Wright G E B, Carleton B, Hayden M R, Ross C J D
Centre for Molecular Medicine and Therapeutics, Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
BC Children's Hospital Research Institute, Vancouver, British Columbia, Canada.
Pharmacogenomics J. 2018 Jan;18(1):187-195. doi: 10.1038/tpj.2016.77. Epub 2016 Oct 25.
Differences in response to medications have a strong genetic component. By leveraging publically available data, the spectrum of such genomic variation can be investigated extensively. Pharmacogenomic variation was extracted from the 1000 Genomes Project Phase 3 data (2504 individuals, 26 global populations). A total of 12 084 genetic variants were found in 120 pharmacogenes, with the majority (90.0%) classified as rare variants (global minor allele frequency <0.5%), with 52.9% being singletons. Common variation clustered individuals into continental super-populations and 23 pharmacogenes contained highly differentiated variants (F>0.5) for one or more super-population comparison. A median of three clinical variants (PharmGKB level 1A/B) was found per individual, and 55.4% of individuals carried loss-of-function variants, varying by super-population (East Asian 60.9%>African 60.1%>South Asian 60.3%>European 49.3%>Admixed 39.2%). Genome sequencing can therefore identify clinical pharmacogenomic variation, and future studies need to consider rare variation to understand the spectrum of genetic diversity contributing to drug response.
对药物反应的差异具有很强的遗传成分。通过利用公开可用的数据，可以广泛研究此类基因组变异的范围。药物基因组变异是从千人基因组计划第三阶段数据（2504人，26个全球人群）中提取的。在120个药物基因中总共发现了12084个遗传变异，其中大多数（90.0%）被归类为罕见变异（全球次要等位基因频率<0.5%），52.9%为单例。常见变异将个体聚类到大陆超级人群中，并且23个药物基因包含一个或多个超级人群比较的高度分化变异（F>0.5）。每个个体发现的临床变异（PharmGKB 1A/B级）中位数为三个，55.4%的个体携带功能丧失变异，因超级人群而异（东亚60.9%>非洲60.1%>南亚60.3%>欧洲49.3%>混血39.2%）。因此，基因组测序可以识别临床药物基因组变异，未来的研究需要考虑罕见变异以了解导致药物反应的遗传多样性范围。
