Ahmed Shabbir, Zhou Jie, Zhou Zhan, Chen Shu-Qing
Institute of Drug Metabolism and Pharmaceutical Analysis and Zhejiang Provincial Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
International Center for Precision Medicine, Zhejiang California International NanoSystems Institute (ZCNI), Hangzhou 310058, China.
Genes (Basel). 2018 Oct 22;9(10):514. doi: 10.3390/genes9100514.
Diverse distributions of pharmacogenetically relevant variants of highly polymorphic CYP2C9, CYP2D6 and CYPOR genes are responsible for some varied drug responses observed across human populations. There is limited data available regarding the pharmacogenetic polymorphisms and frequency distributions of major allele variants in the Pakistani population. The present in silico mutagenesis study conducted on genotype pharmacogenetic variants and comparative analysis with a global population aims to extend the currently limited pharmacogenetic available evidence for the indigenous Pakistani population. Extracted genomic DNA from 244 healthy individuals' venous blood samples were amplified for distinct variant loci in the CYP2C9, CYP2D6 and CYPOR genes. Two-way sequencing results were compared with standard PubMed data and sequence variant loci confirmed by Chromas. This study revealed significant variations in CYP2C9 (rs1799853, rs1057910 and rs72558189), CYP2D6 (rs16947 and rs1135840), and CYPOR (rs1057868, rs781919285 and rs562750402) variants in intraethnic and interethnic frequency distributions. In silico mutagenesis and three-dimensional protein structural alignment analysis approaches clearly exposed the possible varied impact of rare CYPOR (rs781919285 and rs562750402) single nucleotide polymorphisms (SNPs) and confirmed that the influences of CYP2C9 and CYP2D6 variants are consistent with what was found in earlier studies. This investigation highlighted the need to study pharmacogenetic relevance loci and documentation since evidence could be utilized to elucidate genetic backgrounds of drug metabolism, and provide a basis for future pharmacogenomic studies and adequate dose adjustments in Pakistani and global populations.
高度多态的CYP2C9、CYP2D6和CYPOR基因的药物遗传学相关变异的不同分布，是导致在人类群体中观察到一些不同药物反应的原因。关于巴基斯坦人群中药物遗传学多态性和主要等位基因变异频率分布的数据有限。目前对基因型药物遗传学变异进行的计算机模拟诱变研究以及与全球人群的比较分析，旨在扩展目前针对巴基斯坦本土人群有限的药物遗传学现有证据。从244名健康个体的静脉血样本中提取的基因组DNA，针对CYP2C9、CYP2D6和CYPOR基因中的不同变异位点进行扩增。双向测序结果与标准的PubMed数据进行比较，并通过Chromas确认序列变异位点。这项研究揭示了CYP2C9（rs1799853、rs1057910和rs72558189）、CYP2D6（rs16947和rs1135840）以及CYPOR（rs1057868、rs781919285和rs562750402）变异在种族内和种族间频率分布上的显著差异。计算机模拟诱变和三维蛋白质结构比对分析方法清楚地揭示了罕见的CYPOR（rs781919285和rs562750402）单核苷酸多态性（SNP）可能产生的不同影响，并证实CYP2C9和CYP2D6变异的影响与早期研究结果一致。这项调查强调了研究药物遗传学相关位点和记录的必要性，因为这些证据可用于阐明药物代谢的遗传背景，并为巴基斯坦和全球人群未来的药物基因组学研究及适当的剂量调整提供依据。
