title: Genetic variation in TNFA predicts protection from severe bacterial infections in patients with end-stage liver disease awaiting liver transplantation.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Hepatogastroenterology, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.
authors.forename: Renata
authors.initials: R
authors.lastname: Senkerikova
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC - University Medical Centre, Rotterdam, The Netherlands.
authors.forename: Emmeloes
authors.initials: E
authors.lastname: de Mare-Bredemeijer
authors.affiliation: Department of Hepatogastroenterology, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.
authors.forename: Sona
authors.initials: S
authors.lastname: Frankova
authors.affiliation: Department of Immunohematology and Blood Transfusion, University Medical Centre, Leiden, The Netherlands.
authors.forename: Dave
authors.initials: D
authors.lastname: Roelen
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC - University Medical Centre, Rotterdam, The Netherlands.
authors.forename: Thijmen
authors.initials: T
authors.lastname: Visseren
authors.affiliation: Department of Hepatogastroenterology, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.
authors.forename: Pavel
authors.initials: P
authors.lastname: Trunecka
authors.affiliation: Department of Hepatogastroenterology, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.
authors.forename: Julius
authors.initials: J
authors.lastname: Spicak
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC - University Medical Centre, Rotterdam, The Netherlands.
authors.forename: Herold
authors.initials: H
authors.lastname: Metselaar
authors.affiliation: Laboratory of Experimental Hepatology, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.
authors.forename: Milan
authors.initials: M
authors.lastname: Jirsa
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC - University Medical Centre, Rotterdam, The Netherlands.
authors.forename: Jaap
authors.initials: J
authors.lastname: Kwekkeboom
authors.affiliation: Department of Hepatogastroenterology, Institute for Clinical and Experimental Medicine, Prague, Czech Republic. Electronic address: jan.sperl@ikem.cz.
authors.forename: Jan
authors.initials: J
authors.lastname: Sperl
mesh_terms: D000328:Adult; D001424:Bacterial Infections / Q000235:genetics* / Q000276:immunology / Q000517:prevention & control*; D015331:Cohort Studies; D058625:End Stage Liver Disease / Q000150:complications* / Q000235:genetics* / Q000276:immunology; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012189:Retrospective Studies; D051197:Toll-Like Receptor 4 / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000097:blood / Q000235:genetics*
chemical_list: D005819:Genetic Markers; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha
keywords: Inflammatory signalling; Innate immune cells; Liver cirrhosis; Neutrophil exhaustion; Toll-like receptor 4