Pharmacoethnicity in Paclitaxel-Induced Sensory Peripheral Neuropathy.
Pharmacoethnicity in Paclitaxel-Induced Sensory Peripheral Neuropathy.
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DOI：
10.1158/1078-0432.ccr-15-0133
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发表时间：
2015-10-01
期刊：
影响因子：
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通讯作者：
Dolan ME
中科院分区：
文献类型：
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作者：
Komatsu M;Wheeler HE;Chung S;Low SK;Wing C;Delaney SM;Gorsic LK;Takahashi A;Kubo M;Kroetz DL;Zhang W;Nakamura Y;Dolan ME
紫杉醇在世界范围内用于治疗乳腺癌、肺癌、卵巢癌和其他癌症。感觉周围神经病变是一种无法预测、预防或缓解的相关不良反应。为了更好地了解生殖系遗传变异对紫杉醇诱导的周围神经病变的贡献，我们采用了一种综合方法，结合了HapMap淋巴母细胞系（LCL）和亚洲患者的全基因组关联研究（GWAS）数据。在363例LCL中进行了紫杉醇诱导的细胞毒性，并在145例亚洲患者中进行了紫杉醇诱导的神经病变。一种基于基因的方法被用来识别重叠基因，并与欧洲紫杉醇诱导的神经病变的临床队列进行比较。来自人诱导多能干细胞的神经元用于候选基因的功能验证。在亚洲LCL中，AIPL 1附近的SNP与紫杉醇诱导的细胞毒性显著相关（P < 10−6）。AIPL 1表达减少导致神经元对紫杉醇的敏感性降低，通过诱导神经突形态学变化（通过增加相对总生长、突起数量和平均突起长度测量）。使用基于基因的分析，有32个基因在亚洲LCL细胞毒性和亚洲患者神经病变（包括BCR）之间重叠（P < 0.05）。在BCR敲低后，通过轴突形态学特征测量，神经元对紫杉醇的敏感性增加。我们确定了与亚洲紫杉醇诱导的细胞毒性相关的遗传变异，并在神经元细胞模型中功能验证了AIPL 1和BCR。此外，LCL/患者GWAS的整合药物基因组学方法可能有助于优先考虑与化疗诱导的周围神经病变相关的靶基因。
Paclitaxel is used worldwide in the treatment of breast, lung, ovarian and other cancers. Sensory peripheral neuropathy is an associated adverse effect that cannot be predicted, prevented or mitigated. To better understand the contribution of germline genetic variation to paclitaxel-induced peripheral neuropathy, we undertook an integrative approach that combines genome-wide association study (GWAS) data generated from HapMap lymphoblastoid cell lines (LCLs) and Asian patients. GWAS was performed with paclitaxel-induced cytotoxicity generated in 363 LCLs and with paclitaxel-induced neuropathy from 145 Asian patients. A gene-based approach was used to identify overlapping genes and compare to a European clinical cohort of paclitaxel-induced neuropathy. Neurons derived from human induced pluripotent stem cells were used for functional validation of candidate genes. SNPs near AIPL1 were significantly associated with paclitaxel-induced cytotoxicity in Asian LCLs (P < 10−6). Decreased expression of AIPL1 resulted in decreased sensitivity of neurons to paclitaxel by inducing neurite morphological changes as measured by increased relative total outgrowth, number of processes and mean process length. Using a gene-based analysis, there were 32 genes that overlapped between Asian LCL cytotoxicity and Asian patient neuropathy (P < 0.05) including BCR. Upon BCR knockdown, there was an increase in neuronal sensitivity to paclitaxel as measured by neurite morphological characteristics. We identified genetic variants associated with Asian paclitaxel-induced cytotoxicity and functionally validated the AIPL1 and BCR in a neuronal cell model. Furthermore, the integrative pharmacogenomics approach of LCL/patient GWAS may help prioritize target genes associated with chemotherapeutic-induced peripheral neuropathy.