title: Impact of genetic SLC28 transporter and ITPA variants on ribavirin serum level, hemoglobin drop and therapeutic response in patients with HCV infection.
abstract: OBJECTIVE
  In the last decade, pegylated interferon-α (PegIFN-α) plus ribavirin (RBV) was the standard treatment of chronic hepatitis C for genotype 1, and it remains the standard for genotypes 2 and 3. Recent studies reported associations between RBV-induced anemia and genetic polymorphisms of concentrative nucleoside transporters such as CNT3 (encoded by SLC28A3) and inosine triphosphatase (encoded by ITPA). We aimed at studying genetic determinants of RBV kinetics, efficacy and treatment-associated anemia.
  
  
  METHODS
  We included 216 patients from two Swiss study cohorts (61% HCV genotype 1, 39% genotypes 2 or 3). Patients were analyzed for SLC28A2 single nucleotide polymorphism (SNP) rs11854484, SLC28A3 rs56350726, and SLC28A3 rs10868138 as well as ITPA SNPs rs1127354 and rs7270101, and followed for treatment-associated hemoglobin changes and sustained virological response (SVR). In 67 patients, RBV serum levels were additionally measured during treatment.
  
  
  RESULTS
  Patients with SLC28A2 rs11854484 genotype TT had higher dosage- and body weight-adjusted RBV levels than those with genotypes TC or CC (p=0.02 and p=0.06 at weeks 4 and 8, respectively). ITPA SNP rs1127354 was associated with hemoglobin drop ≥3 g/dl during treatment, in genotype (relative risk (RR)=2.1, 95% CI 1.3-3.5) as well as allelic analyses (RR=2.0, 95%CI 1.2-3.4). SLC28A3 rs56350726 was associated with SVR in genotype (RR=2.2; 95% CI 1.1-4.3) as well as allelic analyses (RR=2.0, 95% CI 1.1-3.4).
  
  
  CONCLUSIONS
  The newly identified association between RBV serum levels and SLC28A2 rs11854484 genotype, as well as the replicated association of ITPA and SLC28A3 genetic polymorphisms with RBV-induced anemia and treatment response, may support individualized treatment of chronic hepatitis C and warrant further investigation in larger studies.
authors.affiliation: Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Monika
authors.initials: M
authors.lastname: Rau
authors.forename: Felix
authors.initials: F
authors.lastname: Stickel
authors.forename: Stefan
authors.initials: S
authors.lastname: Russmann
authors.forename: Christine N
authors.initials: CN
authors.lastname: Manser
authors.forename: Philip P
authors.initials: PP
authors.lastname: Becker
authors.forename: Michael
authors.initials: M
authors.lastname: Weisskopf
authors.forename: Johannes
authors.initials: J
authors.lastname: Schmitt
authors.forename: Michael T
authors.initials: MT
authors.lastname: Dill
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Dufour
authors.forename: Darius
authors.initials: D
authors.lastname: Moradpour
authors.forename: David
authors.initials: D
authors.lastname: Semela
authors.forename: Beat
authors.initials: B
authors.lastname: Müllhaupt
authors.forename: Andreas
authors.initials: A
authors.lastname: Geier
mesh_terms: D000740:Anemia / Q000139:chemically induced; D000998:Antiviral Agents / Q000009:adverse effects / Q000097:blood* / Q000627:therapeutic use; D015331:Cohort Studies; D005260:Female; D056726:Genetic Association Studies; D006454:Hemoglobins / Q000378:metabolism; D019698:Hepatitis C, Chronic / Q000097:blood* / Q000188:drug therapy / Q000235:genetics*; D006801:Humans; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011755:Pyrophosphatases / Q000235:genetics*; D012254:Ribavirin / Q000009:adverse effects / Q000097:blood* / Q000627:therapeutic use; D016896:Treatment Outcome; D000097630:Inosine Triphosphatase
chemical_list: D000998:Antiviral Agents; D006454:Hemoglobins; D026901:Membrane Transport Proteins; D011755:Pyrophosphatases; D012254:Ribavirin; C065171:cif nucleoside transporter; C511829:ITPA protein, human; D000097630:Inosine Triphosphatase