title: ITPA polymorphism affects ribavirin-induced anemia and outcomes of therapy--a genome-wide study of Japanese HCV virus patients.
abstract: OBJECTIVE
  Ribavirin-induced anemia is one of the major causes of discontinuation and dose reduction during anti-hepatitis C virus therapy. Factors influencing this anemia, especially host genetic factors, are poorly understood. In this study we investigated predictive factors in hepatitis C virus patients treated with combination therapy.
  
  
  METHODS
  We performed a 2-step genome-wide screening followed by replication analysis and fine-mapping using a total of 923 Japanese hepatitis C virus 1b-infected patients treated with pegylated-interferon plus ribavirin. We also applied logistic regression analysis to search for possible independent associations of clinical parameters and genetic variants with treatment-induced hemoglobin (Hb) decline as well as treatment outcomes.
  
  
  RESULTS
  We identified a variant, located upstream of the inosine triphosphate pyrophosphatase gene on chromosome 20p13 that is significantly associated with treatment-induced anemia (combined P = 6.0 × 10(-14)). Resequencing and fine-mapping revealed several single nucleotide polymorphisms (SNPs) strongly associated with Hb decline, including the nonsynonymous SNP rs1127354 (P = 3.5 × 10(-44)), which was recently reported for other ethnic groups. Another reported SNP, the splicing variant-related SNP rs7270101, was not polymorphic in the Japanese population. Stratified analysis based on rs1127354 genotype revealed that inosine triphosphate pyrophosphatase expression is not correlated with Hb decline, suggesting that rs1127354 is a direct causal variant in the Japanese population. Multivariate analysis demonstrated that age, baseline Hb, baseline platelet count, and rs1127354 were independently associated with severe anemia (Hb <10 g/dL).
  
  
  CONCLUSIONS
  A missense substitution in inosine triphosphate pyrophosphatase gene affects ribavirin-induced anemia in hepatitis C virus-infected Japanese patients.
authors.affiliation: Laboratory for Liver Diseases, RIKEN Center for Genomic Medicine, Hiroshima, Japan.
authors.forename: Hidenori
authors.initials: H
authors.lastname: Ochi
authors.forename: Toshiro
authors.initials: T
authors.lastname: Maekawa
authors.forename: Hiromi
authors.initials: H
authors.lastname: Abe
authors.forename: Yasufumi
authors.initials: Y
authors.lastname: Hayashida
authors.forename: Rikita
authors.initials: R
authors.lastname: Nakano
authors.forename: Michaki
authors.initials: M
authors.lastname: Kubo
authors.forename: Tatsuhiko
authors.initials: T
authors.lastname: Tsunoda
authors.forename: C Nelson
authors.initials: CN
authors.lastname: Hayes
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Kumada
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Chayama
mesh_terms: D000328:Adult; D000368:Aged; D000740:Anemia / Q000139:chemically induced*; D000998:Antiviral Agents / Q000009:adverse effects*; D005260:Female; D055106:Genome-Wide Association Study; D006526:Hepatitis C / Q000188:drug therapy* / Q000235:genetics / Q000821:virology; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011755:Pyrophosphatases / Q000235:genetics*; D012254:Ribavirin / Q000009:adverse effects*; D016896:Treatment Outcome; D000097630:Inosine Triphosphatase
chemical_list: D000998:Antiviral Agents; D011755:Pyrophosphatases; D012254:Ribavirin; C511829:ITPA protein, human; D000097630:Inosine Triphosphatase