Genetic variants of innate immune receptors and infections after liver transplantation

Table 1 Main published findings in the association of innate immune gene variants with the development of infections after liver transplantation

	Innate immune receptor polymorphism	Results	Ref.
Bacterial infections	Donor MBL	Incidence of CSI was 3.8-fold higher in the recipients of MBL variant livers	Bowman et al[123]
		Mutation in the donor MBL2 was associated with CSI (HR = 2.8, P = 0.02)	Worthley et al[124]
		Mutation in donor MBL2 was associated to CSI (HR = 2.58, 95%CI: 1.62-4.10)	de Rooij et al[126]
		Higher incidence of septic shock in recipients of a MBL2 variant liver (HR = 9.64, 95%CI: 2.59-36)	Cervera et al[127]
	Donor ficolin	Mutation of donor ficolin was associated to CSI (HR = 2.33, 95%CI: 1.36-4)	de Rooij et al[126]
	NOD2	NOD2 polymorphism was associated to CSI (HR = 2.0, P = 0.04)	Janse et al[145]
	Donor MASP	Wild-type allele of MASP2 in the donor was associated to CSI (HR = 2.65, 95%CI: 1.22-5.73)	de Rooij et al[126]
	TLR2	Patients with TLR2 polymorphism presented higher rates of Gram positive infection recurrence (27.8% vs 11.8%, P = 0.07) and gram positive septic shock (11.1% vs 1.2%, P = 0.047)	Lee et al[78]
Viral infections	TLR2	CMV load was higher in patients with TLR2 polymorphism (P = 0.03)CMV disease was higher in patients homozygous for the TLR2 polymorphism (HR = 1.91, 95%CI: 0.91-3.4)	Kijpittayarit et al[85]
		TLR2 polymorphism homozygosity was associated to tissue-invasive CMV disease (HR = 3.40, 95%CI: 1.51-7.64)	Kang et al[86]
	MBL	MBL wild-type genotype was associated to a higher incidence of CMV invasive disease in SOT (OR = 6.0, 95%CI: 1.1-32.5)	Cervera et al[129]
		MBL deficient donor is associated to CMV infection (54% vs 32%, P = 0.02)	de Rooij et al[130]
	Ficolin	44% CMV infection in patients receiving a FNC2 wild-type liver vs 27% in patients receiving a variant FCN2 liver (P < 0.02)	de Rooij et al[130]
Fungal infections			No studies in liver transplantation
HCV recurrence	TLR2	Homozygous TLR2 mutation is associated with allograft failure and mortality in HCV-infected recipients (RR = 5.2, 95%CI: 1.65-13.9)	Eid et al[155]
	TLR3	Higher rate of allograft failure and mortality in patients with TLR3 polymorphism (44.3% vs 30.8%, P = 0.09)	Lee et al[156]
		HCV patients with rapid fibrosis progression had impaired TLR7/8-induced interferon response compared with patients with slow fibrosis progression (P = 0.039) and impaired TLR3 and TLR9 cytokine production (P = 0.008)	Howell et al[157]
	NK cells	Lack to antiviral response to HCV therapy associated to the absence of the activating NK receptor haplotype KIR2DS2 (P = 0.008). KIR2L3 haplotype has been correlated to recurrent allograft hepatitis (P = 0.04)	Nellore et al[151]
	IL28B	No difference in the frequencies of IL28B polymorphisms in patients with and without fibrosing cholestatic hepatitis	Duarte-Rojo et al[168]
		Recipients with CC genotype or CT genotype had delayed time to HCV recurrence compared to TT (10.4 vs 6.7 mo, P = 0.002). Recipients with TT genotype had worse graft survival (42% vs 62%, P = 0.02)	Allam et al[162]
		Higher response to antiviral therapy for CC genotype compared to CT or TT (59% vs 25%, P = 0.002). Higher sustained virological response in patients with favorable donor and recipient genotypes (P < 0.01)	Coto-Llerena et al[161]
		Higher progression to cirrhosis (HR = 5.96, 95%CI: 1.29-27.6), liver-related death or re-transplantation among recipients with a CC genotype donor.	Duarte-Rojo et al[167]
		IL28B genotype in the recipient is associated to severe HCV recurrence (OR = 4.27, P = 0.014). Allele IL28B T in the donor tend to have lower incidence of severe HCV recurrence (OR = 0.46, P = 0.19)	Cisneros et al[166]
		Sustained viral response to HCV therapy was 100% if both donor and recipient were CC genotype, while it was only 25% if neither donor nor recipient had CC genotype (P = 0.025)	Firpi et al[163]
		IL28B non-CC in the recipient had a higher risk of severe recurrent HCV (OR = 1.57, P < 0.05). IL28B CC in the donor was associated to higher risk of severe recurrent HCV ( OR = 7.02, P < 0.001)	Biggins et al[164]
No association	TLR	None of a broad range of genetic variants in recipient and donor innate immunity receptors was associated to bacterial or fungal infections after liver transplantation.	de Mare-Bredemeijer et al[71]
	MBL	The presence of donor MBL2 variant is not associated to a higher incidence of CSI (47% vs 36%, P = 0.19)	Curvelo et al[125]
	TLR4	Incidence of Gram-negative infection was not higher in patients with TLR4 mutations (13.5% vs 19.3% in patients with wild-type allele, P = 0.39)	Lee et al[72]
	TLR2	Incidence of Gram-positive bacterial infection was not different related to TLR2 polymorphism (31.6% vs 31.6%)	Lee et al[78]

NOD: Nucleotide-binding and oligomerization domain; TLR: Toll-like receptor; MBL: Mannose-binding lectin; CSI: Clinically significant infections; SOT: Solid organ transplant; MASP: MBL-associated serine proteases; NK: Natural killer; IL: Interleukin.