Michelle Whirl-Carrillo, PhD

Pharmacogenetics is the study of how genes impact drug response, an integral part of personalized medicine. The basis of pharmacogenetics is an understanding of how specific genetic variation results in differing drug efficacy and/or adverse events. More important to patients is the translation of that understanding into drug prescribing and dosing suggestions based on patient genotypes and implementation of a rule-based approach to integrating patient genotypes in the prescribing process. Resources exist to support the translation of pharmacogenetic concepts into the clinic by clinicians, including pharmacists, physicians, and genetic counselors. In this article, 2 such resources are introduced.

 (PharmGKB) is the premier repository of pharmacogenetic information. Its mission is to identify, annotate, aggregate, and disseminate pharmacogenetics knowledge. PharmGKB’s website (

; Figure 1) encompasses a multitude of resources, including genotype-based drug dosing/prescribing guidelines, drug labels with biomarker information, pharmacokinetics and pharmacodynamics drug-centric pathways, and summaries of important pharmacogenetic associations.

The resource began as an National Institutes of Health (NIH)—funded project, in 2000, to store genotype and phenotype data deposited from research sites across the United States. The original users of PharmGKB were researchers looking to discover new connections between drugs and genes. However, it quickly became apparent that potential PharmGKB users were interested in more than these basic research associations. People visiting the PharmGKB website were interested in what genes and, more specifically, what variants had been demonstrated to have an impact on drug response. They wanted to know what the phenotypic result was for a given allele based on peer-reviewed evidence. PharmGKB responded to this demand by transitioning from a basic research database to a knowledge resource and became the primary source for pharmacogenetic information, from preliminary research to associations with the potential to inform patient care. Current PharmGKB users include students, pharmacists, genetic counselors, clinicians, researchers, and the public.

Scientists at PharmGKB scour major pharmacogenetics and pharmacogenomics journals to identify relevant studies and hand curate information. These scientists have PhDs and master’s degrees, along with extensive training in fields such as cellular and molecular biology, pharmacology, and human genetics. They carefully read peer-reviewed articles and capture study details, including patient population, study size, allelic variants, and association statistics (Figure 2). For each article, 1 or more variant-based summary sentences are written to report the major findings. Standardized vocabularies, such as HUGO Gene Nomenclature Committee gene symbols, DrugBank drug names, and National Library of Medicine Medical Subject Headings (MeSH) disease terms, are used in the article annotations and throughout PharmGKB.

As the field of pharmacogenomics progresses, some findings are replicated, sometimes in different or larger populations, sometimes with stronger statistical or in vitro evidence. Conversely, some preliminary findings may not be successfully replicated by follow-up studies. Growing evidence can lead to changing views on the significance or strength of an association. It is important to have an overall understanding of reported associations in addition to understanding individual study findings. PharmGKB scientists write genotype- or haplotype-based summaries of pharmacogenetic associations across all annotated studies in PharmGKB; these are called clinical annotations (Figure 3). These summaries are useful in understanding the totality of evidence for a particular pharmacogenetic association between a given patient genotype and drug response.

The information collected through literature reviews is also used at PharmGKB to construct pharmacokinetics and pharmacodynamics drug-centered pathways (Figure 4

) and “very important pharmacogene” (VIP) reviews. Researchers can use these materials to generate hypotheses and candidate gene lists for future research. Teachers, authors, and lecturers use the pathway figures to illustrate pharmacogenetic concepts. Clinicians and others can use the pathways and reviews to succinctly describe the mechanisms and importance of pharmacogenetic associations to give context to genotype-based drug prescribing guidelines.

PharmGKB provides access to published pharmacogenetic guidelines from multiple groups worldwide, including the Dutch Pharmacogenetic Working Group

 and the Clinical Pharmacogenetics Implementation Consortium

 (CPIC; see below). Specifically, for CPIC guidelines, PharmGKB provides an interface that allows selection of a given genotype or diplotype and returns the CPIC recommendations for the guideline drug(s) (Figure 5).

Additionally, guideline pages present a summary table of recommendations (eg, genotypes/diplotypes and phenotypes). All guideline manuscripts, supplements, and additional supporting documents are available for download from the website.

THE CLINICAL PHARMACOGENETICS IMPLEMENTATION CONSORTIUM

 (cpicpgx.org) was created as a partnership between PharmGKB and the Pharmacogenomics Research Network (PGRN), in 2009, to address barriers to pharmacogenetics implementation. In surveys of CPIC members and American Society for Clinical Pharmacology and Therapeutics (ASCPT) members conducted by CPIC,

 responses indicated that barriers to implementation included uncertainty about which drug/gene pairs were actionable and how to translate genotypes to clinical actions. Responses also included concerns about test costs and reimbursements, as well as general clinician resistance to considering pharmacogenetic information. CPIC’s goal is to address the first 2 barriers with the creation of freely available, peer-reviewed, genotype-based drug prescribing guidelines written by expert pharmacogeneticists and clinicians.

Guidelines are written with the knowledge that patient genotypes are already available and do not provide recommendations as to whether to perform genetic tests. The idea is that, with the growing availability of genomic testing and simultaneously decreasing testing costs, preemptive genotyping or sequencing will become more common and clinicians will be faced with how to act on that information in the patient record.

Each guideline focuses on a drug or drug class and 1 or more genes with a variation known to impact phenotype. Gene and drug background summaries are provided in addition to evidence from a focused literature review supporting the provided prescribing or dosing recommendations. Literature evidence is assigned a quality rating based on specific criteria, and all recommendations are given a strength score (strong, moderate, or optional).

 CPIC guidelines have a standardized format and are written according to a standard operating process that has been published.

 Tables 1 and 2 in guideline manuscripts summarize the prescribing or dosing recommendations. It is important to note that due to journal restrictions on manuscript size, important supporting information (eg, extensive allele variant and function definitions, genetic testing interpretation information, and supporting resources) are included in the guideline supplement. All supplements and other supporting documents are available at pharmgkb.org and cpicpgx.org.

CPIC guidelines are cited by NIH’s Genetic Test Registry, and several have been endorsed by the American Society of Health- System Pharmacists and the ASCPT. Guidelines are also deposited in the National Guideline Clearinghouse (guideline.gov).

Together, PharmGKB and CPIC provide excellent resources for clinicians interested in pharmacogenetic translation and implementation in patient care.

PharmGKB (R24 GM61374) and CPIC (R24 GM115264) are supported by the NIH. Michelle Whirl-Carrillo, PhD, and Teri E. Klein, PhD, are paid scientific advisors to MD Labs and the Rxight Pharmacogenetic Testing Program.

Michelle Whirl-Carrillo, PhD, and Teri E. Klein, PhD, work in the Department of Genetics, Stanford University, Stanford, California. In addition, Michelle Whirl-Carrillo is the associate director of 

, and Teri E. Klein is the co-principal investigator and director of PharmGKB and the co-principal investigator of the 

Clinical Pharmacogenetics Implementation Consortium

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Articles

Pharmacogenetics is the study of how genes impact drug response, an integral part of personalized medicine.

Pharmacogenetic Resources: PharmGKB and Clinical Pharmacogenetics Implementation Consortium

Clinicians have long been aware that patients do not uniformly respond to medications. In some patients, one drug may not be as effective as expected, whereas in other patients, it may cause adverse reactions, sometimes life-threatening. The causes of these variations in drug response include clinical, environmental, and genetic factors. Pharmacogenetics is the study of genetic causes of individual variations in drug response. It is a hybrid between pharmacology (the science of drugs) and genetics (the science of genes and their action).

The term “pharmacogenetics” was first coined by Friedrich Vogel in 1959.

 Then, in the late 1990s, with advancements in DNA technology and modern genomic sciences, a newer term—“pharmacogenomics”&mdash; was introduced. Both terms are used interchangeably, with pharmacogenetics normally referring to the study of individual gene—drug interactions (usually 1 or 2 genes that have a dominant effect on a drug response). Pharmacogenomics, however, is a broader term for the study of genomic influence on drug response, often using high-throughput approaches such as sequencing, single nucleotide polymorphism chip, expression profiling, and proteomics. These findings can then be used to predict how a patient may react to a medication, from both the safety and efficacy standpoints. Pharmacogenetics is a core element of precision medicine.

The earliest documentation of pharmacogenetics dates back to 510 BC, when Pythagoras noted that a subset of people ingesting fava beans experienced potentially fatal hemolytic anemia, whereas others did not.

 This was later found to be due to an inherited deficiency of glucose-6-phosphate dehydrogenase in individuals with fatal reaction to fava beans.

Since the beginning of the 20th century, many landmark discoveries in pharmacogenetics have been made in terms of the evolution of human genetics and molecular pharmacology that have shaped our current understanding and approaches.

 In 1909, British physician Archibald Garrod developed the concept of “chemical individuality,” a phenomenon he summarized in 

 as follows: “Every active drug is a poison, when taken in large enough doses; and in some subjects, a dose which is innocuous to the majority of people has toxic effects, whereas others show exceptional tolerance of the same drug.”

In the 1950s, pharmacogenetics emerged as a distinct discipline, with 3 landmark discoveries clearly demonstrating genetically determined variations in enzyme activity underlying the causes of adverse drug reactions. Bönicke et al described slow and rapid acetylation of isoniazid in 1953,

 which was found, 40 years later, to be due to mutations in 

-acetyltransferase-2. Then in 1956, Alving et al discovered the association of primaquine-induced hemolysis with glucose-6-phosphatedehydrogenase deficiency that altered erythrocyte metabolism.6 This was followed in 1957 by Kalow et al, who characterized serum-cholinesterase deficiency in a subject with succinylcholine apnea.

 That same year, Arno Motulsky was the first to recognize the significance of these key discoveries, and he further refined the concept that inherited “gene-controlled enzymatic factors” may explain individual differences in drug response.

 These discoveries triggered many family studies over the following years, documenting the patterns of inheritance associated with drug effects, eventually leading to discoveries of many genetic determinants for these traits.

The first polymorphic human drug metabolizing gene, Cytochrome P450 family 2 subfamily D member 6 (

), was cloned and characterized in 1987. Subsequently, polymorphisms in various phase 1 and phase 2 drug metabolizing enzymes and drug transporters were identified and associated with various drug response traits.

 With the completion of the first draft of the human genome,

 more evidence emerged from genomewide and candidate gene studies, leading to the identification of genetic factors modulating the responses and toxicities of hundreds of drugs.

Evidence of the clinical utility of pharmacogenomics has also been accumulating.

 As of May 2016, 30 published gene—drug pair Clinical Pharmacogenetics Implementation Consortium (CPIC; cpicpgx.org) guidelines, in which a particular gene variation has implications for how a patient will respond to a given drug, have been documented, along with clinical dosing guidelines.

 A more comprehensive catalog of human genetic variation—associated drug responses (eg, ~200 clinically actionable drug-gene pairs) can be obtained through the Pharmacogenomics Knowledge Base (pharmgkb.org).

The goal of pharmacogenomics in the clinical setting is straightforward: to maximize drug efficacy and minimize the likelihood of adverse drug reactions. The potential clinical benefits of pharmacogenomics are immense. Currently, drug therapy in medicines is still mostly practiced by empirical selection of drugs. Their efficacy may vary widely, and adverse events are common and unpredictable. It is clear that the one-size-fits-all model is not ideal for effective treatment of patients. With accurate and reliable pharmacogenomic information in hand at the point of prescribing, physicians will be able to prescribe medicines that provide the optimal safety and efficacy profile for an individual patient.

With genotype-guided drug and dose selection, we can better target those most likely to benefit and least likely to be harmed, ultimately leading to reduced overall health care costs and improved patient outcomes. For example, Plavix (clopidogrel), one of the most frequently prescribed antiplatelet agents, requires bioactivation mediated by 

. Research shows that patients carrying a 

 loss-of-function allele have a decreased response to clopidogrel and an increased incidence of major adverse cardiac events and stent thrombosis compared with noncarriers.

 Currently, there is strong evidence supporting

 genotyping in patients with acute coronary syndrome undergoing percutaneous coronary intervention. The dosing recommendation based on interpretation of the 

 genotype for clopidogrel is also clearly outlined in the CPIC guideline.

Recognizing the growing need for pharmacogenetics information and guidance from the clinical community, the FDA started incorporating pharmacogenetics information into drug labels and now offers a list of drugs for which biomarkers are included in the labeling. Some labels contain actions that can be taken based on the biomarkers; many do not. In addition, a growing number of institutions are beginning to develop clinical services and infrastructures supporting pharmacogenetics testing.

In January 2015, President Obama launched the Precision Medicine Initiative as “an innovative approach to disease prevention and treatment that takes into account individual differences in people’s genes, environments, and lifestyles”.

 Pharmacogenomics represents one of the most practical applications of precision medicine. Despite challenges involved in bringing pharmacogenetics testing into the clinic, we are starting to see the paradigm shift from whether to order a genetic test to how to use the genetic test results already in the system for prescribing decisions.

Because of their expertise in clinical pharmacology and patient care, pharmacists have a unique role in incorporating pharmacogenomics into the practice of medication therapy management.

 It is therefore important for pharmacists to be knowledgeable in the rapidly expanding fields of pharmacogenomics and to take a prominent role in its clinical application.

 NIH/NIGMS R24 GM61374 and R24 GM115264. Dr. Teri E. Klein and Dr. Michelle Whirl-Carrillo are paid scientific advisors to the 

Li Gong, PhD; Michelle Whirl-Carrillo, PhD; and Teri E. Klein, PhD, work at the Department of Genetics, Stanford University, Stanford, California. In addition, Li Gong is a scientific curator at 

; Michelle Whirl-Carrillo is the associate director of 

; and Teri E. Klein is the coprinicipal investigator and director of 

, and the coprinicipal investigator of the 

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Clinicians have long been aware that patients do not uniformly respond to medications.