Nebert D W
Center for Environmental Genetics, Department of Environmental Health, University of Cincinnati Medical Center, OH 45267-0056, USA.
Clin Genet. 1999 Oct;56(4):247-58. doi: 10.1034/j.1399-0004.1999.560401.x.
Adverse drug reactions, due at least in part to interindividual variability in drug response, rank between the 4th and 6th leading causes of death in the USA. The field of 'pharmacogenetics', which is 'the study of variability in drug response due to heredity', should help in reducing drug-caused morbidity and mortality. The recently coined term 'pharmacogenomics' usually refers to 'the field of new drug development based on our rapidly increasing knowledge of all genes in the human genome'. However, the two terms - pharmacogenetics and pharmacogenomics - are often used interchangeably. A classification of more than five dozen pharmacogenetic differences is presented here. Most of these variations occur in drug-metabolizing enzyme (DME) genes, with some presumed to exist in the DME receptor and drug transporter genes, and others have not yet been explained on a molecular basis. A method for unequivocally defining a quantitative phenotype (drug efficacy, toxicity, etc.) is proposed; this is where help from the clinical geneticist can be especially important. Our current appreciation of the degree of variability (including single-nucleotide polymorphisms, SNPs) in the human genome is described, with emphasis on the need to prove that a particular genotype is indeed the cause of a specific phenotype; this topic has been termed 'functional genomics'. Furthermore, the current amount of admixture amongst almost all ethnic groups will obviously make studies of gene-drug interactions more complicated, as will the withholding of ethnic information about DNA samples during any molecular epidemiologic study. DME genes and DME receptor and drug transporter genes can be regarded as 'modifier genes', because they influence disorders as diverse as risk of cancer, bone marrow toxicity resulting from occupational exposure, and Parkinson's disease; for this reason, the clinical geneticist, as well as the medical genetics counselor, should be knowledgeable in the rapidly expanding fields of pharmacogenetics and pharmacogenomics.
药物不良反应至少部分归因于个体对药物反应的差异，在美国，它位列导致死亡的第4至第6大主要原因。“药物遗传学”领域，即“研究遗传因素导致的药物反应差异”，应有助于降低药物所致的发病率和死亡率。最近创造的术语“药物基因组学”通常指“基于我们对人类基因组中所有基因的快速增长的了解而进行新药开发的领域”。然而，药物遗传学和药物基因组学这两个术语经常被互换使用。本文介绍了五十多种药物遗传学差异的分类。这些变异大多发生在药物代谢酶（DME）基因中，一些推测存在于DME受体和药物转运体基因中，还有一些尚未在分子层面得到解释。本文提出了一种明确界定定量表型（药物疗效、毒性等）的方法；在这方面，临床遗传学家的帮助尤为重要。本文描述了我们目前对人类基因组中变异程度（包括单核苷酸多态性，SNPs）的认识，强调了证明特定基因型确实是特定表型原因的必要性；这个主题被称为“功能基因组学”。此外，几乎所有种族群体目前的混合程度显然会使基因-药物相互作用的研究更加复杂，任何分子流行病学研究中对DNA样本种族信息的隐瞒也会如此。DME基因以及DME受体和药物转运体基因可被视为“修饰基因”，因为它们影响多种疾病，如癌症风险、职业暴露导致的骨髓毒性和帕金森病；因此，临床遗传学家以及医学遗传学顾问应熟悉药物遗传学和药物基因组学快速发展的领域。
