Do common genetic variants in endotoxin signaling pathway contribute to predisposition to alcoholic liver cirrhosis?
BACKGROUND
Tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta), 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-alpha and IL-1beta, 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.
Petrásek
Jan
J
Institute for Clinical and Experimental Medicine, Prague, Czech Republic. jan.petrasek@ikem.cz
Hubácek
Jaroslav A
JA
Stickel
Felix
F
Sperl
Jan
J
Berg
Thomas
T
Ruf
Esther
E
Wichmann
H-Erich
HE
Pfeufer
Arne
A
Meitinger
Thomas
T
Trunecka
Pavel
P
Spicák
Julius
J
Jirsa
Milan
M
D016022:Case-Control Studies; D004731:Endotoxins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D014644:Genetic Variation / Q000235:genetics*; D005838:Genotype; D006262:Health; D006801:Humans; D008104:Liver Cirrhosis, Alcoholic / Q000235:genetics* / Q000378:metabolism; D008297:Male; D015398:Signal Transduction
D004731:Endotoxins