title: The CXCL1 rs4074 A allele is associated with enhanced CXCL1 responses to TLR2 ligands and predisposes to cirrhosis in HCV genotype 1-infected Caucasian patients.
abstract: OBJECTIVE
  CXCL1 is a ligand for CXC chemokine-receptor 2 expressed on hepatic stellate cells (HSC). Thus, CXCL1 might contribute to HSC activation and fibrogenesis. Here, we investigated whether the CXCL1 rs4074 polymorphism affects CXCL1 expression and progression of chronic hepatitis C virus (HCV) infection towards cirrhosis.
  
  
  METHODS
  The study involved 237 patients with chronic HCV genotype 1 infection (75 with cirrhosis) and 342 healthy controls. The CXCL1 rs4074 polymorphism was determined by a LightSNiP assay on the LightCycler system. CXCL1 serum levels and induction in response to HCV proteins were studied by ELISA.
  
  
  RESULTS
  Distributions of CXCL1 genotypes (GG/GA/AA) matched the Hardy-Weinberg equilibrium in all subgroups (HCV-associated cirrhosis: 29.3%/54.7%/16.0%; non-cirrhotic HCV infection: 45.1%/44.4%/10.5%, healthy controls: 46.2%/40.9%/12.9%). HCV-infected cirrhotic patients had a significantly greater CXCL1 rs4074 A allele frequency (43.3%) than patients without cirrhosis (32.7%, OR=1.573, p=0.03) and healthy controls (33.3%, OR=1.529, p=0.02). In vitro carriers of the A allele produced greater amounts of CXCL1 in response to TLR2-ligands including HCV core and NS3, and HCV-infected carriers of the CXCL1 rs4074 A allele had higher CXCL1 serum levels than those with the G/G genotype. Moreover, multivariate Cox-regression analysis confirmed age and the presence of a CXCL1 rs4074 A allele as risk factors for cirrhosis.
  
  
  CONCLUSIONS
  Enhanced production of CXCL1 in response to HCV antigens in carriers of the rs4074 A allele together with its increased frequency in cirrhotic patients with hepatitis C suggest the CXCL1 rs4074 A allele as a genetic risk factor for cirrhosis progression in hepatitis C.
authors.affiliation: Department of Internal Medicine I, University of Bonn, Sigmund-Freud-Str. 25, 53127 Bonn, Germany.
authors.forename: Hans Dieter
authors.initials: HD
authors.lastname: Nischalke
authors.forename: Cordula
authors.initials: C
authors.lastname: Berger
authors.forename: Carolin
authors.initials: C
authors.lastname: Luda
authors.forename: Tobias
authors.initials: T
authors.lastname: Müller
authors.forename: Thomas
authors.initials: T
authors.lastname: Berg
authors.forename: Martin
authors.initials: M
authors.lastname: Coenen
authors.forename: Benjamin
authors.initials: B
authors.lastname: Krämer
authors.forename: Christian
authors.initials: C
authors.lastname: Körner
authors.forename: Jonel
authors.initials: J
authors.lastname: Trebicka
authors.forename: Frank
authors.initials: F
authors.lastname: Grünhage
authors.forename: Frank
authors.initials: F
authors.lastname: Lammert
authors.forename: Jacob
authors.initials: J
authors.lastname: Nattermann
authors.forename: Tilman
authors.initials: T
authors.lastname: Sauerbruch
authors.forename: Ulrich
authors.initials: U
authors.lastname: Spengler
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D001706:Biopsy; D016022:Case-Control Studies; D054360:Chemokine CXCL1 / Q000235:genetics* / Q000502:physiology*; D018450:Disease Progression; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D057809:HEK293 Cells; D016174:Hepacivirus / Q000235:genetics*; D019698:Hepatitis C, Chronic / Q000150:complications*; D006801:Humans; D008024:Ligands; D008099:Liver / Q000473:pathology; D008103:Liver Cirrhosis / Q000208:ethnology / Q000235:genetics* / Q000821:virology*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012307:Risk Factors; D051195:Toll-Like Receptor 2 / Q000502:physiology*; D044465:White People / Q000208:ethnology / Q000235:genetics*
chemical_list: C475829:CXCL1 protein, human; D054360:Chemokine CXCL1; D008024:Ligands; C495342:TLR2 protein, human; D051195:Toll-Like Receptor 2