Zhou Y, Ingelman-Sundberg M, Lauschke V M
Department of Physiology and Pharmacology, Section of Pharmacogenetics, Karolinska Institutet, Stockholm, Sweden.
Clin Pharmacol Ther. 2017 Oct;102(4):688-700. doi: 10.1002/cpt.690. Epub 2017 May 26.
Genetic polymorphisms in cytochrome P450 (CYP) genes can result in altered metabolic activity toward a plethora of clinically important medications. Thus, single nucleotide variants and copy number variations in CYP genes are major determinants of drug pharmacokinetics and toxicity and constitute pharmacogenetic biomarkers for drug dosing, efficacy, and safety. Strikingly, the distribution of CYP alleles differs considerably between populations with important implications for personalized drug therapy and healthcare programs. To provide a global distribution map of CYP alleles with clinical importance, we integrated whole-genome and exome sequencing data from 56,945 unrelated individuals of five major human populations. By combining this dataset with population-specific linkage information, we derive the frequencies of 176 CYP haplotypes, providing an extensive resource for major genetic determinants of drug metabolism. Furthermore, we aggregated this dataset into spectra of predicted functional variability in the respective populations and discuss the implications for population-adjusted pharmacological treatment strategies.
细胞色素P450（CYP）基因的遗传多态性可导致对大量临床重要药物的代谢活性改变。因此，CYP基因中的单核苷酸变异和拷贝数变异是药物药代动力学和毒性的主要决定因素，并构成药物剂量、疗效和安全性的药物遗传生物标志物。值得注意的是，CYP等位基因在不同人群中的分布差异很大，这对个性化药物治疗和医疗保健计划具有重要意义。为了提供具有临床重要性的CYP等位基因的全球分布图，我们整合了来自五个主要人类群体的56945名无关个体的全基因组和外显子组测序数据。通过将该数据集与特定人群的连锁信息相结合，我们得出了176种CYP单倍型的频率，为药物代谢的主要遗传决定因素提供了丰富的资源。此外，我们将该数据集汇总为各人群中预测功能变异性的谱图，并讨论了对人群调整药理学治疗策略的影响。
