A single nucleotide polymorphism of Toll-like receptor 4 identifies the risk of developing graft failure after liver transplantation.
OBJECTIVE
While studies in animal models have linked Toll-like receptor (TLR) 4 signaling to the pathophysiology of ischemia/reperfusion (IR) injury and liver fibrosis, the relevance of TLR4 activation after human liver transplantation is unknown. The TLR4 single nucleotide polymorphism (SNP) D299G is situated within the extracellular domain and diminishes receptor binding to danger-associated molecular patterns.


METHODS
We studied the influence of TLR4 D299G on IR injury and graft survival in 430 deceased donor LT recipients. Compared with livers expressing wild-type (WT) alleles, livers with a TLR4 loss-of-function allele were significantly more likely to have initial good graft function (IGGF) (OR 2.20, p=0.01). In contrast, there was no effect of recipient TLR4 genotype on the rate of IGGF.


RESULTS
The effect of TLR4 D299G on long-term graft survival was analyzed based on hepatitis C virus (HCV) serostatus. In HCV infected recipients, multivariate Cox regression analysis demonstrated a significant association between the presence of recipient, but not donor TLR4 D299G and long-term graft failure (HR 2.48, CI 1.28-4.81; p=0.007). There was no difference in graft survival between TLR4 mutant and WT recipients among non-HCV infected recipients.


CONCLUSIONS
Collectively, these results demonstrate the differential effects of donor and recipient TLR4 signaling in human liver transplantation. Donor TLR4 contributed to sterile injury following cold preservation and the recipient TLR4 genotype was linked with poor allograft survival among HCV infected recipients.
Dhillon
Navdeep
N
Division of Nephrology, Mount Sinai School of Medicine, New York, NY 10029, USA.
Walsh
Liron
L
Krüger
Bernd
B
Ward
Stephen C
SC
Godbold
James H
JH
Radwan
Mohamed
M
Schiano
Thomas
T
Murphy
Barbara T
BT
Schröppel
Bernd
B
D000328:Adult; D000368:Aged; D000483:Alleles; D005260:Female; D006085:Graft Survival / Q000235:genetics* / Q000276:immunology*; D019698:Hepatitis C, Chronic / Q000235:genetics / Q000276:immunology / Q000601:surgery; D006801:Humans; D008099:Liver / Q000293:injuries; D016031:Liver Transplantation / Q000009:adverse effects* / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D015427:Reperfusion Injury / Q000209:etiology / Q000235:genetics / Q000276:immunology; D012307:Risk Factors; D015398:Signal Transduction; D014019:Tissue Donors; D051197:Toll-Like Receptor 4 / Q000235:genetics*
C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4