Cytotoxic T-Lymphocyte Antigen 4 Gene Polymorphisms and Susceptibility to Acute Allograft Rejection1

Slavcheva, E; Albanis, Efsevia; Jiao, Qingsheng; Tran, Hoanh; Bodian, Carol; Knight, Richard J.; Milford, Edgar L.; Schiano, Thomas D.; Tomer, Yaron; Murphy, Barbara

doi:10.1097/00007890-200109150-00032

Cited by 57 publications

(33 citation statements)

References 32 publications

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“…We have previously demonstrated an association between gene polymorphisms in CTLA-4 and acute rejection in solid organ transplantation (20). We now demonstrate that despite a lack of association with acute rejection, the CTLA-4 +49A/G SNP is associated with a significant reduction in liver allograft survival.…”

Section: Discussionmentioning

confidence: 58%

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: 58%

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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“…In view of this, it is important to investigate possible associations for each specific organ. We have recently demonstrated association with an increased risk of rejection in liver and renal transplant recipients and a microsatellite polymorphism in the CTLA4 gene (20). Two other smaller studies have examined the influence of cytokine gene polymorphisms in liver transplant recipients (21,22).…”

Section: Discussionmentioning

confidence: 98%

The Impact of Polymorphisms in Chemokine and Chemokine Receptors on Outcomes in Liver Transplantation

Schröppel

Fischereder

Ashkar

et al. 2002

American Journal of Transplantation

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Chemokines and their corresponding receptors likely play a central role in directing mononuclear cells to the graft sites during rejection. Genes for the chemokine stromal derived factor-1 (SDF1) and CC chemokine receptors CCR2 and CCR5 are characterized by polymorphisms which alter their function. We genotyped DNA of 207 liver transplant recipients by PCR or PCR-RFLP for CCR2-64I, CCR5D32, and SDF1-3ƒA polymorphisms, and examined their association on outcomes in liver allograft recipients. Due to the low number of patients homozygous for CCR2-64I and CCR5D32, only the effects of their heterozygous variants were addressed in this study. None of the investigated polymorphisms showed a significant shift in gene frequency in acute rejection and rejection-free groups, or for graft survival. The gene frequency of the SDF1-3ƒA allele was significantly (p Ω0.034) higher in patients who died (29.0%, n Ω 31) compared to recipients still alive (17.1%, n Ω 172). The mean patient survival time post transplant was 134 months in patients with SDF1 wild-type, significantly (log rank p Ω0.014) longer than 98 months in patients with at least one SDF1-3ƒA allele. The CCR2 and CCR5 polymorphisms were not associated with significant differences in mortality rate. In conclusion, CCR2-64I, CCR5D32, and SDF1-3ƒA genotypes did not influence the risk for acute rejection or graft survival. However, in liver allograft recipients SDF1-3ƒA is significantly associated with higher mortality.

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“…Slavcheva et al 35 found that long alleles of (AT)n repeats of the CTLA4 gene were associated with an increased risk of acute rejection. It has been suggested that the frequency of long alleles of (AT)n repeats was increased among patients with Wegener's granulomatosis.…”

Section: Discussionmentioning

confidence: 99%

CTLA4 −1661A/G and 3′UTR long repeat polymorphisms are associated with ulcerative colitis and influence CTLA4 mRNA and protein expression

Chen

Brant

et al. 2010

Genes Immun

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Reduced cytotoxic T-lymphocyte antigen 4 (CTLA4) expression has been proposed as a risk for autoimmunity. CTLA4 polymorphisms have been associated with several autoimmune diseases, including ulcerative colitis (UC). In this study, we performed genotyping for CTLA4 À1661A/G, À1722T/C and 3 0 untranslated region (AT)n repeat polymorphisms in 300 Chinese UC patients and in 700 healthy controls, and evaluated the effects of polymorphisms on full-length (flCTLA4) and soluble CTLA4 (sCTLA4) expression in UC patients. The frequency of the À1661G allele was higher in UC patients than in healthy controls (16.5 vs 11.4%, P ¼ 0.003, odds ratio (OR) ¼ 1.53, 95% confidence interval (95% CI): 1.17-2.01). The prevalence of (AT)n repeats of the CTLA4 gene carrying long alleles (X116 bp) was more common in UC patients than in healthy controls (22.0 vs 6.3%, Po0.001, OR ¼ 4.21, 95% CI: 2.79-6.33), and was associated with extensive colitis (P ¼ 0.008). Among UC patients, long-allele carriers expressed lower levels of flCTLA4 and sCTLA4 mRNA and sCTLA4 protein than did short-allele carriers (Po0.001, Po0.001, Po0.001, respectively). CTLA4 gene À1661A/G and long 3 0 untranslated region (AT)n repeat polymorphisms are associated with UC in Central China. This is likely from decreased expressions of sCTLA4 mRNA and sCTLA4 protein. Our study suggests that CTLA4 has an important role in susceptibility for UC in Central China.

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Cytotoxic T-Lymphocyte Antigen 4 Gene Polymorphisms and Susceptibility to Acute Allograft Rejection1

Abstract: These initial observations provide the necessary basis to further investigate the risk stratification of transplant recipients based on specific CTLA4 gene polymorphisms.

Cited by 57 publications

References 32 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

The Impact of Polymorphisms in Chemokine and Chemokine Receptors on Outcomes in Liver Transplantation

CTLA4 −1661A/G and 3′UTR long repeat polymorphisms are associated with ulcerative colitis and influence CTLA4 mRNA and protein expression

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