Accessible Unlicensed Requires Authentication Published by De Gruyter March 12, 2009

Do common genetic variants in endotoxin signaling pathway contribute to predisposition to alcoholic liver cirrhosis?

Jan Petrášek, Jaroslav A. Hubáček, Felix Stickel, Jan Šperl, Thomas Berg, Esther Ruf, H.-Erich Wichmann, Arne Pfeufer, Thomas Meitinger, Pavel Trunečka, Julius Špičák and Milan Jirsa

Abstract

Background: Tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), produced by endotoxin-activated Kupffer cells, play a key role in the pathogenesis of alcoholic liver cirrhosis (ALC). Alleles TNFA –238A, IL1B –31T and variant IL1RN*2 of repeat polymorphism in the gene encoding the IL-1 receptor antagonist increase production of TNF-α and IL-1β, respectively. Alleles CD14 –159T, TLR4 c.896G and TLR4 c.1196T modify activation of Kupffer cells by endotoxin. We confirmed the published associations between these common variants and genetic predisposition to ALC by means of a large case-control association study conducted on two Central European populations.

Methods: The study population comprised a Czech sample of 198 ALC patients and 370 controls (MONICA project), and a German sample of 173 ALC patients and 331 controls (KORA-Augsburg), and 109 heavy drinkers without liver disease.

Results: Single locus analysis revealed no significant difference between patients and controls in all tested loci. Diplotype [IL1RN*2/*2; IL1B –31T+] was associated with increased risk of ALC in the pilot study, but not in the validation samples.

Conclusions: Although cytokine mediated immune reactions play a role in the pathogenesis of ALC, hereditary susceptibility caused by variants in the corresponding genes is low in Central European populations.

Clin Chem Lab Med 2009;47:398–404.


Corresponding author: Jan Petrášek, MD, Laboratory of Experimental Hepatology, Institute for Clinical and Experimental Medicine, Vídeňská 1958, 14021, Praha 4, Czech Republic Phone: +420261362773, Fax: +420241721666,

Received: 2008-11-21
Accepted: 2009-1-20
Published Online: 2009-03-12
Published in Print: 2009-04-01

©2009 by Walter de Gruyter Berlin New York