Pharmacogenomic genotypes define genetic ancestry in patients and enable population-specific genomic implementation.,The Pharmacogenomics Journal

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Pharmacogenomic genotypes define genetic ancestry in patients and enable population-specific genomic implementation.
The Pharmacogenomics Journal ( IF 2.9 ) Pub Date : 2019-09-11 , DOI: 10.1038/s41397-019-0095-z
Wenndy Hernandez ₁ , Keith Danahey _{2,

3} , Xun Pei _{2,

4} , Kiang-Teck J Yeo ₄ , Edward Leung _{4,

5} , Samuel L Volchenboum ₃ , Mark J Ratain _{2,

6,

7} , David O Meltzer ₆ , Barbara E Stranger _{1,

8} , Minoli A Perera ₉ , Peter H O'Donnell _{2,

6,

7}

Affiliation

The importance of genetic ancestry characterization is increasing in genomic implementation efforts, and clinical pharmacogenomic guidelines are being published that include population-specific recommendations. Our aim was to test the ability of focused clinical pharmacogenomic SNP panels to estimate individual genetic ancestry (IGA) and implement population-specific pharmacogenomic clinical decision-support (CDS) tools. Principle components and STRUCTURE were utilized to assess differences in genetic composition and estimate IGA among 1572 individuals from 1000 Genomes, two independent cohorts of Caucasians and African Americans (AAs), plus a real-world validation population of patients undergoing pharmacogenomic genotyping. We found that clinical pharmacogenomic SNP panels accurately estimate IGA compared to genome-wide genotyping and identify AAs with ≥70 African ancestry (sensitivity >82%, specificity >80%, PPV >95%, NPV >47%). We also validated a new AA-specific warfarin dosing algorithm for patients with ≥70% African ancestry and implemented it at our institution as a novel CDS tool. Consideration of IGA to develop an institutional CDS tool was accomplished to enable population-specific pharmacogenomic guidance at the point-of-care. These capabilities were immediately applied for guidance of warfarin dosing in AAs versus Caucasians, but also provide a real-world model that can be extended to other populations and drugs as actionable genomic evidence accumulates.

中文翻译：

药物基因组基因型定义了患者的遗传血统，并实现了人群特异性基因组实施。

遗传祖先特征在基因组实施工作中的重要性日益增加，并且正在出版包括针对特定人群的建议的临床药物基因组学指南。我们的目的是测试重点临床药物基因组 SNP panel 估计个体遗传祖先 (IGA) 和实施特定人群药物基因组临床决策支持 (CDS) 工具的能力。主要成分和结构用于评估来自 1000 个基因组的 1572 名个体、两个独立的白种人和非裔美国人 (AA) 队列以及接受药物基因组基因分型的真实世界验证患者群体的遗传组成差异并估计 IGA。我们发现，与全基因组基因分型相比，临床药物基因组 SNP 组合可以准确估计 IGA，并识别具有 ≥70 个非洲血统的 AA（敏感性 >82%，特异性 >80%，PPV >95%，NPV >47%）。我们还针对 ≥70% 非洲血统的患者验证了一种新的 AA 特异性华法林剂量算法，并将其作为一种新型 CDS 工具在我们的机构中实施。 IGA 已考虑开发机构 CDS 工具，以便在护理点提供特定人群的药物基因组学指导。这些功能立即应用于指导 AA 与白种人的华法林剂量，但也提供了一个真实世界的模型，随着可操作的基因组证据的积累，该模型可以扩展到其他人群和药物。

更新日期：2020-01-16

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