Background: Augmented susceptibility to infections increases mortality in patients with end-stage liver disease (ESLD). Activation of pro-inflammatory cytokine production via TLR4, which is a major defense mechanism against severe bacterial infections (SBI), shows inter-individual differences. We aimed to determine the contribution of genetic variants in TLR4 and pro-inflammatory cytokines to severe infections in patients with ESLD. Methods: We retrospectively assessed incidence of SBI requiring hospitalization and i.v. antibiotics administration in a cohort of 243 adult cirrhotic ESLD patients enlisted for orthotopic liver transplantation (OLT) from 1995 to 2010. Patients with non-cirrhotic liver diseases were excluded. All patients were genotyped for TLR4 +1196C/T, CD14 -159C/T, TNFA -238G/A, TNFA -863C/A, IL-1B -31C/T and IL-1RA variable number of tandem repeats (VNTR) allelic variants. Associations were validated in a second cohort of 237 cirrhotic ESLD patients enlisted for OLT from 1995 to 2011 from another center.
Results: Sixty nine (69/243, 28%) patients with ESLD presented with SBI while enlisted for OLT in the first cohort. Patients homozygous for TNFA -238 (GG genotype; (n=221)) showed a significantly increased risk of SBI (OR 9.33, P=0.009) compared to patients with the TNFA -238GA genotype, which is supposed to have increased the transcriptional activity of TNFA. In the second cohort, seventy two (72/237, 30%) ESLD patients suffered from SBI while enlisted for OLT. In this cohort, the association between TNFA -238GG and increased risk for SBI was confirmed (OR 3.76, p=0.032). The association was independent of clinical variables that were also included in multivariate analysis. Conclusion: Our results indicate that a genetic variant in the TNFA gene that increases its transcriptional activity independently modifies the risk of SBI in patients with ESLD. These findings may help to identify those patients who are predisposed to SBI.
Drs. de Mare-Bredemeijer and BartÁkovÁ contributed equally to this work.
To cite this abstract in AMA style:de E, Bartáková R, Franková S, Roelen D, Visseren T, Trunecka P, Spicák J, Metselaar H, Jirsa M, Kwekkeboom J, Sperl J. TNF-alpha -238 G-Allele Predisposes to Severe Bacterial Infection in Patients with End-Stage Liver Disease Enlisted for Liver Transplantation, The [abstract]. Am J Transplant. 2013; 13 (suppl 5). http://atcmeetingabstracts.com/abstract/tnf-alpha-238-g-allele-predisposes-to-severe-bacterial-infection-in-patients-with-end-stage-liver-disease-enlisted-for-liver-transplantation-the/. Accessed September 23, 2017.
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