title: Role of nucleoside transporters SLC28A2/3 and SLC29A1/2 genetics in ribavirin therapy: protection against anemia in patients with chronic hepatitis C.
abstract: OBJECTIVE
  The standard of hepatitis C antiviral therapy combines pegylated interferon-α with ribavirin. This polar guanosine analog improves the sustained virological response (SVR) rates, but may induce hemolytic anemia. As its pharmacokinetics depend on facilitated transmembrane transport, we assessed whether variants in genes that code for concentrative (concentrative nucleoside transporters 2 and 3 coded by SLC28A2 and SLC28A3, respectively) and equilibrative nucleoside transporters (equilibrative nucleoside transporters 1 and 2 coded by SLC29A1 and SLC29A2, respectively) are associated with the therapy response and side effects.
  
  
  METHODS
  Patients (n=169) chronically infected with the hepatitis C virus genotype 1, treated with standard doses of pegylated interferon-α and weight-based doses of ribavirin for up to 48 weeks, were genotyped for 21 variants in nucleoside transporter genes SLC28A2, SLC28A3, SLC29A1, and SLC29A2, selected to include reported functional variants and to span the complete gene loci. The presence or absence of a SVR (n=169) and a relevant decrease (>3 g/dl, n=115) in blood hemoglobin were associated with the genotypes.
  
  
  RESULTS
  The variant SLC28A3 haplotype rs10868138G/rs56350726T (allelic frequency 0.074) was associated with a lower incidence (35.5%) of relevant decreases (>3 g/dl) in blood hemoglobin than in noncarriers (64.3%; P=0.024, n=115). This protection against hemolytic anemia was not associated with decreased SVR rates (n=169).
  
  
  CONCLUSIONS
  A genetic variant in SCL28A3 coding for the concentrative nucleoside transporter 3 protects patients with chronic hepatitis C against hemolytic anemia without affecting SVR in hepatitis C virus genotype 1.
authors.affiliation: pharmazentrum frankfurt/ZAFES, Institute of Clinical Pharmacology, Johann Wolfgang Goethe-University Hospital, Frankfurt am Main, Germany.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Doehring
authors.forename: Wolf Peter
authors.initials: WP
authors.lastname: Hofmann
authors.forename: Christina
authors.initials: C
authors.lastname: Schlecker
authors.forename: Stefan
authors.initials: S
authors.lastname: Zeuzem
authors.forename: Christoph
authors.initials: C
authors.lastname: Sarrazin
authors.forename: Thomas
authors.initials: T
authors.lastname: Berg
authors.forename: Tobias
authors.initials: T
authors.lastname: Müller
authors.forename: Eva
authors.initials: E
authors.lastname: Herrmann
authors.forename: Gerd
authors.initials: G
authors.lastname: Geisslinger
authors.forename: Jörn
authors.initials: J
authors.lastname: Lötsch
mesh_terms: D000328:Adult; D000368:Aged; D000743:Anemia, Hemolytic / Q000139:chemically induced* / Q000235:genetics*; D000998:Antiviral Agents / Q000009:adverse effects* / Q000627:therapeutic use; D033721:Equilibrative Nucleoside Transporter 1 / Q000235:genetics*; D033722:Equilibrative-Nucleoside Transporter 2 / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D006454:Hemoglobins / Q000032:analysis; D016174:Hepacivirus / Q000187:drug effects / Q000235:genetics; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000627:therapeutic use; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics*; D008875:Middle Aged; D011092:Polyethylene Glycols / Q000627:therapeutic use; D020641:Polymorphism, Single Nucleotide; D011994:Recombinant Proteins; D012254:Ribavirin / Q000009:adverse effects* / Q000627:therapeutic use
chemical_list: D000998:Antiviral Agents; D033721:Equilibrative Nucleoside Transporter 1; D033722:Equilibrative-Nucleoside Transporter 2; D006454:Hemoglobins; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D026901:Membrane Transport Proteins; D011994:Recombinant Proteins; C438649:SLC29A1 protein, human; C065171:cif nucleoside transporter; D011092:Polyethylene Glycols; D012254:Ribavirin; C100416:peginterferon alfa-2a