title: Haplotype-tagging RANTES gene variants influence response to antiviral therapy in chronic hepatitis C.
abstract: The response to antiviral therapy for chronic hepatitis C virus (HCV) is complex and is determined by both environmental and genetic factors. Recently, interacting gene polymorphisms of the chemokine RANTES have been shown to affect HIV disease progression. Our aim was to assess if these RANTES variants are associated with response to anti-HCV therapy. Three linked RANTES single nucleotide polymorphisms (403 G/A, Int1.1 T/C, and 3' 222 T/C) were determined in 297 Caucasian patients who were treated for chronic HCV infection and 152 control subjects. Characteristic nucleotide combinations on single chromosomes (haplotypes) were reconstructed and tested for disease association. Four common RANTES haplotypes (prevalence > 3%) were identified in patients and controls [corrected]. There was a strong association of RANTES haplotype distribution with outcome of antiviral combination therapy (P = .007). Specifically, RANTES haplotypes carrying Int1.1 C and 3' 222 C alleles were more frequent in nonresponders than in patients with a sustained response to antiviral therapy (odds ratio 1.9, P = .01). The influence of these RANTES haplotypes on the outcome of therapy was more pronounced in patients infected with HCV genotypes 1 and 4 (odds ratio 2.3, P = .02). Because RANTES haplotypes carrying Int1.1 C are known to down-regulate RANTES transcriptional activity in vitro, the haplotype analysis fits the hypothesis of a diminished T helper 1 lymphocyte response in patients with a negative response to antiviral therapy. In conclusion, RANTES haplotypes might contribute to the polygenic interaction between HCV and the host immune system and could help to risk stratify patients prior to antiviral therapy.
authors.affiliation: Department of Medicine III, University Hospital Aachen, Aachen University, Aachen, Germany.
authors.forename: Hermann E
authors.initials: HE
authors.lastname: Wasmuth
authors.forename: Alexa
authors.initials: A
authors.lastname: Werth
authors.forename: Tobias
authors.initials: T
authors.lastname: Mueller
authors.forename: Thomas
authors.initials: T
authors.lastname: Berg
authors.forename: Christoph G
authors.initials: CG
authors.lastname: Dietrich
authors.forename: Andreas
authors.initials: A
authors.lastname: Geier
authors.forename: Carsten
authors.initials: C
authors.lastname: Gartung
authors.forename: Johann
authors.initials: J
authors.lastname: Lorenzen
authors.forename: Siegfried
authors.initials: S
authors.lastname: Matern
authors.forename: Frank
authors.initials: F
authors.lastname: Lammert
mesh_terms: D000328:Adult; D000368:Aged; D000483:Alleles; D000998:Antiviral Agents / Q000627:therapeutic use*; D018946:Chemokine CCL5 / Q000235:genetics*; D004359:Drug Therapy, Combination; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006239:Haplotypes; D016174:Hepacivirus / Q000235:genetics; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000209:etiology / Q000235:genetics* / Q000821:virology; D006801:Humans; D007438:Introns; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D016896:Treatment Outcome
chemical_list: D000998:Antiviral Agents; D018946:Chemokine CCL5