Feng, Xiaodong_ Xie, Hong-Guang - Applying pharmacogenomics in therapeutics-CRC Press (2016)

34 Applying Pharmacogenomics in Therapeutics
INTRODUCTION
Pharmacogenetics studies the influence of genetic variations on drug efficacy,
absorption, metabolism, elimination, and safety in healthy subjects and patients
(Haga and LaPointe 2013; Johnson 2003; Shin et al. 2009). Pharmacogenetics can
be used to maximize drug effectiveness and minimize adverse drug reactions with
respect to a patient’s genetic background, thereby ensuring an optimized drug therapy.
In recent years, the development of biotechnology has paved the way for a new era
of pharmacogenetics, which undertakes a genome-wide approach to study the effects
of multiple genes on drug responses (Cordero and Ashley 2012; Pirmohamed 2001;
Squassina et al. 2010). These technologies allow physicians to have a comprehensive
view of a patient’s unique genetic information. The implementation of a patient’s
genetic data into clinical decision can facilitate alertness to potential adverse drug
reactions, prescription of the most appropriate treatments, prediction of the patient’s
response to medications, achievement of optimal treatment outcomes, explanation
for lack of therapeutic consequences of a treatment, and the search for alternative
therapies. Furthermore, a comprehensive understanding of an individual’s genotype,
phenotype, and environmental factors forms a structured framework that can help
optimize the effectiveness of clinical treatments and eventually enable “personalized
medicine” (Crews et al. 2012; Levy et al. 2014).
Pharmacogenetics has a history spanning over 80 years. In 1926, hemolytic anemia
was first reported in malaria individuals treated with 6-methoxy-8- aminoquinoline,
possibly due to different responses to the drug among individuals (Beutler 2008;
Cordes 1926). However, the cause of acute hemolysis in these patients, the deficiency
in glucose-6-phosphate dehydrogenase (G6PD), was not discovered until
three decades later (Alving et al. 1956). A similar case showing that single-gene
changes can alter drug effects was discovered from routine injection of succinylcholine,
a muscle relaxant during anesthesia. In patients lacking butyrylcholinesterase,
the injection caused unexpected adverse drug reactions, such as prolonged paralysis
(Kalow 1956). The definitive evidence that genetics affects drug effects was traced
back to a study of monozygotic twins in the late 1960s (Vesell and Page 1968). This
study revealed the remarkable similarity in phenylbutazone metabolism in identical
twins who shared 100% of their genomes in contrast with fraternal twins who shared
only 50% of their genomes, suggesting the determining role of genetics in drug
metabolism (Motulsky 1957; Motulsky and Qi 2006). Recognizing that individual
patients had differential drug responses, Friedrich Vogel coined the term pharmacogenetics
in 1959 (Vogel 1959). However, until two decades ago, genetics played
only a minor role in clinical pharmacology, therapeutic development, and drug prescription,
presumably due to the fact that the clinical effects of only a small number
of drugs are strongly influenced by a single gene, which obscured our appreciation
of the importance of pharmacogenetics in medicine. Since the 1990s, the advance of
genomics science, especially the completion of the Human Genome Project (http://
www.genome.gov/10001772), has set off a surge of interest in the study of pharmacogenomics.
New sequencing technologies have become the driving force for this
field. These technologies allow high-throughput analysis of thousands of genetic loci
and their effects associated with drug responses.