Genetic variation in TNFA predicts protection from severe bacterial infections in patients with end-stage liver disease awaiting liver transplantation

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• 作者：Renata Senkerikova¹ ; ^&dagger ; ; Emmeloes de Mare-Bredemeijer³ ; ^&dagger ; ; Sona Frankova¹ ; Dave Roelen⁴ ; Thijmen Visseren³ ; Pavel Trunecka¹ ; Julius Spicak¹ ; Herold Metselaar³ ; Milan Jirsa² ; Jaap Kwekkeboom³ ; Jan Sperl¹ ; ^{jan.sperl@ikem.cz" class="auth_mail}
• 关键词：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-伪 ; tumour necrosis factor-alpha ; IL-1尾 ; 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
• 刊名：Journal of Hepatology
• 出版年：April, 2014
• 年：2014
• 卷：60
• 期：4
• 页码：773-781
• 全文大小：904 K

文摘

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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.鈭?59C/T, TNFA c.鈭?38G/A, TNFA c.鈭?63C/A, IL1B c.鈭?1C/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.鈭?38A (rs361525) was associated with lower serum levels of TNF-伪, 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.鈭?38A 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.鈭?38A 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.