Importance of genetic polymorphisms in liver transplantation outcomes

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

¹for 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.