Impact of single nucleotide polymorphisms on P450 oxidoreductase and peroxisome proliferator-activated receptor alpha on tacrolimus pharmacokinetics in renal transplant recipients

• Published in: The pharmacogenomics journal Vol. 19; no. 1; pp. 42 - 52
• Main Authors: Si, Shuhui, Wang, Zijie, Yang, Haiwei, Han, Zhijian, Tao, Jun, Chen, Hao, Wang, Ke, Guo, Miao, Tan, Ruoyun, Wei, Ji-Fu, Gu, Min
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-02-2019; Nature Publishing Group
• Subjects: 38/22; 38/23; 45/23; 45/41; 692/308/2779; 692/699/1585; Biomedical and Life Sciences; Biomedicine; Cytochrome P450; DNA sequencing; Gene Expression; Genes; Genotypes; Health risk assessment; Human Genetics; Kidney transplantation; Mutation; Next-generation sequencing; Oncology; Oxidoreductase; Pharmacokinetics; Pharmacotherapy; Por gene; Psychopharmacology; Quantitative analysis; Rapamycin; Single-nucleotide polymorphism; Systematic review; Tacrolimus; Transplantation; Transplants & implants
• ISSN: 1470-269X; 1473-1150
• DOI: 10.1038/s41397-018-0061-1

The P450 oxidoreductase (
POR
) and peroxisome proliferator-activated receptor alpha (
PPARA
) genes are associated with the activity of cytochrome P450 enzymes in vivo. We aimed to investigate the impact of single nucleotide polymorphisms (SNPs) in the
POR
and
PPARA
genes on the pharmacokinetics of tacrolimus (TAC) in renal transplant recipients. A total of 220 recipients were assessed and 105 recipients were included for final quantitative analysis. Blood samples were collected and DNA was extracted. Targeting sequencing based on next-generation sequencing was applied to detect the SNPs in the
POR
and
PPARA
genes. In addition, a systematic review and meta-analysis was performed to comprehensively evaluate the influence of
POR
and
PPARA
mutations on the TAC concentrations. A total of 81 SNPs were obtained. Three SNPs (
POR*28
, Chr7:75619677 and Chr7:75614288) were found to be significantly associated with the TAC pharmacokinetics at 3 months, 6 months, and more than 12 months. No significant association was observed in the combined effect analysis of
CYP3A4*1
G
and
CYP3A5*3
with three significant SNPs in the
POR
gene. Age, post-transplant duration, and the use of sirolimus were identified as the most important factors that influenced the TAC concentrations. A meta-analysis of four studies results and our cohort indicated that compared with recipients carrying the CT or TT genotypes, recipients carrying the CC genotypes of
POR*28
showed significantly higher TAC concentrations. Our study suggested the positive influence of mutations in the
POR
gene on TAC exposure at 3 months after kidney transplantation.