Genome-wide association study identifies the common variants in CYP3A4 and CYP3A5 responsible for variation in tacrolimus trough concentration in Caucasian kidney transplant recipients

• Published in: The pharmacogenomics journal Vol. 18; no. 3; pp. 501 - 505
• Main Authors: Oetting, W S, Wu, B, Schladt, D P, Guan, W, Remmel, R P, Mannon, R B, Matas, A J, Israni, A K, Jacobson, P A
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 22.05.2018; Nature Publishing Group
• Subjects: 45/43; 631/208; 631/208/205; Alleles; Biomedical and Life Sciences; Biomedicine; CYP3A protein; Cytochrome P-450; Cytochrome P450; DNA sequencing; Dosage and administration; Gene Expression; Gene frequency; Genetic aspects; Genetic diversity; Genetic effects; Genetic variance; Genome-wide association studies; Genomes; Health aspects; Human Genetics; Kidney transplantation; Kidney transplants; Metabolism; Oncology; original-article; Pharmacogenomics; Pharmacokinetics; Pharmacological research; Pharmacotherapy; Physiological aspects; Population genetics; Psychopharmacology; Tacrolimus; Variability
• ISSN: 1470-269X; 1473-1150
• DOI: 10.1038/tpj.2017.49

The immunosuppressant tacrolimus (TAC) is metabolized by both cytochrome P 450 3A4 (CYP3A4) and CYP3A5 enzymes. It is common for European Americans (EA) to carry two CYP3A5 loss-of-function (LoF) variants that profoundly reduces TAC metabolism. Despite having two LoF alleles, there is still considerable variability in TAC troughs and identifying additional variants in genes outside of the CYP3A5 gene could provide insight into this variability. We analyzed TAC trough concentrations in 1345 adult EA recipients with two CYP3A5 LoF alleles in a genome-wide association study. Only CYP3A4*22 was identified and no additional variants were genome-wide significant. Additional high allele frequency genetic variants with strong genetic effects associated with TAC trough variability are unlikely to be associated with TAC variation in the EA population. These data suggest that low allele frequency variants, identified by DNA sequencing, should be evaluated and may identify additional variants that contribute to TAC pharmacokinetic variability.