Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Japan.
Pharmacogenet Genomics. 2011 Sep;21(9):552-8. doi: 10.1097/FPC.0b013e328348e48f.
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.
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.
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.
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.
尽管表阿霉素在临床上应用已久，但仍存在无法预测的严重不良反应，这仍是限制其应用的重要因素。为了寻找影响表阿霉素致白细胞减少/中性粒细胞减少风险的遗传因素，我们进行了全基因组关联研究。
我们研究了 270 例患者，其中 67 例患者发生 3 或 4 级白细胞减少/中性粒细胞减少，203 例患者无毒性（排除了 1 或 2 级的患者）进行全基因组关联研究。我们进一步使用另外 48 例 3/4 级白细胞减少/中性粒细胞减少的患者，对 P 值小于 0.0001 的单核苷酸多态性（SNP）进行了检查。
合并分析表明，微管相关蛋白 1 基因[rs2916733；合并最小 P 值 Fisher 检验=2.27×10 ，比值比（OR）=2.74，95%置信区间（CI）=1.96-3.83；非风险基因型作为参考]与表阿霉素引起的白细胞减少/中性粒细胞减少显著相关。仅乳腺癌患者的亚组分析显示，标记 SNP rs2916733 的相关性也存在类似趋势（合并最小 P 值 Fisher 检验=6.76×10 ，OR=2.80，95%CI=1.86-4.21）。我们随后进行了单体型分析，发现由 rs2916733 和 rs1031309 组成的单体型与 rs2916733 连锁不平衡（r=0.64），其相关性更强（P=2.20×10 ，OR=2.88，95%CI=2.05-4.03），而单个标志性 SNP（rs2916733；P=2.27×10 ，OR=2.74，95%CI=1.96-3.83）的相关性较弱，提示该单体型中可能存在影响表阿霉素引起药物不良反应（ADR）易感性的致病变异。
我们的研究结果表明，微管相关蛋白 1 基因座的遗传变异与表阿霉素引起的 ADR 风险存在相关性，这可能有助于开发预测 ADR 风险的诊断系统，从而改善癌症患者的预后和生活质量。然而，这些结果应被视为初步结果，有待在更大的、有足够效力和对照的样本中进行验证。
