title: A genome-wide association study identifies four genetic markers for hematological toxicities in cancer patients receiving gemcitabine therapy.
abstract: OBJECTIVE
  Genetic factors are thought to be one of the causes of individual variability in the adverse reactions observed in cancer patients who received gemcitabine therapy. However, genetic factors determining the risk of adverse reactions of gemcitabine are not fully understood.
  
  
  METHODS
  To identify a genetic factor(s) determining the risk of gemcitabine-induced leukopenia/neutropenia, we conducted a genome-wide association study, by genotyping over 610 000 single nucleotide polymorphisms (SNPs), and a replication study in a total of 174 patients, including 54 patients with at least grade 3 leukopenia/neutropenia and 120 patients without any toxicities.
  
  
  RESULTS
  We identified four loci possibly associated with gemcitabine-induced leukopenia/neutropenia [rs11141915 in DAPK1 on chromosome 9q21, combined P=1.27×10, odds ratio (OR)=4.10; rs1901440 on chromosome 2q12, combined P=3.11×10, OR=34.00; rs12046844 in PDE4B on chromosome 1p31, combined P=4.56×10, OR=4.13; rs11719165 on chromosome 3q29, combined P=5.98×10, OR=2.60]. When we examined the combined effects of these four SNPs, by classifying patients into four groups on the basis of the total number of risk genotypes of these four SNPs, significantly higher risks of gemcitabine-induced leukopenia/neutropenia were observed in the patients having two and three risk genotypes (P=6.25×10, OR=11.97 and P=4.13×10, OR=50.00, respectively) relative to patients with zero or one risk genotype.
  
  
  CONCLUSIONS
  We identified four novel SNPs associated with gemcitabine-induced severe leukopenia/neutropenia. These SNPs might be applicable in predicting the risk of hematological toxicity in patients receiving gemcitabine therapy.
authors.affiliation: Laboratory for Pharmacogenetics bLaboratory for Statistical Analysis, RIKEN Center for Genomic Medicine, Yokohama, Japan.
authors.forename: Kazuma
authors.initials: K
authors.lastname: Kiyotani
authors.forename: Satoko
authors.initials: S
authors.lastname: Uno
authors.forename: Taisei
authors.initials: T
authors.lastname: Mushiroda
authors.forename: Atsushi
authors.initials: A
authors.lastname: Takahashi
authors.forename: Michiaki
authors.initials: M
authors.lastname: Kubo
authors.forename: Naoki
authors.initials: N
authors.lastname: Mitsuhata
authors.forename: Shinomi
authors.initials: S
authors.lastname: Ina
authors.forename: Chikashi
authors.initials: C
authors.lastname: Kihara
authors.forename: Yasutoshi
authors.initials: Y
authors.lastname: Kimura
authors.forename: Hiroki
authors.initials: H
authors.lastname: Yamaue
authors.forename: Koichi
authors.initials: K
authors.lastname: Hirata
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Zembutsu
mesh_terms: D000368:Aged; D051017:Apoptosis Regulatory Proteins / Q000235:genetics*; D054316:Biomarkers, Pharmacological / Q000097:blood; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics*; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000235:genetics*; D064550:Death-Associated Protein Kinases; D003841:Deoxycytidine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D005260:Female; D055106:Genome-Wide Association Study / Q000379:methods*; D005838:Genotype; D006801:Humans; D007970:Leukopenia / Q000139:chemically induced / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009503:Neutropenia / Q000139:chemically induced / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012307:Risk Factors; D000093542:Gemcitabine
chemical_list: D051017:Apoptosis Regulatory Proteins; D054316:Biomarkers, Pharmacological; D003841:Deoxycytidine; C579096:DAPK1 protein, human; D064550:Death-Associated Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C517360:PDE4B protein, human; D000093542:Gemcitabine