Associations of chemokine system polymorphisms with clinical outcomes and treatment responses of chronic hepatitis C.

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.

• Authors: Kittichai Promrat, David H McDermott, Carlos M Gonzalez, David E Kleiner, Deloris E Koziol, Matthew Lessie, Maya Merrell, Alejandro Soza, Theo Heller, Marc Ghany, Yoon Park, Harvey J Alter, Jay H Hoofnagle, Philip M Murphy, T Jake Liang
• Journal: Gastroenterology (Gastroenterology) Vol. 124 Issue 2 Pg. 352-60 (Feb 2003) ISSN: 0016-5085 [Print] United States
• PMID: 12557141 (Publication Type: Journal Article)

Chemical References

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

Topics

• 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, genetics, pathology, therapy)
• Homozygote
• Humans
• Interferons (therapeutic use)
• Liver Cirrhosis (pathology, virology)
• Male
• Middle Aged
• Polymorphism, Genetic
• Receptors, CCR2
• Receptors, CCR5 (genetics)
• Receptors, Chemokine (genetics)
• Treatment Outcome
• Viral Load