Laboratory for Pharmacogenetics bLaboratory for Statistical Analysis, RIKEN Center for Genomic Medicine, Yokohama, Japan.
Pharmacogenet Genomics. 2012 Apr;22(4):229-35. doi: 10.1097/FPC.0b013e32834e9eba.
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.
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.
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.
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.
遗传因素被认为是导致接受吉西他滨治疗的癌症患者出现不良反应个体差异的原因之一。然而，确定吉西他滨不良反应风险的遗传因素尚未完全阐明。
为了确定决定吉西他滨诱导的白细胞减少/中性粒细胞减少风险的遗传因素，我们通过基因分型超过 610 000 个单核苷酸多态性（SNP）进行了全基因组关联研究，并在总共 174 名患者中进行了复制研究，包括 54 名至少出现 3 级白细胞减少/中性粒细胞减少的患者和 120 名无任何毒性的患者。
我们确定了四个可能与吉西他滨诱导的白细胞减少/中性粒细胞减少相关的基因座[染色体 9q21 上的 DAPK1 中的 rs11141915，联合 P=1.27×10，比值比（OR）=4.10；染色体 2q12 上的 rs1901440，联合 P=3.11×10，OR=34.00；染色体 1p31 上的 PDE4B 中的 rs12046844，联合 P=4.56×10，OR=4.13；染色体 3q29 上的 rs11719165，联合 P=5.98×10，OR=2.60]。当我们根据这四个 SNP 的总风险基因型将患者分为四组来检查这些 SNP 的联合效应时，与具有零个或一个风险基因型的患者相比，具有两个和三个风险基因型的患者发生吉西他滨诱导的白细胞减少/中性粒细胞减少的风险显著更高（P=6.25×10，OR=11.97；P=4.13×10，OR=50.00）。
我们确定了四个与吉西他滨诱导的严重白细胞减少/中性粒细胞减少相关的新 SNP。这些 SNP 可能适用于预测接受吉西他滨治疗的患者发生血液学毒性的风险。
