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, anti-cytomegalovirus 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.

Tacrolimus Trough Concentration Variability and Disparities in African American Kidney Transplantation

“…Up to 85% of AAs express the CYP 3A5 *1 functional allele, resulting in substantially enhanced metabolic capacity for numerous drugs, including tacrolimus; non-AAs express this allele at a much lower rate (~25%). 8, 27 The impact of CYP 3A5 on tacrolimus variability is not fully elucidated, with both positive and negative associations in the literature. 11, 33–35 However, given the limitations of these studies, including small sample-size and limited information on race, the true impact of CYP 3A5 polymorphisms of tacrolimus trough variability has yet to be determined.…”

“…Prospective genotyping for CYP 3A5 prior to transplant may inform clinicians and improve the accuracy of early tacrolimus dosing, leading to reduced variability. 8, 37 Unfortunately, 2 randomized controlled trials (RCTs) failed to demonstrate improvements in outcomes with CYP 3A5 genotype-guided dosing of tacrolimus. However, there were a number of limitations to these studies; most importantly the low frequency of the *1 functional allele due to low numbers of patients of African descent in these trials (both conducted in Europe).…”

“…7 Tacrolimus is metabolized primarily via the cytochrome P450 3A4/5 isoenzyme system (CYP 3A4/5) and because of this is prone to drug-drug interactions and variation due to genetic polymorphisms. 7, 8 There are a number of studies demonstrating that high intrapatient tacrolimus variability is associated with increased risk of acute rejection, graft dysfunction and graft loss. 9–16 …”

“…21–26 AAs are substantially more likely to express the CYP 3A5 *1 polymorphism, which is linked to increased tacrolimus clearance and variability. 8, 27–29 We recently conducted an analysis demonstrating that early posttransplant mean 12-hour tacrolimus trough concentrations are significantly lower in AA kidney transplant recipients, as compared to non-AAs, and this was associated with higher rates of acute rejection. 30 Yet, there is paucity in the data examining the impact of tacrolimus trough variability on racial disparities in transplantation.…”

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

“…[115] This study demonstrated that there are considerably more CYP3A5 non-expressers in African populations than was previously presumed. In 197 adult African kidney transplant recipients, Oetting et al [116] also found that the variants CYP3A5*3, CYP3A5*6, and CYP3A5*7 explained a great proportion of the observed Tac C 0 variability in African recipients. Taken together, these studies illustrate the importance ethnicity-specific genotypes (CYP3A5*6 and CYP3A5*7) for Tac clearance.…”