Genome-Wide Association Study of Tacrolimus Pharmacokinetics Identifies Novel Single Nucleotide Polymorphisms in the Convalescence and Stabilization Periods of Post-transplant Liver Function

Abstract

After liver transplantation, the liver function of a patient is gradually restored over a period of time that can be divided into a convalescence period (CP) and a stabilizing period (SP). The plasma concentration of tacrolimus, an immunosuppressant commonly used to prevent organ rejection, varies as a result of variations in its metabolism. The effects of genetic and clinical factors on the plasma concentration of tacrolimus appear to differ in the CP and SP. To establish a model explaining the variation in tacrolimus trough concentration between individuals in the CP and SP, we conducted a retrospective, single-center, discovery study of 115 pairs of patients (115 donors and 115 matched recipients) who had undergone liver transplantation. Donors and recipients were genotyped by a genome-wide association study (GWAS) using an exome chip. Novel exons were identified that influenced tacrolimus trough concentrations and were verified with bootstrap analysis. In donors, two single-nucleotide polymorphisms showed an effect on the CP (rs1927321, rs1057192) and four showed an effect on the SP (rs776746, rs2667662, rs7980521, rs4903096); in recipients, two single-nucleotide polymorphisms showed an effect in the SP (rs7828796, rs776746). Genetic factors played a crucial role in tacrolimus metabolism, accounting for 44.8% in the SP, which was higher than previously reported. In addition, we found that CYP3A5, which is known to affect the metabolism of tacrolimus, only influenced tacrolimus pharmacokinetics in the SP.

The influence of recipient SLCO1B1 rs2291075 polymorphism on tacrolimus dose–corrected trough concentration in the early period after liver transplantation

“…Multivariate linear regression analysis was used to screen the influence factors of tacrolimus pharmacokinetics. The incorporated cofactors included daily drug dose, serum albumin concentration, hemoglobin, glutamate pyruvate transaminase, and total bilirubin; all reported to have the potential effects on tacrolimus pharmacokinetics [ 6 , 8 ], as well as FIS genotype classification and recipient SLCO1B1 rs2291075. The results (Table 1 ) have shown that daily dose, FIS genotype classification, and total bilirubin were the consistent predictors for tacrolimus elimination in convalescence period and stabilizing period after liver transplantation.…”

“…The CYP3A5 protein expression quantity was reduced obviously in donor liver and recipient intestine in convalescence phase, which resulted in high tacrolimus C/D ratios. And the CYP3A5 protein produced by donor liver and recipient intestine cells returned to nearly normal levels in stationary phase [ 6 ]. The quantity of functional CYP3A5 was very low in SE subgroup liver transplantation patients due to donor and recipient CYP3A5 rs776746 polymorphisms which produced in CYP3A5 protein without enzyme activity.…”

“…The early postoperative period after liver transplantation was divided into convalescence phase (1–14 days) and stationary phase (15–28 days) according to the change of liver function and tacrolimus C/D values [ 6 ]. A chi-squared test was used to compare the distributions of genotypes and alleles of recipients and donors.…”

“…Adequate immunosuppression is necessary to prevent rejection and to increase the survival rate of transplantation; overimmunosuppression could give rise to a series of serious adverse drug reactions, such as infection, diabetes, and renal insufficiency. However, the narrow therapeutic index and large interindividual variabilities of tacrolimus complicate its routine dosage adjustment [3][4][5][6].…”

Production of tacrolimus using coconut oil as an alternative to glucose

“…It was discovered in Japan and isolated in 1984 by researchers of Fujisawa Pharmaceutical Co., during a selection of immunosuppressive activity in compounds isolated from fermentation broths using the bacteria Streptomyces tsukubaensis (Nakamura, 2019). In 1987, the first description of this immunosuppressant was published, and it was intended for the treatment of transplants (Kino et al, 1987;Liu et al, 2019). It was found that this drug is also indicated in other clinical cases such as in the treatment of dermatological disorders, atopic dermatitis (Dähnhardt, Bastian, Dähnhardt-Pfeiffer, Buchner, & Fölster-Holst, 2019), and ophthalmic diseases such as conjunctivitis (Erdinest, Ben-Eli, & Solomon, 2019).…”