Donor ABCB1 Variant Associates with Increased Risk for Kidney Allograft Failure

Moore, Jason H.; McKnight, Amy Jayne; Döhler, Bernd; Simmonds, Matthew J.; Courtney, Aisling E.; Brand, Stephan; Briggs, David; Ball, Simon; Cockwell, Paul; Patterson, Christopher; Maxwell, Alexander P.; Gough, Stephen; Opelz, Gerhard; Borrows, Richard

doi:10.1681/asn.2012030260

Cited by 66 publications

(61 citation statements)

References 40 publications

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“…This SNP has recently been studied and did not show a relationship with graft survival in a large cohort of transplant patients. 16 We did not find an association between CYP3A5 and transplant outcomes. Carriers of the CYP3A5*1/*1 variant are expressers of CYP3A5 and have higher dose requirements and lower cyclosporine trough levels in comparison with CYP3A5*3/*3 carriers.…”

Section: Demographiccontrasting

confidence: 54%

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Association of CYP3A variants with kidney transplant outcomes

et al. 2015

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Cyclosporine is used extensively in kidney transplantation and is a substrate for cytochrome P450 enzymes. The role of cytochrome p450 polymorphisms in kidney transplant outcome has not yet been fully elucidated. We investigate the clinical impact of single nucleotide polymorphisms in CYP3A4, CYP3A5, PPARa, and POR*28 in 255 kidney transplant recipients. We examine for any association with graft survival, time to first cancer, and delayed graft function, and also measure cyclosporine levels at days 3, 10, and months 1, 3, 6, and 12 after transplantation. The CYP3A4*22 allele is significant associated with the development of cancer post-kidney transplantation (HR 0.20, 95% CI 0.07-0.57, p ¼ 0.003). It is not significantly associated with graft survival. No other SNP's were associated with graft survival time to first cancer, or delayed graft function. There was a non-significant trend of lower cyclosporine dose requirement in CYP3A4*22 carriers. Independent replication of our findings is now warranted to confirm or reject the role of CYP3A variants in cancer development following kidney transplantation.

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Section: Demographiccontrasting

confidence: 54%

“…Finally, we did not collect donor DNA. A study by Moore et al 16 has demonstrated an association with donor CC genotype at C3435T within ABCB1 and kidney allograft failure.…”

Section: Demographicmentioning

confidence: 99%

Association of CYP3A variants with kidney transplant outcomes

et al. 2015

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“…In a discovery cohort of 811 patients, the 3435CC donor genotype was significantly associated with an increased risk of long-term graft failure, compared with that in non-CC carriers, and this finding was validated in two independent patients cohorts (n = 675 and 2985). The reasons for this inverse result are currently unclear [101].…”

Section: Cyclosporinementioning

confidence: 99%

Impact of Genetic Polymorphisms of ABCB1 (MDR1, P-Glycoprotein) on Drug Disposition and Potential Clinical Implications: Update of the Literature

et al. 2015

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ATP-binding cassette transporter B1 (ABCB1; P-glycoprotein; multidrug resistance protein 1) is an adenosine triphosphate (ATP)-dependent efflux transporter located in the plasma membrane of many different cell types. Numerous structurally unrelated compounds, including drugs and environmental toxins, have been identified as substrates. ABCB1 limits the absorption of xenobiotics from the gut lumen, protects sensitive tissues (e.g. the brain, fetus and testes) from xenobiotics and is involved in biliary and renal secretion of its substrates. In recent years, a large number of polymorphisms of the ABCB1 [ATP-binding cassette, sub-family B (MDR/TAP), member 1] gene have been described. The variants 1236C>T (rs1128503, p.G412G), 2677G>T/A (rs2032582, p.A893S/T) and 3435C>T (rs1045642, p.I1145I) occur at high allele frequencies and create a common haplotype; therefore, they have been most widely studied. This review provides an overview of clinical studies published between 2002 and March 2015. In summary, the effect of ABCB1 variation on P-glycoprotein expression (messenger RNA and protein expression) and/or activity in various tissues (e.g. the liver, gut and heart) appears to be small. Although polymorphisms and haplotypes of ABCB1 have been associated with alterations in drug disposition and drug response, including adverse events with various ABCB1 substrates in different ethnic populations, the results have been majorly conflicting, with limited clinical relevance. Future research activities are warranted, considering a deep-sequencing approach, as well as well-designed clinical studies with appropriate sample sizes to elucidate the impact of rare ABCB1 variants and their potential consequences for effect sizes.

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“…In a very large cohort (n = 4471 white kidney transplant recipients), it was the 3435CC donor genotype (not 3435TT as in the study by Ma et al) that was associated with a worse death-censored graft survival. [70] The discrepancies between these studies are unexplained. Again differences in sample size, patient characteristics, and duration of follow-up may form an explanation.…”

Section: Nephrotoxicitymentioning

confidence: 99%

Pharmacogenetic aspects of the use of tacrolimus in renal transplantation: recent developments and ethnic considerations

Tang

Andrews

Gelder

et al. 2016

Expert Opinion on Drug Metabolism & Toxicology

120

114

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Introduction: Tacrolimus (Tac) is effective in preventing acute rejection but has considerable toxicity and inter-individual variability in pharmacokinetics and pharmacodynamics. Part of this is explained by polymorphisms in genes encoding Tac-metabolizing enzymes and transporters. A better understanding of Tac pharmacokinetics and pharmacodynamics may help to minimize different outcomes amongst transplant recipients by personalizing immunosuppression. Areas covered: The pharmacogenetic contribution of Tac metabolism will be examined, with a focus on recent discoveries, new developments and ethnic considerations. Expert opinion: The strongest and most consistent association in pharmacogenetics is between the CYP3A5 genotype and Tac dose requirement, with CYP3A5 expressers having a~40-50% higher dose requirement compared to non-expressers. Two recent randomized-controlled clinical trials using CYP3A5 genotype, however, did not show a decrease in acute rejections nor reduced toxicity. CYP3A4*22, CYP3A4*26, and POR*28 are also associated with Tac dose requirements and may be included to provide the expected improvement of Tac therapy. Studies focusing on the intracellular drug concentrations and on calcineurin inhibitor-induced nephrotoxicity also seem promising. For all studies, however, the ethnic prevalence of genotypes should be taken into account, as this may significantly impact the effect of pre-emptive genotyping.ARTICLE HISTORY

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Donor ABCB1 Variant Associates with Increased Risk for Kidney Allograft Failure

Cited by 66 publications

References 40 publications

Association of CYP3A variants with kidney transplant outcomes

Association of CYP3A variants with kidney transplant outcomes

Impact of Genetic Polymorphisms of ABCB1 (MDR1, P-Glycoprotein) on Drug Disposition and Potential Clinical Implications: Update of the Literature

Pharmacogenetic aspects of the use of tacrolimus in renal transplantation: recent developments and ethnic considerations

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