摘要
2001年,人类基因组测序这项工作强调了它的显著复杂性和异质性,并有望推进我们对疾病的理解。这些治疗希望潜在于研究合作,如人类基因组计划(HGP),以及其他关于个性化医疗的基因和基因组DNA科技进步。个性化医疗的关键要素是根据每个病人的特殊疾病开发相应治疗。遗传药理学和药物基因组学(通常一起使用或互换)是指对遗传差异的研究,及其对药物代谢、治疗反应、不良反应的影响 (即药物动力学和药效学)。这些基因信息可以用于指导临床决策和优化病人护理。本系列综述强调了遗传药理学和药物基因组学的使用促进了分子医学进步,并通过多种学科的共同发展,开始在科学和医学的缺口上架起一道桥梁。这组评论介绍了数据科学以及最新实验方法和统计方法,这些方法被用来分析大量的、大规模的来自遗传药理学和药物基因组学研究的以基因组为基础的数据(Penrod and Moore)。此外,全基因组关联研究(GWAS)概述了作为一个强大的和有效的工具来识别易感基因和针对复杂疾病的药物疗法,如老年性黄斑变性(AMD)( Rosen, Kaushal, and SanGiovanni)。同样, 淋巴母细胞系(LCLs)的效用被评论为一个有效的模型系统,用于执行体外人类药物基因组学研究 (Jack, Rotroff, and Motsinger-Reif)。在临床研究方面,概述了最新的遗传药理学和药物基因组学应用与神经系统疾病关联性,包括帕金森氏病和阿尔茨海默氏病,以及常见的精神疾病,比如精神分裂症(SCZ),自闭症谱系障碍(ASD),注意缺陷多动障碍(ADHD) (Gilman and Mao)。日益增长的抗肥胖药物领域,也提出了基因和基因变异影响它们的有效性 (Guzman and Martin)。广泛的心血管相关话题,如“阿司匹林抵抗”,随着心血管疾病与非甾体类抗炎药物的关系被探索,已知潜在的遗传因素影响冠心病和缺血性中风过程中抗血栓形成 (Stitham and Hwa)。此外,有一篇关于检查最新的美国和欧洲临床试验的专业综述,关于以遗传药理学为指导的华法林剂量(Baranova and Maitland-van der Zee),也有一篇详细的调查遗传变异性及其与降压药和降血脂药物之间的关系的综述(Vanichakarn and Stitham)。另外也讨论了一些遗传药理学和药物基因组学以及在主流的临床实践的实施,所面临的主要障碍。特别是,在研究过程中一个常见的障碍表现是缺乏一致性和再现性。而研究设计的差异、小样本含量和患者人群的异质性已经被指出,疾病的遗传基础和遗传可能性的复杂性令人吃惊。单基因疾病、基因多效性等问题,多变或不完全外显率,以及表达不一致性,使得显性基因关联非常困难。此外,这些同样的问题是多层面、多基因疾病本质组成,无数潜在环境的影响亦增加了它的复杂性。正如本期综述中所概述的,我们已经取得了巨大进展,去解决这些局限性。但是,进一步的跨学科合作仍是需要的。成指数增长的信息(每年将增加成千上万的出版物)使基因标记整合到日常临床实践是必须的的和不可避免的。数十亿美元被政府和私人投资到该行业,期待在不久的将来将取得回报。自第一个人类基因组图谱完成,十多年已经过去了。药理遗传学和基因组研究发现成千上万有利于疾病易感、发展、和(或)治疗效果的基因变异。此外,这些进步让我们更好的了解许多疾病的分子基础,这可能导致以基因为基础的治疗方法和诊断性测试的发展。但就目前我们所知,对个体化医疗研究还有许多事情要做。所以我们是“如此接近,又如此遥远”。
Current Molecular Medicine
Title:Editorial (Thematic Issue: Pharmacogenetics and Molecular Medicine: “So Close and Yet So Far”)
Volume: 14 Issue: 7
Author(s): Jason H. Moore and John Hwa
Affiliation:
摘要: The sequencing of the first human genome in 2001 highlighted remarkable complexity and heterogeneity [1] and brought great anticipation in advancing our understanding of disease. The therapeutic promise implicit in research ventures like the Human Genome Project (HGP) and other advancements in genetic-genomic DNA technology lies within the concept of personalized medicine. A key element of personalized medicine is to develop medical treatment that is tailored to the specific disease process of each patient. Pharmacogenetics and pharmacogenomics (often used together or interchangeably) refer to the study of genetic differences and their effect on drug metabolism, therapeutic response, and adverse reactions (i.e., pharmacokinetics and pharmacodynamics). The genetic information can be used to guide clinical decision-making and optimize patient care. Highlighted in this review series are examples by which the use of pharmacogenetics and pharmacogenomics has promoted the advancement of molecular medicine, and started to bridge the gap between science and medicine through a shared progression across a variety of disciplines. This collection of reviews introduces the field of data science, along with the latest experimental approaches and statistical methods being used to analyze the vast amounts of large-scale, genome-based data from pharmacogenetic-pharmacogenomic studies (Penrod and Moore). Furthermore, genome-wide association studies (GWAS) are outlined as a powerful and effective tool to identify susceptibility loci and targeted pharmacotherapies for complex diseases, such as age-related macular degeneration (AMD) (Rosen, Kaushal, and SanGiovanni). Similarly, the utility of lymphoblastoid cell lines (LCLs) is reviewed as an efficient model system for performing human pharmacogenomic studies in vitro (Jack, Rotroff, and Motsinger-Reif). In terms of clinical studies, the latest pharmacogenetic-pharmacogenomic applications relating to neurological disorders, including Parkinson’s and Alzheimer’s disease, as well as common mental illnesses, such as schizophrenia (SCZ), autism spectrum disorder (ASD), and attention deficit hyperactivity disorder (ADHD) are outlined (Gilman and Mao). The growing field of anti-obesity medications, together with the genes and gene variants thought to impact their effectiveness is also presented (Guzman and Martin). Among a wide array of cardiovascularrelated topics, the timely issue of "aspirin resistance", along with the cardiovascular risks associated with nonsteroidal anti-inflammatory drugs is explored, as are the underlying genetic factors affecting antithrombotic agents in coronary artery disease and ischemic stroke (Stitham and Hwa). Furthermore, there is a focused review examining the latest U.S. and European clinical trials regarding pharmacogenetic-guided warfarin dosing (Baranova and Maitland-van der Zee), as well as a detailed look into genetic variability and its relation to antihypertensive and lipidlowering medications (Vanichakarn and Stitham). Some of the major obstacles facing pharmacogenetic and pharmacogenomic research, as well as its implementation to mainstream clinical practice are also discussed. In particular, a common hindrance revealed in the series is the lack of consistency and reproducibility across studies. While differences in study design, small sample size, and heterogeneity among patient populations have been noted, the complexity within the genetic basis of disease and heritability is staggering. Even with monogenic disorders, issues such as pleiotropy, variable or incomplete penetrance, as well as inconsistent expressivity, can make genotype-phenotype associations quite difficult [2]. Moreover, these same issues are compounded by the multifaceted nature of polygenic diseases, and coupled with a myriad of potential environmental influences adding to the complexity [3]. As outlined in this review series, tremendous progress has been made to address these limitations however further cross-disciplinary collaborations are needed. The exponential expansion of information (tens of thousands of publications being added annually) makes incorporation of genetic markers into everyday clinical practice both needed and inevitable. Billions of dollars are being invested by both the government and private industry, and the rewards are expected to pay off in the near future [4]. More than a decade has passed since the mapping of the first human genome. Pharmacogenetic and genomic research has revealed thousands of genetic variants that contribute to disease susceptibility, progression, and/or treatment outcomes. Moreover, these advancements have provided tremendous insights into the molecular basis of many diseases, potentially leading to the development of genetic-based therapies and diagnostic tests. But as far as we have come, towards personalized medicine there remains much to be done. We are “so close and yet so far”.
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Cite this article as:
Moore H. Jason and Hwa John, Editorial (Thematic Issue: Pharmacogenetics and Molecular Medicine: “So Close and Yet So Far”), Current Molecular Medicine 2014; 14 (7) . https://dx.doi.org/10.2174/1566524014666140811122704
DOI https://dx.doi.org/10.2174/1566524014666140811122704 |
Print ISSN 1566-5240 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5666 |
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