Polymorphism in Cytochrome P450 3A4 Is Ethnicity Related
Polymorphism in Cytochrome P450 3A4 Is Ethnicity Related
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DOI：
10.3389/fgene.2019.00224
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发表时间：
2019-03-19
影响因子：
3.7
通讯作者：
Kerem, Zohar
中科院分区：
文献类型：
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作者：
Guttman, Yelena;Nudel, Adi;Kerem, Zohar
细胞色素P450 3A4(细胞色素P450 3A4)(细胞色素P450 3A4)是主要的食物和药物代谢酶，它的突变能否作为个性化精确医学的生物标志物？经典的遗传学研究只提供了有限的数据，关于CYP3A4突变的频率及其在食品-药物相互作用中的作用。在这里，在对一个包含141,456人的大型数据库的分析中，我们发现了856个SNPs(单核苷酸多态)，其中312个是错义突变，远远超过之前报道的数十个。进一步分析数据表明，突变频率在不同种族之间是不同的。等级聚类法将突变分为七组，每组对应于特定的种族。据我们所知，这是第一次对不同种族群体的CYP3A4等位基因频率进行全面分析。我们建议将基于种族的CYP3A4 SNPs分类作为迈向精确饮食和药物的第一步。了解哪种多态以及何时可能具有临床意义是一项极其复杂的任务。通过建模的方法，我们可以预测单变异体活性部位的配体结合姿态的变化。这些变化可能意味着被忽视的改变蛋白质的CYP3A4突变通过改变药物代谢和外国直接投资的临床效果。可以得出结论，饮食习惯，因此外国直接投资，是种族问题。因此，CYP3A4基因的种族相关多态性和饮食可能是对药物治疗反应的一种潜在机制。这里提出的方法有能力突出任何感兴趣的基因的临床相关突变，从而补充经典基因筛查工具的武器库。
Can mutations in Cytochrome P450 3A4 (CYP3A4), the major food- and drug-metabolizing enzyme, serve as biomarkers for personalized precise medicine? Classical genetic studies provide only limited data regarding the frequencies of CYP3A4 mutations and their role in food- drug interactions. Here, in an analysis of one large database of 141,456 individuals, we found 856 SNPs (single nucleotide polymorphism), of which 312 are missense mutations, far more than the previously reported dozens. Analyzing the data further, it is demonstrated that the frequency of mutations differs among ethnic groups. Hierarchical clustering divided the mutations to seven groups, each corresponding to a specific ethnicity. To the best of our knowledge this is the first comprehensive analysis of CYP3A4 allele frequencies in distinct ethnic groups. We suggest ethnicity based classification of CYP3A4 SNPs as the first step toward precise diet and medicine. Understanding which and when polymorphism might have clinical significance is a tremendously complex task. Using modeling approach, we could predict changes in the binding poses of ligands in the active site of single variants. These changes might imply clinical effects of the overlooked protein-altering CYP3A4 mutations, by modifying drug metabolism and FDI. It may be concluded that dietary habits, and hence FDI, are matters of ethnicity. Consequently, ethnic-related polymorphism in CYP3A4 and diet may be one underlying mechanism of response to medical regimes. The approaches presented here have the power to highlight mutations of clinical relevance in any gene of interest, thus to complement the arsenal of classic genetic screening tools.