IL-3 and CTLA4 gene polymorphisms may influence the tacrolimus dose requirement in Chinese kidney transplant recipients

Abstract

The highly variable pharmacokinetics and narrow therapeutic window of tacrolimus (TAC) has hampered its clinical use. Genetic polymorphisms may contribute to the variable response, but the evidence is not compelling, and the explanation is unclear. In this study we attempted to find previously unknown genetic factors that may influence the TAC dose requirements. The association of 105 pathway-related single nucleotide polymorphisms (SNPs) with TAC dose-adjusted concentrations (C0/D) was examined at 7, 30 and 90 d post-operation in 382 Chinese kidney transplant recipients. In CYP3A5 non-expressers, the patients carrying the IL-3 rs181781 AA genotype showed a significantly higher TAC logC0/D than those with the AG genotype at 30 and 90 d post-operation (AA vs AG, 2.21±0.06 vs 2.01±0.03, P=0.004; and 2.17±0.06 vs 2.03±0.03, P=0.033, respectively), and than those with the GG genotype at 30 d (AA vs GG, 2.21±0.06 vs 2.04±0.03, P=0.011). At 30 d, the TAC logC0/D in the grouped AG+GG genotypes of CTLA4 rs4553808 was significantly lower than that in the AA genotype (P=0.041) in CYP3A5 expressers, but it was higher (P=0.008) in the non-expressers. We further validated the influence of CYP3A5 rs776746, CYP3A4 rs2242480 and rs4646437 on the TAC C0/D; other candidate SNPs were not associated with the differences in TAC C0/D. In conclusion, genetic polymorphisms in the immune genes IL-3 rs181781 and CTLA4 rs4553808 may influence the TAC C0/D. They may, together with CYP3A5 rs776746, CYP3A4 rs2242480 and rs4646437, contribute to the variation in TAC dose requirements. When conducting individualized therapy with tacrolimus, these genetic factors should be taken into account.

Effect of CYP3A4, CYP3A5, and ABCB1 Polymorphisms on Intravenous Tacrolimus Exposure and Adverse Events in Adult Allogeneic Stem Cell Transplant Patients

“…Although the primary role of tacrolimus in this setting is to prevent GVHD, we were unable to accurately depict the impact of pharmacogenetics or drug exposure on incidence of GVHD because patients received other immunosuppressants such as cyclophosphamide or mycophenolate mofetil post-transplant. Additionally, other genetic polymorphisms (eg, PXR, POR, as well as others) [18,[36][37][38] are not accounted for in this study, which could possibly explain some of the observed variability in i.v. tacrolimus exposure among this patient population.…”

Renchangianins F and G: two new sesquiterpenoids from Kadsura renchangiana

“…The only difference between the two compounds was that they possessed a different substituted group in C-9. The 1 H NMR signals at δ H 2.11 (3H, s) and 13 C NMR signals at δ C 170.8 showed the presence of acetoxy group in 2. HMBC correlations (Figure 3) of H-9 (δ H 4.52) with C=O (δ C 170.8), and of the methyl at δ H 2.11 (3H, s) with C=O at δ C 170.8 confirmed the acetoxy group was located at C-9.…”

“…In our previous study, five new dibenzocyclooctadiene lignans [12,13] and a new triterpenoid [14] from the stems of Kadsura renchangiana indigenous to southern area of China have been reported. Our further investigation on the same plant led to the isolation and identification of two new sesquiterpenoids, renchangianins F and G (1 and 2, Figure 1).…”

Incorporation of Gene‐Environment Interaction Terms Improved the Predictive Accuracy of Tacrolimus Stable Dose Algorithms in Chinese Adult Renal Transplant Recipients

“…Cytochrome P450 (CYP) 3A4 is the most abundant metabolic enzyme in liver, and in vivo CYP3A4 activity was found to explain an additional 23% to 29% of the variability of tacrolimus pharmacokinetics . A number of CYP3A4 polymorphisms were found to affect the expression and activity of CYP3A4 enzyme as well as tacrolimus pharmacokinetics, including CYP3A4 20230T>C (rs2242480), CYP3A4 (rs4646437), CYP3A4 *1B‐392A>G (rs2740574) and CYP3A4 *22 C>T (rs35599367), although the results were less consistent . For instance, the CYP3A4 rs2242480 allele was reported to increase the activity of the CYP3A4 enzyme .…”

“…9 A number of CYP3A4 polymorphisms were found to affect the expression and activity of CYP3A4 enzyme as well as tacrolimus pharmacokinetics, including CYP3A4 20230T>C (rs2242480), CYP3A4 (rs4646437), CYP3A4*1B-392A>G (rs2740574) and CYP3A4*22 C>T (rs35599367), although the results were less consistent. 10,[14][15][16][17][18] For instance, the CYP3A4 rs2242480 allele was reported to increase the activity of the CYP3A4 enzyme. 19 It can also influence tacrolimus dose-adjusted concentrations in stable kidney transplant recipients.…”