title: Influence of the CXCL1 rs4074 A allele on alcohol induced cirrhosis and HCC in patients of European descent.
abstract: OBJECTIVE
  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).
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Internal Medicine I, University of Bonn, Bonn, Germany.
authors.forename: Hans Dieter
authors.initials: HD
authors.lastname: Nischalke
authors.forename: Cordula
authors.initials: C
authors.lastname: Berger
authors.forename: Philipp
authors.initials: P
authors.lastname: Lutz
authors.forename: Bettina
authors.initials: B
authors.lastname: Langhans
authors.forename: Franziska
authors.initials: F
authors.lastname: Wolter
authors.forename: Marianne
authors.initials: M
authors.lastname: Eisenhardt
authors.forename: Benjamin
authors.initials: B
authors.lastname: Krämer
authors.forename: Pavlos
authors.initials: P
authors.lastname: Kokordelis
authors.forename: Andreas
authors.initials: A
authors.lastname: Glässner
authors.forename: Tobias
authors.initials: T
authors.lastname: Müller
authors.forename: Jonas
authors.initials: J
authors.lastname: Rosendahl
authors.forename: Janett
authors.initials: J
authors.lastname: Fischer
authors.forename: Thomas
authors.initials: T
authors.lastname: Berg
authors.forename: Frank
authors.initials: F
authors.lastname: Grünhage
authors.forename: Ludger
authors.initials: L
authors.lastname: Leifeld
authors.forename: Michael
authors.initials: M
authors.lastname: Soyka
authors.forename: Jacob
authors.initials: J
authors.lastname: Nattermann
authors.forename: Tilman
authors.initials: T
authors.lastname: Sauerbruch
authors.forename: Felix
authors.initials: F
authors.lastname: Stickel
authors.forename: Ulrich
authors.initials: U
authors.lastname: Spengler
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000437:Alcoholism / Q000097:blood / Q000208:ethnology / Q000235:genetics*; D000483:Alleles; D006528:Carcinoma, Hepatocellular / Q000097:blood / Q000139:chemically induced / Q000208:ethnology / Q000235:genetics*; D016022:Case-Control Studies; D054360:Chemokine CXCL1 / Q000097:blood / Q000235:genetics*; D000431:Ethanol / Q000009:adverse effects; D005260:Female; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006801:Humans; D008104:Liver Cirrhosis, Alcoholic / Q000097:blood / Q000208:ethnology / Q000235:genetics*; D008113:Liver Neoplasms / Q000097:blood / Q000139:chemically induced / Q000208:ethnology / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D044465:White People
chemical_list: C475829:CXCL1 protein, human; D054360:Chemokine CXCL1; D000431:Ethanol