title: Genome-wide association study of interferon-related cytopenia in chronic hepatitis C patients.
abstract: OBJECTIVE
  Interferon-alfa (IFN)-related cytopenias are common and may be dose-limiting. We performed a genome wide association study on a well-characterized genotype 1 HCV cohort to identify genetic determinants of peginterferon-α (pegIFN)-related thrombocytopenia, neutropenia, and leukopenia.
  
  
  METHODS
  1604/3070 patients in the IDEAL study consented to genetic testing. Trial inclusion criteria included a platelet (Pl) count ≥80×10(9)/L and an absolute neutrophil count (ANC) ≥1500/mm(3). Samples were genotyped using the Illumina Human610-quad BeadChip. The primary analyses focused on the genetic determinants of quantitative change in cell counts (Pl, ANC, lymphocytes, monocytes, eosinophils, and basophils) at week 4 in patients >80% adherent to therapy (n=1294).
  
  
  RESULTS
  6 SNPs on chromosome 20 were positively associated with Pl reduction (top SNP rs965469, p=10(-10)). These tag SNPs are in high linkage disequilibrium with 2 functional variants in the ITPA gene, rs1127354 and rs7270101, that cause ITPase deficiency and protect against ribavirin (RBV)-induced hemolytic anemia (HA). rs1127354 and rs7270101 showed strong independent associations with Pl reduction (p=10(-12), p=10(-7)) and entirely explained the genome-wide significant associations. We believe this is an example of an indirect genetic association due to a reactive thrombocytosis to RBV-induced anemia: Hb decline was inversely correlated with Pl reduction (r=-0.28, p=10(-17)) and Hb change largely attenuated the association between the ITPA variants and Pl reduction in regression models. No common genetic variants were associated with pegIFN-induced neutropenia or leucopenia.
  
  
  CONCLUSIONS
  Two ITPA variants were associated with thrombocytopenia; this was largely explained by a thrombocytotic response to RBV-induced HA attenuating IFN-related thrombocytopenia. No genetic determinants of pegIFN-induced neutropenia were identified.
authors.affiliation: Duke Clinical Research Institute, Duke University Medical Center, Durham, NC 27701, USA.
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Thompson
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Clark
authors.forename: Abanish
authors.initials: A
authors.lastname: Singh
authors.forename: Dongliang
authors.initials: D
authors.lastname: Ge
authors.forename: Jacques
authors.initials: J
authors.lastname: Fellay
authors.forename: Mingfu
authors.initials: M
authors.lastname: Zhu
authors.forename: Qianqian
authors.initials: Q
authors.lastname: Zhu
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Urban
authors.forename: Keyur
authors.initials: K
authors.lastname: Patel
authors.forename: Hans L
authors.initials: HL
authors.lastname: Tillmann
authors.forename: Susanna
authors.initials: S
authors.lastname: Naggie
authors.forename: Nezam H
authors.initials: NH
authors.lastname: Afdhal
authors.forename: Ira M
authors.initials: IM
authors.lastname: Jacobson
authors.forename: Rafael
authors.initials: R
authors.lastname: Esteban
authors.forename: Fred
authors.initials: F
authors.lastname: Poordad
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Lawitz
authors.forename: Jonathan
authors.initials: J
authors.lastname: McCone
authors.forename: Mitchell L
authors.initials: ML
authors.lastname: Shiffman
authors.forename: Greg W
authors.initials: GW
authors.lastname: Galler
authors.forename: John W
authors.initials: JW
authors.lastname: King
authors.forename: Paul Y
authors.initials: PY
authors.lastname: Kwo
authors.forename: Kevin V
authors.initials: KV
authors.lastname: Shianna
authors.forename: Stephanie
authors.initials: S
authors.lastname: Noviello
authors.forename: Lisa D
authors.initials: LD
authors.lastname: Pedicone
authors.forename: Clifford A
authors.initials: CA
authors.lastname: Brass
authors.forename: Janice K
authors.initials: JK
authors.lastname: Albrecht
authors.forename: Mark S
authors.initials: MS
authors.lastname: Sulkowski
authors.forename: David B
authors.initials: DB
authors.lastname: Goldstein
authors.forename: John G
authors.initials: JG
authors.lastname: McHutchison
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Muir
mesh_terms: D000328:Adult; D000998:Antiviral Agents / Q000009:adverse effects; D005260:Female; D055106:Genome-Wide Association Study; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000235:genetics*; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000009:adverse effects*; D007970:Leukopenia / Q000139:chemically induced* / Q000235:genetics*; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D009503:Neutropenia / Q000139:chemically induced* / Q000235:genetics*; D011092:Polyethylene Glycols / Q000009:adverse effects*; D020641:Polymorphism, Single Nucleotide; D011755:Pyrophosphatases / Q000235:genetics; D011994:Recombinant Proteins / Q000009:adverse effects; D012254:Ribavirin / Q000009:adverse effects; D013921:Thrombocytopenia / Q000139:chemically induced / Q000235:genetics; D000097630:Inosine Triphosphatase
chemical_list: D000998:Antiviral Agents; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011092:Polyethylene Glycols; D011755:Pyrophosphatases; D011994:Recombinant Proteins; D012254:Ribavirin; C511829:ITPA protein, human; D000097630:Inosine Triphosphatase; C417083:peginterferon alfa-2b; C100416:peginterferon alfa-2a