Table 5.
Genes and their single nucleotide polymorphisms investigated in association with tacrolimus metabolism after liver transplantation
| Ref. | Etiology/Population/N | Genes | Key points |
| Liu et al[66] | Various | Recipient, donor | Donor FAM26F (rs1057192) and rs1927321 were associated with Tac concentration in recovery phase (first 2 wk) |
| GWAS, association found for: CYP3A5 (rs776746), TELO2 (rs266762), ESYT1 (rs7980521), FAM26F (rs1057192), chr14: 39860228 (rs4903096) chr9: 118304139 (rs1927321), chr8: 83368297 (rs7828796) | |||
| Eastern Asian | |||
| 115 | Donor CYP3A5 (rs776746), TELO2 (rs266762), ESYT1 (rs7980521) and rs4903096 were associated with Tac concentration in stabilizing phase (third to fourth post-transplantation week) | ||
| Recipient CYP3A5 (rs776746) and rs7828796 were associated with Tac concentration in stabilizing phase (third to fourth post-transplantation week) | |||
| Ou et al[70] | Various | Recipient, donor: CYP3A5 (rs776746)1, TLR 1 (rs574361, rs4833095), TLR2 (rs4696480), TLR3 (rs5743316, rs3775291), TLR4 (rs1927907), TLR7 (rs3853839), TLR9 (rs187084, rs352139, rs5743836) | Donor and recipient CYP3A5*3 genotype were associated with increased Tac concentration |
| Eastern Asian | Donor TLR9 rs352139 AA genotype and TLR4 rs1927907 GG genotype were associated with increased Tac concentration | ||
| 297 | |||
| Patients with donor TLR9 rs352139 G allele had increased CYP3A5 mRNA expression in transplanted liver tissue | |||
| No significant association was found for other eight SNPs | |||
| Deng et al[74] | Not stated | Recipient: CYP3A5 (rs776746)1, CYP2C8 (rs11572080), ABCB1 (rs1045642, rs1128503) | Association with early renal injury was monitored |
| Eastern Asian | CYP3A5*3 was associated with the risk of early renal glomerular lesion | ||
| 136 | CYP2C8*3 was associated with the risk of the tubulointerstitial injury | ||
| No association between ABCB1 SNPs and renal injury | |||
| Kato et al[67] | Various | Recipient, donor: CYP3A5 (rs776746)1 | Differences between administration routes of Tac were investigated |
| Eastern Asian | CYP3A5 genotype influenced Tac concentration when Tac was applied orally, but not when applied intravenously | ||
| 61 | |||
| Gómez-Bravo et al[68] | Not stated | Recipient, donor: CYP3A4 [rs67666821 (CYP3A4*20), rs35599367 (CYP3A4*22)], CYP3A5 (rs776746)1 | CYP3A5*3 genotype was associated with increased Tac concentration |
| European | The presence of rare CYP3A4 SNPs (CYP3A4*20 and CYP3A4*22) in donor liver increases Tac plasma concentrations | ||
| 90 | |||
| Recipient CYP3A4*22 is also associated with increased Tac concentration | |||
| Liu et al[65] | Not stated | Recipient, donor: CYP2B6 (rs3745274), CYP3A4 (rs4646437), CYP3A5 (rs776746, rs15524, rs4646450, rs3800959)1 | CYP3A5 rs776746 GG (CYP3A5*3), rs4646450 CC and rs15524 TT genotypes were associated with higher Tac concentrations |
| Eastern Asian | |||
| 373 | In the short term both donor and recipient CYP3A5 genotype contributed equally, but later the donor genotype had greater effect | ||
| No significant association for the remaining 5 SNPs was found, 13 other SNPs were determined, but excluded from analysis because of low MAF | |||
| Zhang et al[71] | Various | Recipient, donor: CYP3A5 (rs776746)1, SUMO4 (rs237025) | Donor and recipient CYP3A5*3 genotype are associated with increased Tac concentration |
| Eastern Asian | Donor SUMO4 rs237025 AA genotype was independently associated with decreased Tac concentration and with higher CYP3A5 mRNA expression | ||
| 297 | |||
| Chen et al[69] | Not stated | Recipient: CYP3A5 (rs776746), ABCB1 (rs1128503, rs2032582, rsl045642) | In a population pharmacokinetic model recipient ABCB1 rsl045642 (C3435T) was independently associated with Tac pharmacokinetic |
| Eastern Asian | |||
| 125 | As data on donor CYP3A5 (rs776746) were not included into the model conclusion should be taken cautiously | ||
| Ren et al[72] | Not stated | Recipient, donor: CYP3A5 (rs776746)1, FMO3 (rs1800822, rs2266782, rs1736557, rs909530, rs2266780) | Donor and recipient CYP3A5*3 genotype were associated with increased Tac concentration |
| Eastern Asian | Donor FMO3 rs1800822 allele T and rs909530 allele T were associated with decreased Tac concentration, independently on CYP3A5 genotype | ||
| 110 | |||
| Liao et al[73] | HCC | Recipient, donor: CYP3A5 (rs776746)1, C6 (rs9200, rs10052999) | Donor and recipient CYP3A5*3 genotype were confirmed to be associated with greater Tac concentration |
| Eastern Asian | Recipient C6 rs9200 G allele and donor rs10052999 CC/TT genotype were associated with decreased Tac concentration | ||
| 135 |
1
for CYP3A5 (rs776746) CYP3A5*3 denotes GG genotype, patients with that genotype are CYP3A5 non-expressors. ABCB1: ATP binding cassette subfamily B member 1; C6: Complement C6; CYP: Cytochrome P450; ESYT1: Extended synaptotagmin 1; FAM26F: Gene family with sequence similarity 26, member F; FMO3: Flavin containing monooxygenase 3; MAF: Minor allele frequency; SUMO4: Small ubiquitin like modifier 4; Tac: Tacrolimus; TELO2: Telomere maintenance 2; TLR: Toll like receptor.