A genome-wide association study identifies four genetic markers for hematological toxicities in cancer patients receiving gemcitabine therapy

Kazuma Kiyotani, Satoko Uno, Taisei Mushiroda, Atsushi Takahashi, Michiaki Kubo, Naoki Mitsuhata, Shinomi Ina, Chikashi Kihara, Yasutoshi Kimura, Hiroki Yamaue, Koichi Hirata, Yusuke Nakamura, Hitoshi Zembutsu

研究成果: ジャーナルへの寄稿学術論文査読

20 被引用数 (Scopus)

抄録

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. PATIENTS AND 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. CONCLUSION: 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.

本文言語英語
ページ(範囲)229-235
ページ数7
ジャーナルPharmacogenetics and genomics
22
4
DOI
出版ステータス出版済み - 04-2012
外部発表はい

All Science Journal Classification (ASJC) codes

  • 遺伝学(臨床)
  • 薬理学、毒性学および薬学一般
  • 遺伝学
  • 分子医療
  • 分子生物学

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