Genomewide Association Study of Tacrolimus Concentrations in African American Kidney Transplant Recipients Identifies Multiple CYP3A5 Alleles

Abstract

We previously reported that tacrolimus (TAC) trough blood concentrations for African American (AA) kidney allograft recipients were lower than those observed in white patients. Subtherapeutic TAC troughs may be associated with acute rejection (AR) and AR-associated allograft failure. This variation in TAC troughs is due, in part, to differences in the frequency of the cytochrome P450 CYP3A5*3 allele (rs776746, expresses nonfunctional enzyme) between white and AA recipients; however, even after accounting for this variant, variability in AA-associated troughs is significant. We conducted a genomewide association study of TAC troughs in AA kidney allograft recipients to search for additional genetic variation. We identified two additional CYP3A5 variants in AA recipients independently associated with TAC troughs: CYP3A5*6 (rs10264272) and CYP3A5*7 (rs41303343). All three variants and clinical factors account for 53.9% of the observed variance in troughs, with 19.8% of the variance coming from demographic and clinical factors including recipient age, glomerular filtration rate, anticytomegalovirus drug use, simultaneous pancreas-kidney transplant and antibody induction. There was no evidence of common genetic variants in AA recipients significantly influencing TAC troughs aside from the CYP3A gene. These results reveal that additional and possibly rare functional variants exist that account for the additional variation.

Keywords: basic (laboratory) research/science; genetics; genomics; immunosuppressant; calcineurin inhibitor: tacrolimus; immunosuppression/immune modulation; microarray/gene array; molecular biology: DNA; molecular biology: single polynucleotide polymorphism.

Conflict of interest statement

Disclosure: The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.

© Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.

Figures

Figure 1. Manhattan plot of single-nucleotide polymorphisms (SNPs) associated with tacrolimus trough concentrations

Overall, 644 224 SNPs were analyzed toward natural log of dose-normalized tacrolimus trough concentrations (nanograms per milliliter per total daily dose in milligrams) with no additional covariates. All SNPs are shown in order from chromosome 1 to 22. The red line is at the level of statistical significance (p −8). The major peak is above the CYP3A locus.

Figure 2. Mean tacrolimus trough concentration by the number of loss-of-function (LoF) alleles

The effect of the genotype on dose-normalized tacrolimus trough concentrations (nanograms per milliliter per total daily dose in milligrams) with time is shown. Triangles and solid line indicate homozygous WT for all three alleles, square and dashed line indicate heterozygous for one wild-type allele and one LoF allele, and diamond and dashed line indicate either homozygous for an LoF allele or a compound heterozygote for two different LoF alleles.

Figure 3. Box plot of dose-normalized tacrolimus trough concentration (nanograms per milliliter per total daily dose in milligrams) versus number of loss-of-function alleles

Horizontal bars represent 95% confidence levels.