holopainen

Partanen

2001

The Journal of Immunology

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CTLA4 and CD28 are important regulators of T lymphocyte activation. Gene region 2q33 carrying genes for both CTLA4 and CD28 has been shown to be linked to many autoimmune diseases. Disease associations with particular CTLA4 gene polymorphisms have been reported. Recently, first lines of evidence emerged for functional effects of CTLA4 gene polymorphisms. Two independent studies reported a reduced inhibitory function of CTLA4 in individuals with certain CTLA4 genotypes: those with a high number of microsatellite repeats in one study and those with allele +49*G in exon 1 in the other one. We analyzed the strength of linkage disequilibrium between the three known CTLA4 polymorphisms among 577 independent chromosomes. Our results show that the polymorphisms previously suggested to be the functional risk factors nearly always occur together in a very frequent haplotype. Due to this strong linkage disequilibrium, we conclude that the previous reports studying merely a single polymorphism could not distinguish which variation actually caused the functional difference. Hence, either mutagenesis approaches or studies with data on all linked polymorphisms are still needed to determine the genuine functional risk polymorphism in this gene region.

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CTLA4 gene haplotypes cannot protect from IDDM in the presence of high-risk HLA DQ8 or DQ2 alleles in German families.

Cited by 31 publications

References 0 publications

The Impact of Costimulatory Molecule Gene Polymorphisms on Clinical Outcomes in Liver Transplantation

The Impact of Costimulatory Molecule Gene Polymorphisms on Clinical Outcomes in Liver Transplantation

Genetics of type 1 diabetes mellitus

Technical Note: Linkage Disequilibrium and Disease-Associated CTLA4 Gene Polymorphisms

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