A genome-wide association study identifies four genetic markers for hematological toxicities in cancer patients receiving gemcitabine therapy
| Autor: | Kazuma Kiyotani, Taisei Mushiroda, Hitoshi Zembutsu, Satoko Uno, Koichi Hirata, Yusuke Nakamura, Hiroki Yamaue, Yasutoshi Kimura, Atsushi Takahashi, Michiaki Kubo, Shinomi Ina, Chikashi Kihara, Naoki Mitsuhata |
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| Rok vydání: | 2012 |
| Předmět: |
Oncology
medicine.medical_specialty Leukopenia business.industry Genome-wide association study Single-nucleotide polymorphism Odds ratio Pharmacology Neutropenia medicine.disease Gemcitabine Genetic marker Internal medicine Genotype Genetics medicine Molecular Medicine General Pharmacology Toxicology and Pharmaceutics medicine.symptom business Molecular Biology Genetics (clinical) medicine.drug |
| Zdroj: | Pharmacogenetics and Genomics. 22:229-235 |
| ISSN: | 1744-6872 |
| DOI: | 10.1097/fpc.0b013e32834e9eba |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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