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在临床实践中实施基于基因组的个性化心脏病学。

Implementing genome-driven personalized cardiology in clinical practice.

机构信息

Consulting Professor of Surgery, Emeritus Faculty of Surgery and of Biomedical Engineering, Duke University School of Medicine and Graduate School, Durham, NC 27710, USA.

出版信息

J Mol Cell Cardiol. 2018 Feb;115:142-157. doi: 10.1016/j.yjmcc.2018.01.008. Epub 2018 Jan 16.

Abstract

Genomics designates the coordinated investigation of a large number of genes in the context of a biological process or disease. It may be long before we attain comprehensive understanding of the genomics of common complex cardiovascular diseases (CVDs) such as inherited cardiomyopathies, valvular diseases, primary arrhythmogenic conditions, congenital heart syndromes, hypercholesterolemia and atherosclerotic heart disease, hypertensive syndromes, and heart failure with preserved/reduced ejection fraction. Nonetheless, as genomics is evolving rapidly, it is constructive to survey now pertinent concepts and breakthroughs. Today, clinical multimodal electronic medical/health records (EMRs/EHRs) incorporating genomic information establish a continuously-learning, vast knowledge-network with seamless cycling between clinical application and research. It can inform insights into specific pathogenetic pathways, guide biomarker-assisted precise diagnoses and individualized treatments, and stratify prognoses. Complex CVDs blend multiple interacting genomic variants, epigenetics, and environmental risk-factors, engendering progressions of multifaceted disease-manifestations, including clinical symptoms and signs. There is no straight-line linkage between genetic cause(s) or causal gene-variant(s) and disease phenotype(s). Because of interactions involving modifier-gene influences, (micro)-environmental, and epigenetic effects, the same variant may actually produce dissimilar abnormalities in different individuals. Implementing genome-driven personalized cardiology in clinical practice reveals that the study of CVDs at the level of molecules and cells can yield crucial clinical benefits. Complementing evidence-based medicine guidelines from large ("one-size fits all") randomized controlled trials, genomics-based personalized or precision cardiology is a most-creditable paradigm: It provides customizable approaches to prevent, diagnose, and manage CVDs with treatments directly/precisely aimed at causal defects identified by high-throughput genomic technologies. They encompass stem cell and gene therapies exploiting CRISPR-Cas9-gene-editing, and metabolomic-pharmacogenomic therapeutic modalities, precisely fine-tuned for the individual patient. Following the Human Genome Project, many expected genomics technology to provide imminent solutions to intractable medical problems, including CVDs. This eagerness has reaped some disappointment that advances have not yet materialized to the degree anticipated. Undoubtedly, personalized genetic/genomics testing is an emergent technology that should not be applied without supplementary phenotypic/clinical information: Genotype≠Phenotype. However, forthcoming advances in genomics will naturally build on prior attainments and, combined with insights into relevant epigenetics and environmental factors, can plausibly eradicate intractable CVDs, improving human health and well-being.

摘要

基因组学指定在生物过程或疾病的背景下对大量基因进行协调研究。我们可能需要很长时间才能全面了解遗传性心肌病、瓣膜病、原发性心律失常条件、先天性心脏综合征、高胆固醇血症和动脉粥样硬化性心脏病、高血压综合征以及射血分数保留/降低的心衰等常见复杂心血管疾病 (CVD) 的基因组学。尽管如此,随着基因组学的快速发展,现在调查相关概念和突破是建设性的。如今,整合基因组信息的临床多模态电子医疗/健康记录 (EMR/EHR) 建立了一个不断学习的、庞大的知识网络,在临床应用和研究之间实现无缝循环。它可以深入了解特定的发病机制途径,指导基于生物标志物的精确诊断和个体化治疗,并对预后进行分层。复杂的 CVD 融合了多种相互作用的基因组变异、表观遗传学和环境风险因素,导致多种疾病表现的进展,包括临床症状和体征。遗传原因或因果基因突变与疾病表型之间没有直接的线性联系。由于涉及修饰基因影响、(微)环境和表观遗传效应的相互作用,相同的变异实际上可能在不同个体中产生不同的异常。在临床实践中实施基于基因组的个性化心脏病学表明,在分子和细胞水平上研究 CVD 可以带来至关重要的临床益处。补充来自大型(一刀切)随机对照试验的循证医学指南,基于基因组的个性化或精准心脏病学是一个最值得信赖的范例:它提供了可定制的方法来预防、诊断和管理 CVD,直接针对高通量基因组技术识别的因果缺陷进行精确治疗。它们包括利用 CRISPR-Cas9 基因编辑的干细胞和基因疗法,以及代谢组学-药物基因组学治疗方式,针对个体患者进行精确调整。继人类基因组计划之后,许多人期望基因组学技术为包括 CVD 在内的棘手医学问题提供迫在眉睫的解决方案。这种渴望带来了一些失望,因为进展尚未达到预期的程度。毫无疑问,个性化基因/基因组检测是一项新兴技术,如果没有补充表型/临床信息,不应应用:基因型≠表型。然而,基因组学的未来进展自然将建立在先前的成果之上,并结合对相关表观遗传学和环境因素的深入了解,可以合理地消除棘手的 CVD,改善人类健康和福祉。

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