Background & Aims
Augmented susceptibility to infections increases mortality in patients with end-stage
liver disease (ESLD). We sought to determine the contribution of selected genetic
variants involved in inflammatory signalling downstream of the Toll-like receptor
4 (TLR4) to severe bacterial infections (SBIs) in patients with ESLD.
Methods
We retrospectively assessed incidence of SBIs in 336 adult ESLD patients enlisted
for orthotopic liver transplantation (OLT) and genotyped them for TLR4 c.+1196C/T, CD14 c.−159C/T, TNFA c.−238G/A, TNFA c.−863C/A, IL1B c.−31C/T and IL1RN variable number of tandem repeats allelic variants. Principal findings were validated
in an independent cohort of 332 ESLD patients.
Results
Thirty-four percent of patients from the identification cohort and 40% of patients
from the validation cohort presented with SBI while enlisted for OLT. The presence
of the variant allele TNFA c.−238A (rs361525) was associated with lower serum levels of TNF-α, and with significantly
decreased risk of SBI in both cohorts. Multivariate analysis showed that the relative
protection from SBI associated with this allele almost completely negated the increased
susceptibility to SBI owed to advanced ESLD. Although not predictive of overall mortality,
the presence of the TNFA c.−238A allele was associated with a complete prevention of SBI-related pre-transplant
deaths.
Conclusions
Our results suggest that genetic variability in inflammatory signalling is associated
with the development of SBI in patients with ESLD. Specifically, we identified the
importance of the TNFA c.−238A allele as a strong predictor of protection from SBI, and as a genetic marker
associated with significantly improved pre-transplant survival in patients with SBI.
Abbreviations:
SBI (severe bacterial infections), ESLD (end-stage liver disease), OLT (orthotopic liver transplantation), TLR (toll-like receptors), TLR4 (toll-like receptor 4), LPS (lipopolysaccharide), SNP (single nucleotide polymorphism), TNF-α (tumour necrosis factor-alpha), IL-1β (interleukin-1 beta), TNFA (tumour necrosis factor alpha), IL1B (interleukin 1 beta), IL1RN (interleukin 1 receptor antagonist), VNTR (variable number of tandem repeats), IL-1RA (interleukin-1 receptor antagonist), SBP (spontaneous bacterial peritonitis), EASL (European Association for the Study of the Liver), CRP (C-reactive protein), PCR (polymerase chain reaction), HWE (Hardy-Weinberg equilibrium), CV (coefficient variability), OR (odds ratio), CI (Confidence Interval), MELD (model for end-stage liver disease)Keywords
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Article info
Publication history
Published online: December 19, 2013
Accepted:
December 6,
2013
Received in revised form:
December 5,
2013
Received:
May 1,
2013
Identification
Copyright
© 2013 European Association for the Study of the Liver. Published by Elsevier Inc. All rights reserved.
