Expression Genetics in Drug Therapy

了解疾病和药物反应的遗传基础有可能改善治疗并实现早期干预或预防。然而，主要的遗传因素仍然只有部分了解，即使候选基因的数量正在迅速增长，作为全基因组关联研究的结果。改变蛋白质序列的多态性很容易检测到，但越来越多的证据表明，调节多态性更普遍，影响mRNA的表达，加工和翻译。然而，调控变体难以检测，而且它们的功能取决于组织背景和环境，因此大多数仍然隐藏。该提案的中心目标是在约200个药物基因组学候选基因中全面发现调节多态性，随后进行分子研究以了解潜在机制，并在药物治疗中进行临床评估-这是药物基因组学中的第一个系统性研究。我们已经开发了一种全面的方法来发现调节多态性，测量等位基因mRNA的表达，加工和翻译在相关的人类靶组织。这种方法已经揭示了编码药物代谢酶和受体的基因中意外和频繁的调节变体，获得了已证实功能的基因型与临床结果之间的有力联系（例如：DRD 2，TPH 2，ACE，VKORC 1，CETP和CYP 3A 4）。这些结果支持调节多态性在药物反应中的关键作用。该提案的主要重点是药物代谢基因和对药代动力学-药效学的影响。此外，在其他正在进行的研究的基础上，该项目包括编码药物受体/靶点的基因，重点是中枢神经系统疾病（精神分裂症）和心血管疾病（心肌梗死，脂质代谢），将在经验丰富的临床科学家领导的关联研究中进行测试。在“从临床到实验室”的座右铭的推动下，已经开始了对雌激素和糖皮质激素受体的新的遗传研究，后者将在儿童糖皮质激素耐药肾病综合征中进行测试。长期目标是开发和验证遗传生物标志物面板，以优化个性化药物治疗。

Understanding the genetic basis of disease and drug response has the potential to improve therapy and enable early intervention or prevention. However, the main genetic factors remain only partially understood, even while the number of candidate genes is rapidly growing, as a result of genome-wide association studies. Polymorphisms that alter protein sequence are readily detectable, but growing evidence indicates that regulatory polymorphisms are more prevalent, affecting mRNA expression, processing, and translation. Yet, regulatory variants are difficult to detect, and moreover, their functions depend on tissue context and environment, so that a majority remains hidden. The central goal of this proposal is a comprehensive discovery of regulatory polymorphisms in ~200 pharmacotherapeutic candidate genes, followed by molecular studies to understand the underlying mechanisms, and clinical evaluation in drug therapy - the first such systematic study in pharmacogenomics. We have developed a comprehensive approach to the discovery of regulatory polymorphisms, measuring allelic mRNA expression, processing, and translation in relevant human target tissues. This approach has already revealed unexpected and frequent regulatory variants in genes encoding drug metabolizing enzymes and receptors, gaining a powerful link between genotype of proven function and clinical outcomes (examples: DRD2, TPH2, ACE, VKORC1, CETP, and CYP3A4). These results support a critical role for regulatory polymorphisms in drug response. The main focus in this proposal is on drug metabolism genes and impact on pharmacokinetics-pharmacodynamics. In addition, building on other ongoing studies, the project includes genes encoding drug receptors/targets, with focus on CNS disorders (schizophrenia) and cardiovascular diseases (myocardial infarction, lipid metabolism), to be tested in association studies led by experienced clinical scientists. Driven by the motto 'from clinic to laboratory', new genetic studies have been initiated on estrogen and glucocorticoid receptors, the latter to be tested in glucocorticoid-resistant nephrotic syndrome in children. The long-term goal is to develop and validate genetic biomarker panels for optimizing personalized drug therapy.