title: Associations of chemokine system polymorphisms with clinical outcomes and treatment responses of chronic hepatitis C.
abstract: OBJECTIVE
  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.affiliation: The Liver Diseases Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA. promrat@nih.gov
authors.forename: Kittichai
authors.initials: K
authors.lastname: Promrat
authors.forename: David H
authors.initials: DH
authors.lastname: McDermott
authors.forename: Carlos M
authors.initials: CM
authors.lastname: Gonzalez
authors.forename: David E
authors.initials: DE
authors.lastname: Kleiner
authors.forename: Deloris E
authors.initials: DE
authors.lastname: Koziol
authors.forename: Matthew
authors.initials: M
authors.lastname: Lessie
authors.forename: Maya
authors.initials: M
authors.lastname: Merrell
authors.forename: Alejandro
authors.initials: A
authors.lastname: Soza
authors.forename: Theo
authors.initials: T
authors.lastname: Heller
authors.forename: Marc
authors.initials: M
authors.lastname: Ghany
authors.forename: Yoon
authors.initials: Y
authors.lastname: Park
authors.forename: Harvey J
authors.initials: HJ
authors.lastname: Alter
authors.forename: Jay H
authors.initials: JH
authors.lastname: Hoofnagle
authors.forename: Philip M
authors.initials: PM
authors.lastname: Murphy
authors.forename: T Jake
authors.initials: TJ
authors.lastname: Liang
mesh_terms: D000328:Adult; D000368:Aged; D000410:Alanine Transaminase / Q000097:blood; D000483:Alleles; D000998:Antiviral Agents / Q000627:therapeutic use; D018946:Chemokine CCL5 / Q000235:genetics*; D015331:Cohort Studies; D018450:Disease Progression; D005260:Female; D005787:Gene Frequency; D016174:Hepacivirus / Q000302:isolation & purification; D019698:Hepatitis C, Chronic / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D006720:Homozygote; D006801:Humans; D007372:Interferons / Q000627:therapeutic use; D008103:Liver Cirrhosis / Q000473:pathology / Q000821:virology; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D054390:Receptors, CCR2; D019713:Receptors, CCR5 / Q000235:genetics*; D019707:Receptors, Chemokine / Q000235:genetics*; D016896:Treatment Outcome; D019562:Viral Load
chemical_list: D000998:Antiviral Agents; C515334:CCR2 protein, human; D018946:Chemokine CCL5; D054390:Receptors, CCR2; D019713:Receptors, CCR5; D019707:Receptors, Chemokine; D007372:Interferons; D000410:Alanine Transaminase