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

J Hepatol. 2012 Apr;56(4):758-64. doi: 10.1016/j.jhep.2011.10.019. Epub 2011 Dec 13.

Abstract

Background & aims: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Alleles
  • Biopsy
  • Case-Control Studies
  • Chemokine CXCL1 / genetics*
  • Chemokine CXCL1 / physiology*
  • Disease Progression
  • European Continental Ancestry Group / ethnology
  • European Continental Ancestry Group / genetics*
  • Female
  • Gene Frequency
  • Genetic Predisposition to Disease / genetics*
  • Genotype
  • HEK293 Cells
  • Hepacivirus / genetics*
  • Hepatitis C, Chronic / complications*
  • Humans
  • Ligands
  • Liver / pathology
  • Liver Cirrhosis / ethnology
  • Liver Cirrhosis / genetics*
  • Liver Cirrhosis / virology*
  • Male
  • Middle Aged
  • Polymorphism, Single Nucleotide / genetics
  • Risk Factors
  • Toll-Like Receptor 2 / physiology*

Substances

  • CXCL1 protein, human
  • Chemokine CXCL1
  • Ligands
  • TLR2 protein, human
  • Toll-Like Receptor 2