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The pharmacoepigenomics informatics pipeline defines a pathway of novel and known warfarin pharmacogenomics variants.

ABSTRACT: AIM:'Pharmacoepigenomics' methods informed by omics datasets and pre-existing knowledge have yielded discoveries in neuropsychiatric pharmacogenomics. Now we evaluate the generality of these methods by discovering an extended warfarin pharmacogenomics pathway. MATERIALS & METHODS:We developed the pharmacoepigenomics informatics pipeline, a scalable multi-omics variant screening pipeline for pharmacogenomics, and conducted an experiment in the genomics of warfarin. RESULTS:We discovered known and novel pharmacogenomics variants and genes, both coding and regulatory, for warfarin response, including adverse events. Such genes and variants cluster in a warfarin response pathway consolidating known and novel warfarin response variants and genes. CONCLUSION:These results can inform a new warfarin test. The pharmacoepigenomics informatics pipeline may be able to discover new pharmacogenomics markers in other drug-disease systems.

SUBMITTER: Allyn-Feuer A

PROVIDER: S-EPMC6021929 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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The pharmacoepigenomics informatics pipeline defines a pathway of novel and known warfarin pharmacogenomics variants.

Allyn-Feuer Ari A Ade Alex A Luzum Jasmine A JA Higgins Gerald A GA Athey Brian D BD

Pharmacogenomics 20180205 5

<h4>Aim</h4>'Pharmacoepigenomics' methods informed by omics datasets and pre-existing knowledge have yielded discoveries in neuropsychiatric pharmacogenomics. Now we evaluate the generality of these methods by discovering an extended warfarin pharmacogenomics pathway.<h4>Materials & methods</h4>We developed the pharmacoepigenomics informatics pipeline, a scalable multi-omics variant screening pipeline for pharmacogenomics, and conducted an experiment in the genomics of warfarin.<h4>Results</h4>W ...[more]

PMID: 29400612

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Project description:Pharmacogenomics is universally relevant for worldwide modern therapeutics and yet needs further development in resource-limited countries. While there is an abundance of genetic association studies in controlled medical settings, there is a paucity of studies with a naturalistic design in real-life clinical practice in patients with comorbidities and under multiple drug treatment regimens. African patients are often burdened with communicable and noncommunicable comorbidities, yet the application of pharmacogenomics in African clinical settings remains limited. Using warfarin as a model, this study aims at minimizing gaps in precision/personalized medicine research in African clinical practice. We present, therefore, pharmacogenomic profiles of a cohort of 503 black Africans (n = 252) and Mixed Ancestry (n = 251) patients from Southern Africa, on warfarin and co-prescribed drugs in a naturalized noncontrolled environment. Seventy-three (n = 73) single nucleotide polymorphisms (SNPs) in 29 pharmacogenes were characterized using a combination of allelic discrimination, Sanger sequencing, restriction fragment length polymorphism, and Sequenom Mass Array. The common comorbidities were hypertension (43-46%), heart failure (39-45%), diabetes mellitus (18%), arrhythmia (25%), and HIV infection (15%). Accordingly, the most common co-prescribed drugs were antihypertensives, antiarrhythmic drugs, antidiabetics, and antiretroviral therapy. We observed marked variation in major pharmacogenes both at interethnic levels and within African subpopulations. The Mixed Ancestry group presented a profile of genetic variants reflecting their European, Asian, and African admixture. Precision medicine requires that African populations begin to capture their own pharmacogenetic SNPs as they cannot always infer with absolute certainty from Asian and European populations. In the current historical moment of the COVID-19 pandemic, we also underscore that the spectrum of drugs interacting with warfarin will likely increase, given the systemic and cardiovascular effects of COVID-19, and the anticipated influx of COVID-19 medicines in the near future. This observational clinical pharmacogenomics study of warfarin, together with past precision medicine research, collectively, lends strong support for incorporation of pharmacogenetic profiling in clinical settings in African patients for effective and safe administration of therapeutics.

Dataset Information

The pharmacoepigenomics informatics pipeline defines a pathway of novel and known warfarin pharmacogenomics variants.

Publications

The pharmacoepigenomics informatics pipeline defines a pathway of novel and known warfarin pharmacogenomics variants.

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