Pharmacogenomics focuses on the use of genomic information to optimize drug response and is an important component of precision medicine. Current challenges in the field include the interpretation of rare variant information, the integration of variation across the genes in drug response pathways, and the implementation of pharmacogenomic knowledge in the clinic. A central repository of knowledge is critical in addressing all these challenges. Since 2000, the Pharmacogenomics Knowledgebase (PharmGKB) has become the premier repository of information about how human genetic variation impacts drug response phenotypes. The PharmGKB focuses on the manual curation of knowledge gained from the primary literature and from the careful analysis of large biological data sets. We have extracted information from 9,724 articles, capturing more than 10,843 published associations between genetic variants and drug response phenotypes, covering 591 drugs, 973 genes, and 3,328 unique genetic variations. We create aggregations of this information, including 107 pathways of drug response and metabolism, 54 summaries of very important pharmacogenes, 63 dosing guidelines, and 1,601 clinical annotations summarizing the level of evidence supporting use in clinical practice. We use our position as an independent resource to organize data-sharing consortia, and clinical implementation collaborations. In this proposal, we outline a plan to extend the activities of the PharmGKB by implementing a plan of curation, tool-building and collaborations that address the key challenges to the field. We will expand our curation efforts to increase efficiency of literature-based curation, and add curation of knowledge gathered from deep sequencing of clinical samples. We will focus on curating complex drug responses involving multiple genes which may vary in their coding regions or their regulatory control. We will build an application programming interface that allows us to develop multiple user-interfaces to the knowledge in PharmGKB for different scientific audiences on multiple devices. Finally, we will collaborate with key efforts focused on advancing genomic medicine, where we will bring deep expertise in the use of genomics to improve the precision of drug selection and dosing.

Public Health Relevance

An important component of precision medicine is the ability to use a patient's genetic background to choose drugs (and doses) that will maximize efficacy and minimize side effects. For 14 years, the Pharmacogenomics KnowledgeBase (PharmGKB, http://www.pharmgkb.org/) has aggregated information about human genetic variation and how it impacts drug response. In this proposal, we outline a plan to continue our growth, engage in collaborations to advance precision medicine, and create new user-interfaces that are suitable for phones, tablets and large-screen monitors.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Resource-Related Research Projects (R24)
Project #
3R24GM061374-17S1
Application #
9321550
Study Section
Special Emphasis Panel (ZGM1 (KB))
Program Officer
Ravichandran, Veerasamy
Project Start
2000-04-01
Project End
2019-07-31
Budget Start
2016-08-01
Budget End
2017-07-31
Support Year
17
Fiscal Year
2016
Total Cost
$78,500
Indirect Cost
$28,500
Name
Stanford University
Department
Genetics
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94304
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Amare, Azmeraw T; Schubert, Klaus Oliver; Tekola-Ayele, Fasil et al. (2018) Association of the Polygenic Scores for Personality Traits and Response to Selective Serotonin Reuptake Inhibitors in Patients with Major Depressive Disorder. Front Psychiatry 9:65
Bank, P C D; Caudle, K E; Swen, J J et al. (2018) Comparison of the Guidelines of the Clinical Pharmacogenetics Implementation Consortium and the Dutch Pharmacogenetics Working Group. Clin Pharmacol Ther 103:599-618

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