Association of CYP3A variants with kidney transplant outcomes

Abstract

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.

Incidence, risk factors and outcomes of malignancies after kidney transplantation in Singapore: a 12-year experience

“…(28) More recently, a 2015 study on the clinical impact of cytochrome p450 in KTX found that the CYP3A4*22 allele was significantly associated with the development of cancer after KTX. (29) The relationship of genetic polymorphism in our multiethnic population with CYP3A4*22 and cancer development is still uncertain.…”

Genetic Variations Associated with Anti-Tuberculosis Drug-Induced Liver Injury

“…A tag-SNP of the GSTP1 gene has a significantly different frequency in an AT-DILI group as compared to a non-AT-DILI group [67]. DNA methylation levels in a CpG island in the promoter region of the GSTP1 gene also associate with AT-DILI [68]. …”

Pharmacogenetics and drug-induced nephrotoxicity in renal transplant recipients

“…CNIs are significantly metabolized in the liver and the gastrointestinal tract by the cytochromes P450 3A enzymes (in particular, CYP3A4 and CYP3A5), 6 which are also subjected to cellular efflux functions mainly by P-gp that is one of the adenosine triphosphate (ATP)-binding cassette transporters, the so-called multidrug resistance 1 (MDR1) or ATP-binding cassette subfamily B 1 (ABCB1). 7 CsA is extensively bio-transformed to approximately 30 metabolites, the primary metabolites appear to be the monohydroxylated AM1 (M-17) and AM9 (M-1) and the N-demethylated AM4n (M-21). 8 These primary metabolites are produced by CYP3A4, whereas only AM9 is produced by CYP3A5.…”

“…CsA-induced hypomagnesemia appears to facilitate the development of chronic IF through upregulation of fibrogenic molecules, which may activate the expression of tissue inhibitor of matrix metalloproteinase 1 (TIMMP1). 7 , 26 CsA is also one of the incisive causes of the post-transplant hyperuricemia and gout that is a painful disorder induced through some inflammatory reactions resulting in production of monosodium urate crystals in joint fluid and periarticular tissue. The urinary clearance of uric acid is decreased by CsA, in large part because of its inhibitory impacts on the tubular secretion of uric acid.…”

“…The functional expression of CYP3A5 in the kidney appears to have a protective impact on the renal dysfunction development, in large part through lowering the exposure of renal cells to CNIs. 7 Homozygous carriers of the CYP3A5*3 allele, possessing SNPs in the intron 3 of the CYP3A5 gene (genomic 6986A>G), may generate inadvertent mRNA splicing and a truncated and non-functional protein of CYP3A5, however high expression of CYP3A5 has been reported among the homozygous and heterozygous carriers of the wild-type CYP3A5*1 allele. 40 As a result, the metabolism and clearance of CNIs may be enhanced within the carriers of the CYP3A5*1 allele.…”