Influence of the CXCL1 rs4074 A allele on alcohol induced cirrhosis and HCC in patients of European descent

• Published in: PloS one Vol. 8; no. 11; p. e80848
• Main Authors: Nischalke, Hans Dieter, Berger, Cordula, Lutz, Philipp, Langhans, Bettina, Wolter, Franziska, Eisenhardt, Marianne, Krämer, Benjamin, Kokordelis, Pavlos, Glässner, Andreas, Müller, Tobias, Rosendahl, Jonas, Fischer, Janett, Berg, Thomas, Grünhage, Frank, Leifeld, Ludger, Soyka, Michael, Nattermann, Jacob, Sauerbruch, Tilman, Stickel, Felix, Spengler, Ulrich
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 18.11.2013; Public Library of Science (PLoS)
• Subjects: Adult; Age; Aged; Aged, 80 and over; Alcoholics; Alcoholism; Alcoholism - blood; Alcoholism - ethnology; Alcoholism - genetics; Alcohols; Alleles; Carcinoma, Hepatocellular - blood; Carcinoma, Hepatocellular - chemically induced; Carcinoma, Hepatocellular - ethnology; Carcinoma, Hepatocellular - genetics; Carriers; Case-Control Studies; Chemokine CXCL1 - blood; Chemokine CXCL1 - genetics; Chemokines; Cirrhosis; CXC chemokines; Cytokines; Disease control; Enzyme-linked immunosorbent assay; Ethanol - adverse effects; European Continental Ancestry Group; Female; Gastroenterology; Gene expression; Gene polymorphism; Genetic aspects; Genetic Predisposition to Disease; Genotypes; Hepatitis; Hepatocellular carcinoma; Hepatology; Heterozygote; Hospitals; Humans; Internal medicine; Laboratories; Ligands; Liver; Liver cancer; Liver cirrhosis; Liver Cirrhosis, Alcoholic - blood; Liver Cirrhosis, Alcoholic - ethnology; Liver Cirrhosis, Alcoholic - genetics; Liver diseases; Liver Neoplasms - blood; Liver Neoplasms - chemically induced; Liver Neoplasms - ethnology; Liver Neoplasms - genetics; Male; Medical imaging; Medical research; Medicine; Middle Aged; Neutrophils; Patients; Polymorphism; Polymorphism, Single Nucleotide; Risk Factors; Rodents; Serum levels; Stellate cells; TLR2 protein; TLR4 protein; Toll-like receptors; Tomography; Ultrasonic imaging; Germany
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0080848

CXCL1 (CXC chemokine-ligand-1) is a ligand for CXC chemokine receptor 2 expressed on hepatic stellate cells (HSC). Thus, CXCL1 might contribute to HSC activation and fibrogenesis. In the present study, we investigated the influence of the CXCL1 rs4074 polymorphism on the occurrence of alcohol induced liver cirrhosis and hepatocellular carcinoma (HCC). The study involved 458 patients with alcoholic cirrhosis (170 with HCC), 115 alcoholics without liver disease and 342 healthy controls. All subjects were genotyped for the CXCL1 rs4074 polymorphism and CXCL1 serum levels of 132 patients were measured. In vitro CXCL1 secretion in TLR-transfected cell lines were studied by ELISA. Distribution of the CXCL1 genotypes (GG/GA/AA) was 159/219/80 in patients with alcoholic cirrhosis, 52/44/19 in alcoholic controls and 158/140/44 in healthy controls. Patients with alcohol-induced cirrhosis were significantly more often carriers of the CXCL1 rs4074 A allele (65.3%) than alcoholics without liver disease (54.8%, OR=1.55; 95%CI=1.025-2.350; p=0.04) and healthy controls (53.8%, OR=1.62; 95%CI=1.212-2.151; p=0.001). Accordingly, the frequency of the CXCL1 rs4074 A allele was significantly higher in the cirrhotic patients than in the subjects without cirrhosis (41.4% vs. 33.9%, OR=1.38, 95% CI:1.14-1.66, p=0.001). Furthermore cirrhotic carriers of the CXCL1 rs4074 A allele had significantly higher CXCL1 serum levels than carriers of the GG genotype. In contrast to sera from healthy controls, sera from patients with alcoholic cirrhosis induced CXCL1 secretion in TLR2- (p=0.016) and TLR4- (p=0.008) transfected HEK293 cells. This finding indicates that sera from patients with alcoholic cirrhosis contain soluble ligands that can induce CXCL1 production via stimulation of TLRs. The enhanced CXCL1 serum levels in carriers of the rs4074 A allele together with their increased frequency in patients with alcohol induced cirrhosis suggest the CXCL1 rs4074 A allele as a genetic risk factor for alcoholic cirrhosis.