title: Genome-wide association study of epirubicin-induced leukopenia in Japanese patients.
abstract: OBJECTIVE
  Despite long-term clinical experience with epirubicin, unpredictable severe adverse reactions remain an important determinant to limit the drug use. To identify a genetic factor(s) affecting the risk of epirubicin-induced leukopenia/neutropenia, we performed a genome-wide association study.
  
  
  METHODS
  We studied 270 patients consisting of 67 patients with grade 3 or 4 leukopenia/neutropenia, and 203 patients showing no toxicity (patients with grade 1 or 2 were excluded from the study) for genome-wide association study. We further examined the single nucleotide polymorphisms (SNPs) showing P values of less than 0.0001 using an additional set of 48 patients with grade 3/4 leukopenia/neutropenia.
  
  
  RESULTS
  The combined analysis indicated that rs2916733 in microcephalin 1 [combined PFisher min=2.27×10, odds ratio (OR)=2.74 with 95% confidence interval (CI)=1.96-3.83; the nonrisk genotype as reference] was significantly associated with epirubicin-induced leukopenia/neutropenia. A subgroup analysis of patients with only breast cancer showed a similar trend of association for the marker SNP rs2916733 (combined PFisher min=6.76×10, OR=2.80 with 95% CI=1.86-4.21). We subsequently performed haplotype analysis and found that a haplotype constructed from rs2916733 and rs1031309, which was in linkage disequilibrium with rs2916733 (r=0.64), showed stronger association (P=2.20×10, OR=2.88 with 95% CI=2.05-4.03) than a single landmark SNP (rs2916733; P=2.27×10, OR=2.74 with 95% CI=1.96-3.83), suggesting that causative variant(s) that could influence the susceptibility of epirubicin-induced adverse drug reactions (ADRs) might exist in this haplotype.
  
  
  CONCLUSIONS
  Our findings show that genetic variants in the microcephalin 1 locus are suggestively associated with the risk of epirubicin-induced ADRs and might be applicable in development of diagnostic system for predicting the risk of the ADRs, leading to better prognosis and quality of life for patients with cancer. However, these results should be considered preliminary until replicated in adequately larger powered and controlled samples.
authors.affiliation: Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Japan.
authors.forename: Yuvaraj
authors.initials: Y
authors.lastname: Srinivasan
authors.forename: Mitsunori
authors.initials: M
authors.lastname: Sasa
authors.forename: Junko
authors.initials: J
authors.lastname: Honda
authors.forename: Atsushi
authors.initials: A
authors.lastname: Takahashi
authors.forename: Satoko
authors.initials: S
authors.lastname: Uno
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Kamatani
authors.forename: Michiaki
authors.initials: M
authors.lastname: Kubo
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Zembutsu
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000009:adverse effects* / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy; D016022:Case-Control Studies; D018797:Cell Cycle Proteins; D003598:Cytoskeletal Proteins; D016889:Endometrial Neoplasms / Q000188:drug therapy; D015251:Epirubicin / Q000009:adverse effects* / Q000627:therapeutic use; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D007564:Japan; D007970:Leukopenia / Q000139:chemically induced* / Q000235:genetics*; D015810:Linkage Disequilibrium; D008113:Liver Neoplasms; D008297:Male; D009369:Neoplasms / Q000188:drug therapy*; D009419:Nerve Tissue Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D012307:Risk Factors
chemical_list: D000903:Antibiotics, Antineoplastic; D018797:Cell Cycle Proteins; D003598:Cytoskeletal Proteins; C460645:MCPH1 protein, human; D009419:Nerve Tissue Proteins; D015251:Epirubicin