Pharmacogenomic genotypes define genetic ancestry in patients and enable population-specific genomic implementation

Wenndy Hernandez; Keith Danahey; Xun Pei; Kiang Teck J. Yeo; Edward Leung; Samuel L. Volchenboum; Mark J. Ratain; David O. Meltzer; Barbara E. Stranger; Minoli A. Perera; Peter H. O’Donnell

doi:10.1038/s41397-019-0095-z

Pharmacogenomic genotypes define genetic ancestry in patients and enable population-specific genomic implementation

Wenndy Hernandez, Keith Danahey, Xun Pei, Kiang Teck J. Yeo, Edward Leung, Samuel L. Volchenboum, Mark J. Ratain, David O. Meltzer, Barbara E. Stranger, Minoli A. Perera, Peter H. O’Donnell^*

^*Corresponding author for this work

Pharmacology

Research output: Contribution to journal › Article › peer-review

20 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	126-135
Number of pages	10
Journal	Pharmacogenomics Journal
Volume	20
Issue number	1
DOIs	https://doi.org/10.1038/s41397-019-0095-z
State	Published - Feb 1 2020

Funding

Acknowledgements This research was supported by an NIH/National Heart, Lung, and Blood Institute/Ruth L. Kirschstein National Research Service Award (NRSA) Individual Postdoctoral Fellowship 1F32HL123311-01A1 (WH), KL2 TR 002387 (WH); NIH K23 GM 100288-01A1 (PHO), NIH/National Heart, Lung, and Blood Institute grant 5 U01 HL105198-09 (PHO and MJR); NIH U54 MD010723 (DOM and MAP); The William F. O’Connor Foundation, and The University of Chicago Comprehensive Cancer Center support grant. We would also like to thank Andrew Skol, Ph.D. for his invaluable guidance in data analysis.

ASJC Scopus subject areas

Molecular Medicine
Genetics
Pharmacology

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Hernandez, W., Danahey, K., Pei, X., Yeo, K. T. J., Leung, E., Volchenboum, S. L., Ratain, M. J., Meltzer, D. O., Stranger, B. E., Perera, M. A., & O’Donnell, P. H. (2020). Pharmacogenomic genotypes define genetic ancestry in patients and enable population-specific genomic implementation. Pharmacogenomics Journal, 20(1), 126-135. https://doi.org/10.1038/s41397-019-0095-z

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Pharmacogenomic genotypes define genetic ancestry in patients and enable population-specific genomic implementation

Abstract

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ASJC Scopus subject areas

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