title: Relationship between polymorphisms of the inosine triphosphatase gene and anaemia or outcome after treatment with pegylated interferon and ribavirin.
abstract: BACKGROUND
  A genome-wide association study revealed an association between variants of the inosine triphosphatase (ITPA) gene and ribavirin (RBV)-induced anaemia. The aim of this study was to replicate this finding in an independent Japanese cohort and to define a method to allow pretreatment prediction of anaemia in combination with other factors.
  
  
  METHODS
  Genotype 1b chronic hepatitis C patients (n=132) treated with pegylated interferon (PEG-IFN)-α and RBV for 48 weeks were genotyped for ITPA rs1127354 and examined for anaemia and treatment outcome.
  
  
  RESULTS
  Variants of the ITPA gene protected against severe anaemia throughout the 48-week treatment period and were associated with lower incidence of anaemia-related RBV dose reduction. A combination of the ITPA genotype with baseline haemoglobin (Hb) and creatinine clearance (CLcr) levels predicted severe anaemia with high accuracy (90% sensitivity and 62% specificity). Among a subset of patients with the IL28B genotype of TT at rs8099917, patients with variants of the ITPA gene were associated with a higher rate of receiving >80% of the expected RBV dose, a higher rate of sustained virological response (SVR), and a lower rate of relapse.
  
  
  CONCLUSIONS
  The variants of the ITPA gene, which could protect against haemolytic anaemia and RBV dose reduction, were associated with a high rate of SVR by standard PEG-IFN and RBV therapy in a subset of Japanese patients with the favourable TT genotype at rs8099917 of IL28B. A combination of ITPA genetic polymorphisms with baseline Hb and CLcr levels further improves the predictive accuracy of severe anaemia.
authors.affiliation: Division of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Kurosaki
authors.forename: Yasuhito
authors.initials: Y
authors.lastname: Tanaka
authors.forename: Keisuke
authors.initials: K
authors.lastname: Tanaka
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Suzuki
authors.forename: Yoshihide
authors.initials: Y
authors.lastname: Hoshioka
authors.forename: Nobuharu
authors.initials: N
authors.lastname: Tamaki
authors.forename: Tomoji
authors.initials: T
authors.lastname: Kato
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Yasui
authors.forename: Takanori
authors.initials: T
authors.lastname: Hosokawa
authors.forename: Ken
authors.initials: K
authors.lastname: Ueda
authors.forename: Kaoru
authors.initials: K
authors.lastname: Tsuchiya
authors.forename: Teiji
authors.initials: T
authors.lastname: Kuzuya
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Nakanishi
authors.forename: Jun
authors.initials: J
authors.lastname: Itakura
authors.forename: Yuka
authors.initials: Y
authors.lastname: Takahashi
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Asahina
authors.forename: Kentaro
authors.initials: K
authors.lastname: Matsuura
authors.forename: Fuminaka
authors.initials: F
authors.lastname: Sugauchi
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Enomoto
authors.forename: Nao
authors.initials: N
authors.lastname: Nishida
authors.forename: Katsushi
authors.initials: K
authors.lastname: Tokunaga
authors.forename: Masashi
authors.initials: M
authors.lastname: Mizokami
authors.forename: Namiki
authors.initials: N
authors.lastname: Izumi
mesh_terms: D000328:Adult; D000368:Aged; D000743:Anemia, Hemolytic / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control; D000998:Antiviral Agents / Q000009:adverse effects / Q000627:therapeutic use*; D003404:Creatinine / Q000097:blood / Q000378:metabolism; D004334:Drug Administration Schedule; D005260:Female; D005838:Genotype; D006454:Hemoglobins; D016174:Hepacivirus / Q000187:drug effects; D019698:Hepatitis C, Chronic / Q000150:complications / Q000188:drug therapy* / Q000235:genetics; D006801:Humans; D016898:Interferon-alpha / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D055118:Medication Adherence; D008875:Middle Aged; D011092:Polyethylene Glycols / Q000009:adverse effects / Q000627:therapeutic use*; D020641:Polymorphism, Single Nucleotide; D011755:Pyrophosphatases / Q000235:genetics* / Q000378:metabolism; D011994:Recombinant Proteins / Q000009:adverse effects / Q000627:therapeutic use; D012008:Recurrence; D012254:Ribavirin / Q000009:adverse effects / Q000627:therapeutic use*; D016896:Treatment Outcome; D000097630:Inosine Triphosphatase
chemical_list: D000998:Antiviral Agents; D003404:Creatinine; D006454:Hemoglobins; D016898:Interferon-alpha; D011092:Polyethylene Glycols; D011755:Pyrophosphatases; D011994:Recombinant Proteins; D012254:Ribavirin; D000097630:Inosine Triphosphatase; C100416:peginterferon alfa-2a