Genetic architectures of ADME genes in five Eurasian admixed populations and implications for drug safety and efficacy
Genetic architectures of ADME genes in five Eurasian admixed populations and implications for drug safety and efficacy
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五个欧亚混血人群 ADME 基因的遗传结构及其对药物安全性和有效性的影响
DOI：
10.1136/jmedgenet-2014-102530
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发表时间：
2014-09-01
影响因子：
4
通讯作者：
Xu, Shuhua
中科院分区：
文献类型：
--
作者：
Li, Jing;Lou, Haiyi;Xu, Shuhua
背景药物的吸收、分布、代谢和排泄（ADME）导致人体内药物反应的高度异质性。然而，尽管ADME基因在不同种族中存在遗传差异，但中国所有人群均采用相同的药物剂量标准。特别是中国西北部的少数民族，其祖先主要来自欧亚西部民族，这可能违反了这一统一的标准。方法本研究采用Affyscore SNP Array 6.0软件对中国西北地区塔吉克族、维吾尔族、哈萨克族、柯尔克孜族和回族5个少数民族282个ADME基因的遗传多样性进行了分析，试图找出其中高度差异的SNP和单倍型，并进一步探讨其临床意义。结果5个少数民族ADME基因的遗传多样性与中国汉族人群有显著差异。例如，我们确定了10个功能性SNPs的等位基因频率差异，14个功能性SNPs的高度不同的杂合状态和8个基因之间的混合少数民族人口和汉族人口的显着单倍型差异。我们进一步证实了这些差异主要是由于欧洲基因流的作用，即这种基因流增加了混合种群的遗传多样性。结论ADME基因在中国不同民族间存在显著差异。我们认为，如果不考虑人群分层，使用相同剂量的物质（如抗肿瘤药物），可能会导致潜在的临床风险。
Background Drug absorption, distribution, metabolism and excretion (ADME) contribute to the high heterogeneity of drug responses in humans. However, the same standard for drug dosage has been applied to all populations in China although genetic differences in ADME genes are expected to exist in different ethnic groups. In particular, the ethnic minorities in northwestern China with substantial ancestry contribution from Western Eurasian people might violate such a single unified standard. Methods In this study, we used Affymetrix SNP Array 6.0 to investigate the genetic diversity of 282 ADME genes in five northwestern Chinese minority populations, namely, Tajik, Uyghur, Kazakh, Kirgiz and Hui, and attempted to identify the highly differential SNPs and haplotypes and further explore their clinical implications. Results We found that genetic diversity of many ADME genes in the five minority groups was substantially different from those in the Han Chinese population. For instance, we identified 10 functional SNPs with substantial allele frequency differences, 14 functional SNPs with highly different heterozygous states and eight genes with significant haplotype differences between these admixed minority populations and the Han Chinese population. We further confirmed that these differences mainly resulted from the European gene flow, that is, this gene flow increased the genetic diversity in the admixed populations. Conclusions These results suggest that the ADME genes vary substantially among different Chinese ethnic groups. We suggest it could cause potential clinical risk if the same dosage of substances (eg, antitumour drugs) is used without considering population stratification.