Importance of genetic polymorphisms in liver transplantation outcomes

Table 1 Genes and their single nucleotide polymorphisms investigated in association with acute cellular rejection after liver transplantation

Ref.	Etiology/Population	Genes and best 95%CI OR	Key points
	N (non-ACR/ACR)
Yu et al[13]	Various	Recipient CD276: rs2127015 (0.05-0.93); NS for: rs11072431, rs11574495, rs12593558, rs12594627, rs3816661 rs7176654; Recipient TREML2: rs4714431, rs6915083, rs7754593, rs9394767 NS1	Recipient's CD276 (rs2127015) T allele is weakly associated with ACR and with CD276 mRNA expression
	Eastern Asian
	334/54
Ostojic et al[14]	Alcoholic	Recipient CXCL9: rs10336 NS; Recipient CXCL10: rs3921 NS	No association found. CXCL9 (rs10336) is associated with earlier ACR occurrence and higher plasma CXCL9 concentrations
	European
	156/59
Sun et al[12]	Various	Recipient IL-17: rs2275913 (0.07-0.77)2	Associated with increased IL-17 plasma concentration and with cyclosporine metabolism (CYP3A4 and CYP3A5 expression)
	Eastern Asian
	66/40
Verma et al[16]	Various	Recipient FOXP3: rs3761547, rs3761548, and rs2232365 NS	Association found only in a very small subgroup of steroid resistant ACR patients (N = 5) for rs3761548
	Asian
	86/16
			Associated with the degree of mixed lymphocyte reaction
Thude et al[15]	Various	Recipient KLRB1: rs1135816 NS	No association found
	European
	163/178
Thude et al[8]	Various	Recipient HPA-3 a/b: rs5910 (1.749–41.8); Recipient/donor incompatibility: rs5910 (1.78–7.39); HPA-1, -2, -3, -5, -15 NS for all	HPA-3 incompatibility and HPA-3 b/b genotype were associated with higher incidence of ACR
	European
	53/43
			There was no difference in the time of ACR occurrence
Fereidooni et al[10]	Various	Recipient IL28B: rs12979860 NS	No association found
	Western Asian
	101/39
Valero-Hervás et al[11]	Various	Recipient C3 complement rs2230199 (0.09-0.77)	C3FF genotype is associated with lower incidence of ACR, independently after multivariate analysis for sex, HCV infection, therapy and donor type
	European
	277/185

¹Although a statistical significance for rs6915083 and rs7754593 of TREML2 is noted in the manuscript, the 95% ORs include 1 and should not be considered a significant association.

²Calculated from study data by authors of this review. ACR: Acute cellular rejection; C3: Complement component 3; CD: Cluster of differentiation; CXCL: Chemokine (C‐X‐C motif) ligand; CYP: Cytochrome P450; FOXP3: Forkhead box P3; HCV: Hepatitis C virus; HPA: Human platelet antigen; IL: Interleukin; KLRB1: Killer cell lectin-like receptor B1; mRNA: messenger ribonucleic acid; N: Number; NS: Not significant; TREML2: Triggering receptor expressed on myeloid cell‐like transcript 2; 95%CI OR: 95% confidence interval for odds ratio.

Table 2 Genes and their single nucleotide polymorphisms investigated in association with new-onset of diabetes mellitus after liver transplantation

Ref.	Etiology/Population	Genes and best 95%CI OR	Key points
	N (non-NODM/NODM)
Mottaghi et al[31]	Various	Recipient AGT: rs699 - 7.326 (2.0-26.8), rs4762 – NS	The presence of AGT rs699 T allele may significantly increase the NODM risk
	Iran
	62/53
Husen et al[25]	Various	Recipient Mtor: rs2295080 (1.48-23.4); rs12139042, rs2536 – NS	rs2295080 CC genotype is associated with a risk of DM on everolimus-based IS
	European
	115/121		DM was a secondary objective, with a very low N of DM patients
Cen et al[26]	Hepatitis C, HCC	Recipient ADIPOQ: rs1501299 (0.05-0.61)2, rs822396 (0.13-0.70)3; NS for recipient SNPs: ADIPOR2 rs767870, TLR4 rs1927907, CCL5 rs2107538 and rs2280789, CYP3A5 rs776746, PPARA rs4823613, ACE rs4291, HSD11B1 rs4844880, KCNJ11 rs5219, KCNQ1 rs2237892	ADIPOQ rs1501299 and rs822396 are associated with a risk of NODM
	China
	181/75		rs1501299 is an independent risk factor
Zhang et al[28]	Various	Recipients SUMO4: rs237025 (1.42-5.91); Donors SUMO4: rs237025 (1.542–9.007)	Donor and recipient rs237025 G allele and their combination were independent predictive factors for NODM
	China
	102/24

¹In the cited article the N of non-diabetic patients is wrongly stated to be 127, which is a total N.

²Calculated from study data for codominant model by authors of this review.

³Calculated from study data for dominant model by authors of this review. ACE: Angiotensin I converting enzyme; ADIPOQ: Adiponectin, C1Q and collagen domain containing; ADIPOR2: Adiponectin receptor 2; AGT: Angiotensinogen; CCL5: Chemokine (C-C motif) ligand 5; CYP: Cytochrome P450; DM: Diabetes mellitus; HCC: Hepatocellular carcinoma; HSD11B1: Hydroxysteroid 11-beta dehydrogenase 1; IS: Immunosuppression; KCNJ11: Potassium inwardly-rectifying channel, subfamily J, member 11; KCNQ1: Potassium voltage-gated channel, KQT: Like subfamily, member 1; mTOR: Mammalian target of rapamycin; N: Number; NODM: New-onset diabetes mellitus; NS: Not significant; PPARA: Peroxisome proliferator-activated receptor alpha; SNP: Single nucleotide polymorphism; SUMO4: Small ubiquitin like modifier 4; TLR4: Toll like receptor 4; 95%CI OR: 95% confidence interval for odds ratio.

Table 3 Genes and their single nucleotide polymorphisms investigated in association with non-alcoholic fatty liver disease after liver transplantation

Ref.	Etiology/Population	Genes and best 95%CI OR	Key points
	N (no steatosis/steatosis)
Míková et al[37]	Various	Donor TM6SF2: rs58542926 (1.28-4.42); Donor PNPLA3: rs738409 (1.28-3.27); Additive: TM6SF2 + PNPLA3 (2.01-13.0); Recipient NS for all	Donor TM6SF2 A allele and PNPLA3 G allele are associated with steatosis in both univariate and multivariate adjusted analyses
	European
	139/129		The additive effect of donor TM6SF2 A allele and donor PNPLA3 G allele is strongly associated with steatosis
			No association when recipients SNPs were analyzed
John et al[40]	HCV	Recipient adiponectin: rs1501299 (1.09-5.5), rs266729 (0.14-0.75); rs2241766, rs17300539 – NS; Donor – NS for all	Recipient but not donor adiponectin rs1501299 GG genotype is significantly, but weakly associated with de novo steatosis after adjustment for race and HCV genotype
	North American
	72/39
Kim et al[39]	Various	Recipient PNPLA3: rs738409 (1.00-9.34)1; Donor – NS; Additive donor + recipent: (1.32-117.0)2	If both, donor and recipient have G allele, the recipient has higher risk for steatosis weak association, small number of patients
	Eastern Asian
	23/9
Trunečka et al[38]	Various	Donor PNPLA3: rs738409 (1.05-1.75); Recipient PNPLA3: rs738409 (1.02-1.57)	PNPLA3 G allele in donors [OR (95%CI) = 1.62 (1.12-2.33)], but not in recipients is independently associated with steatosis after adjustment for age, disease etiology, BMI, diabetes, hypertension, therapy and lipids
	European
	89/87

¹Calculated from study data for log-additive model by authors of this review.

²Calculated from study data by authors of this review. BMI: Body mass index; HCV: Hepatitis C virus; N-number; NS: Not significant; OR: Odds ratio; PNPLA3: Patatin-like phospholipase domain-containing 3; SNP: Single nucleotide polymorphism; TM6SF2: Transmembrane 6 superfamily member 2; 95%CI OR: 95% confidence interval for odds ratio.

Table 4 Genes and their single nucleotide polymorphisms investigated in association with hepatocellular carcinoma recurrence after liver transplantation

Ref.	Etiology/Population	Genes and best 95%CI OR	Key points
	N (non HCC/HCC)
Shi et al[53]	Various	Donor TLR 4: rs1927914 (1.886-12.5)1; Recipient TLR 4: rs1927914 NS	Donor TLR4 TT variant is an independent risk factor for HCC recurrence [OR 95%CI = 6.499 (1.799-23.481), after correction], and is associated with shorter recurrence free survival and overall survival
	Eastern Asian
	49/34
Zhang et al[52]	HBV	Recipient IL-15: rs10519613 (1.636–16.168), rs13122930 NS; Donor IL-15: rs10519613 NS; rs13122930 NS	Recipient IL-15 rs10519613 CA/AA genotype is an independent risk factor for shorter tumor free survival and overall survival after correcting for histologic grade, tumor thrombus, tumor stage and UCSF criteria
	Eastern Asian
	74/38
			OR 95 CI for tumor free survival = 2.214 (1.041–4.708), for overall survival = 3.152 (1.358–7.315)
de la Fuente et al[54]	Various	Recipient TLR9: rs187084 (0.01–0.87); rs5743836 – NS	TLR9 rs187084 TT genotype was associated with a decreased risk of HCC recurrence
	European
	139/20

¹Calculated from study data by authors of this review for dominant model. HBV: Hepatitis B virus; HCC: Hepatocellular carcinoma; IL: Interleukin; N: Number; NS: Not significant; OR: Odds ratio; TLR: Toll like receptor; UCSF: University of California San Francisco; 95%CI OR: 95% confidence interval for odds ratio.

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.