The Role of Pharmacogenetics in Precision Medicine

JULY 22, 2016
Li Gong, PhD; Michelle Whirl-Carrillo, PhD; and Teri E, Klein, PhD
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 1959.1 Then, in the late 1990s, with advancements in DNA technology and modern genomic sciences, a newer term—“pharmacogenomics”— 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.2 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.3 In 1909, British physician Archibald Garrod developed the concept of “chemical individuality,” a phenomenon he summarized in The Inborn Errors of Metabolism 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.”4

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 1953,5 which was found, 40 years later, to be due to mutations in N-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.7 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.8 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 (CYP2D6), 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.9-11 With the completion of the first draft of the human genome,12,13 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.14 As of May 2016, 30 published gene–drug pair Clinical Pharmacogenetics Implementation Consortium (CPIC; 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.15 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 (

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