Department of Biochemistry, Abdul Wali Khan University Mardan (AWKUM), Mardan-23200, Khyber Pakhtunkhwa, Pakistan.
Shifa College of Pharmaceutical Sciences, Shifa Tameer-e-Millat University, H-8/4, Islamabad.
Gene. 2020 Jul 1;746:144659. doi: 10.1016/j.gene.2020.144659. Epub 2020 Apr 7.
The genetic polymorphism of cytochrome P450 (CYPs)drug-metabolizing enzymes are well studied in human populations for drug safety and efficacy. CYP2C9 is a highly polymorphic CYP enzyme that oxidizing the indigenous compounds and xenobiotics. The present study was pursued to evaluate the genetic variation across the CYP2C9 gene among major groups of the Pakistani population. The CYP2C9 genomic region holding important warfarin drug-metabolizing SNPs was sequenced from 159 individuals belong from five major ethnic groups of Pakistani population. The population genetic analyses of the high-quality sequences data was performed using Arlequin v3.5, DnaSP v6.12 and Network 5 resources. The data analyses unveiled that genetic variance among samples mainly arose from population-scale differentiation among these ethnic groups with global Fst of 0.78, P-value < 0.0001. The highest pairwise population genetic variation observed between Saraiki and Baloch groups based on different statistical tests. Whereas, uniform genetic composition across CYP2C9 loci was inferred among Punjabi, Pathan and Sindhi groups with minimal genetic differentiation. Several SNPs, including the previously reported warfarin associated variants, i.e. rs2860905, rs1799853 (CYP2C92) and rs72558189 (CYP2C914) were detected in these population groups with diverse allelic frequencies. Besides, a novel intronic SNP, i.e. not available in dbSNP and Ensemble databases, was identified for a Sindhi individual sample. This novel SNP predicted to influence the CYP2C9 alternative transcript splicing. The pharmacogeneticsassessment of the CYP2C9 genetic variations identified in current study may important to test against the warfarin efficacy for different ethnicity of Pakistani population.
细胞色素 P450（CYPs）药物代谢酶的遗传多态性在人类群体中已被广泛研究，以评估药物的安全性和疗效。CYP2C9 是一种高度多态性的 CYP 酶，可氧化内源性化合物和外源性化合物。本研究旨在评估巴基斯坦主要人群中 CYP2C9 基因的遗传变异。从属于巴基斯坦五个主要族群的 159 个人中，对 CYP2C9 基因的基因组区域进行测序，以确定重要的华法林药物代谢 SNP。使用 Arlequin v3.5、DnaSP v6.12 和 Network 5 资源对高质量序列数据进行群体遗传学分析。数据分析表明，样本之间的遗传方差主要源于这些族群之间的种群尺度分化，其中全球 Fst 为 0.78，P 值<0.0001。基于不同的统计检验，在 Saraiki 和 Baloch 族群之间观察到最高的成对群体遗传变异。然而，在 Punjabi、Pathan 和 Sindhi 族群中，CYP2C9 基因座的遗传组成是一致的，遗传分化最小。在这些族群中检测到包括先前报道的与华法林相关的变异，即 rs2860905、rs1799853（CYP2C92）和 rs72558189（CYP2C914）在内的几个 SNP，其等位基因频率各异。此外，在一个 Sindhi 个体样本中发现了一个新的内含子 SNP，该 SNP 尚未在 dbSNP 和 Ensemble 数据库中报道。这个新的 SNP 预测会影响 CYP2C9 替代转录剪接。本研究中鉴定的 CYP2C9 遗传变异的药物遗传学评估可能对华法林在不同种族的巴基斯坦人群中的疗效检测具有重要意义。
