Associations of Chemokine System Polymorphisms With Clinical Outcomes and Treatment Responses of Chronic Hepatitis C

Gastroenterology. 2003 Feb;124(2):352-60. doi: 10.1053/gast.2003.50061.

Abstract

Background & aims: CCR5Delta32, a 32-base pair deletion of the CC chemokine receptor (CCR) 5 gene, is associated with slowed human immunodeficiency virus disease progression in heterozygotes and protection against infection in homozygotes. A recent study found a higher than expected frequency of CCR5Delta32/Delta32 in patients with hepatitis C virus infection. The roles of other disease-associated chemokine system polymorphisms have not been evaluated in hepatitis C virus infection.

Methods: Six chemokine system polymorphisms (CCR5Delta32, CCR5 promoter 59029-G/A, CCR2 -64I, RANTES [regulated upon activation, normal T cells expressed and secreted] -403 -G/A, and -28 -C/G and stromal derived factor 1 -3'A) were studied in 417 patients with liver diseases (339 with hepatitis C) and 2380 blood donors. The clinical parameters of hepatitis C virus infection were compared between carriers and noncarriers of each genetic variant.

Results: The frequency of CCR5Delta32 homozygosity was 0.8% in whites with hepatitis C virus and 1.1% in controls (P = 0.75). The CCR5Delta32 allele was not associated with any of the clinical parameters of hepatitis C virus infection. Hepatitis C virus-seropositive whites with the RANTES -403-A allele were less likely to have severe hepatic inflammation compared with those without (odds ratio, 0.34; P = 0.03). In multivariate analysis, the CCR5 promoter 59029 -A allele was marginally associated with a sustained response to interferon therapy (odds ratio, 3.07; P = 0.048).

Conclusions: In this cohort, the frequency of CCR5Delta32 homozygosity in patients with hepatitis C was similar to controls. The high prevalence of CCR5Delta32 homozygosity in the hepatitis C virus patients of the earlier study likely reflects resistance to human immunodeficiency virus infection in hemophiliacs rather than a susceptibility to hepatitis C virus infection. Expression of CCR5 and RANTES may be important in the modulation of hepatic inflammation and response to interferon therapy in chronic hepatitis C.

MeSH terms

  • Adult
  • Aged
  • Alanine Transaminase / blood
  • Alleles
  • Antiviral Agents / therapeutic use
  • Chemokine CCL5 / genetics*
  • Cohort Studies
  • Disease Progression
  • Female
  • Gene Frequency
  • Hepacivirus / isolation & purification
  • Hepatitis C, Chronic / drug therapy
  • Hepatitis C, Chronic / genetics*
  • Hepatitis C, Chronic / pathology
  • Hepatitis C, Chronic / therapy*
  • Homozygote
  • Humans
  • Interferons / therapeutic use
  • Liver Cirrhosis / pathology
  • Liver Cirrhosis / virology
  • Male
  • Middle Aged
  • Polymorphism, Genetic*
  • Receptors, CCR2
  • Receptors, CCR5 / genetics*
  • Receptors, Chemokine / genetics*
  • Treatment Outcome
  • Viral Load

Substances

  • Antiviral Agents
  • CCR2 protein, human
  • Chemokine CCL5
  • Receptors, CCR2
  • Receptors, CCR5
  • Receptors, Chemokine
  • Interferons
  • Alanine Transaminase