Cardiovascular Pharmacogenetics: From Discovery of Genetic Association to Clinical Adoption of Derived Test.

IF 19.3 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pharmacological Reviews Pub Date : 2024-08-15 DOI:10.1124/pharmrev.123.000750
Benoît Delabays, Katerina Trajanoska, Joshua Walonoski, Vincent Mooser
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Abstract

Recent breakthroughs in human genetics and in information technologies have markedly expanded our understanding at the molecular level of the response to drugs, i.e., pharmacogenetics (PGx), across therapy areas. This review is restricted to PGx for cardiovascular (CV) drugs. First, we examined the PGx information in the labels approved by regulatory agencies in Europe, Japan, and North America and related recommendations from expert panels. Out of 221 marketed CV drugs, 36 had PGx information in their labels approved by one or more agencies. The level of annotations and recommendations varied markedly between agencies and expert panels. Clopidogrel is the only CV drug with consistent PGx recommendation (i.e., "actionable"). This situation prompted us to dissect the steps from discovery of a PGx association to clinical translation. We found 101 genome-wide association studies that investigated the response to CV drugs or drug classes. These studies reported significant associations for 48 PGx traits mapping to 306 genes. Six of these 306 genes are mentioned in the corresponding PGx labels or recommendations for CV drugs. Genomic analyses also highlighted the wide between-population differences in risk allele frequencies and the individual load of actionable PGx variants. Given the high attrition rate and the long road to clinical translation, additional work is warranted to identify and validate PGx variants for more CV drugs across diverse populations and to demonstrate the utility of PGx testing. To that end, pre-emptive PGx combining genomic profiling with electronic medical records opens unprecedented opportunities to improve healthcare, for CV diseases and beyond. SIGNIFICANCE STATEMENT: Despite spectacular breakthroughs in human molecular genetics and information technologies, consistent evidence supporting PGx testing in the cardiovascular area is limited to a few drugs. Additional work is warranted to discover and validate new PGx markers and demonstrate their utility. Pre-emptive PGx combining genomic profiling with electronic medical records opens unprecedented opportunities to improve healthcare, for CV diseases and beyond.

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心血管药物遗传学:从发现遗传关联到临床采用衍生测试。
人类遗传学和信息技术的最新突破极大地拓展了我们在分子水平上对药物反应的理解,即药物遗传学(PGx),涉及多个治疗领域。本综述仅限于心血管(CV)药物的 PGx。首先,我们研究了欧洲、日本和北美监管机构批准的标签中的 PGx 信息以及专家小组的相关建议。在 221 种上市的 CV 药物中,有 36 种药物的标签中的 PGx 信息获得了一个或多个机构的批准。不同机构和专家小组的注释和建议水平存在明显差异。氯吡格雷是唯一一种具有一致的 PGx 建议(即 "可采取行动")的 CV 药物。这种情况促使我们剖析从发现 PGx 关联到临床转化的各个步骤。我们发现有 101 项全基因组关联研究调查了对冠心病药物或药物类别的反应。这些研究报告了映射到 306 个基因上的 48 个 PGx 性状的重要关联。在这 306 个基因中,有 6 个基因在相应的 PGx 标签或 CV 药物建议中被提及。基因组分析还突显了人群间风险等位基因频率的巨大差异,以及可采取行动的 PGx 变异的个体负荷。考虑到高损耗率和临床转化的漫长道路,有必要开展更多的工作,在不同人群中识别和验证更多 CV 药物的 PGx 变异,并证明 PGx 检测的效用。为此,将基因组分析与电子病历相结合的预防性 PGx 为改善冠心病及其他疾病的医疗保健带来了前所未有的机遇。意义声明 尽管人类分子遗传学和信息技术取得了惊人的突破,但支持心血管领域药物遗传学(PGx)检测的一致证据仅限于少数几种药物。我们需要做更多的工作来发现和验证新的药物基因标记物,并证明它们的效用。将基因组分析与电子病历相结合的先期药物基因学检测为改善心血管疾病及其他疾病的医疗保健提供了前所未有的机遇。
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来源期刊
Pharmacological Reviews
Pharmacological Reviews 医学-药学
CiteScore
34.70
自引率
0.50%
发文量
40
期刊介绍: Pharmacological Reviews is a highly popular and well-received journal that has a long and rich history of success. It was first published in 1949 and is currently published bimonthly online by the American Society for Pharmacology and Experimental Therapeutics. The journal is indexed or abstracted by various databases, including Biological Abstracts, BIOSIS Previews Database, Biosciences Information Service, Current Contents/Life Sciences, EMBASE/Excerpta Medica, Index Medicus, Index to Scientific Reviews, Medical Documentation Service, Reference Update, Research Alerts, Science Citation Index, and SciSearch. Pharmacological Reviews offers comprehensive reviews of new pharmacological fields and is able to stay up-to-date with published content. Overall, it is highly regarded by scholars.
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