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Brian D. Chapron
J. Steven Leeder
C H A P T E R
5
Pharmacogenetics, Pharmacogenomics, and Pharmacoproteomics in Newborns and Children
INTRODUCTION
It is readily accepted that genetic factors play an important role in influencing a
child’s potential physical characteristics, such as height, weight, or hair color.
Genetic factors are also important (although not sole) determinants of
interindividual and intraindividual variability in susceptibility to pediatric
diseases as well as in the disposition of and response to medications used to
treat those diseases. Pharmacotherapy in adults has benefited from knowledge
of pharmacogenetic principles acquired over the past 60 to 70 years, but
application to pediatric therapeutics is still in its infancy. In 2003, the
International Human Genome Sequencing Consortium announced the successful
completion of the Human Genome Project initiated in 1990, 2 years after being
presented in draft form.1 Since then, whole genomic sequencing has become
dramatically more accessible and affordable. Numerous companies now offer
full genomic sequencing services both to clinicians and directly to consumers,
often at a cost of under a thousand dollars (compared to the $2.7B cost of the
first genome by the Human Genome Project Consortium). More targeted
approaches, focusing on predetermined subsets of genes with potential
implications for human health, can be purchased for even less. Following the
vanguard of genomics has been a host of other “-omics” sciences. In 2002, the
Human Plasma Proteome Project was initiated. As of the time of the writing this
chapter, over 3,500 proteins have been conclusively identified as part of the
Human Plasma Proteome Project, and there is inconclusive evidence for at least
1,000 additional proteins.2 Comparable advances in characterizing the human
lipidome and metabolome have also been made. A truly enormous and
progressively expanding amount patient-specific data is now at our fingertips,
but precisely how to interpret and clinically apply these data has proved a
persistent challenge. Nevertheless, there is continued hope that investments in
these “-omics” fields will decrease morbidity and mortality through the
development of more effective strategies to diagnose, treat, and prevent human
disease. Society has every right to expect that children and adults will benefit
equally from this investment of public funds. However, children present unique
challenges in this context because developmental changes in drug disposition
and response are superimposed upon a basal level of pharmacogenetic
variability. The purpose of this chapter is to introduce the concepts of
pharmacogenetics and pharmacogenomics and to describe how
pharmacoproteomics (and other “-omic” fields of endeavor spawned in the
genome era) can be employed to navigate the complex relationship between
genotype and phenotype at a given stage of childhood development.
HISTORICAL CONSIDERATIONS
In 1841, Alexander Ure reported that hippuric acid was formed from benzoic
acid in the body, leading physiologic chemists to discover that many foreign
substances excreted by humans were chemically altered relative to the forms
that had been administered—the process we now refer to as drug
biotransformation (or less properly, drug metabolism). At the beginning of the
20th century, Archibald Garrod proposed that enzymes were implicated in the
detoxification of foreign substances. A key element of his later work was the
concept that disproportionate responses to foreign substances could result from
deficiency of the required detoxifying enzyme. A variation in the theme of
altered responses to foreign substances (xenobiotics) became apparent with the
synthesis of phenylthiocarbamide in 1931 when, in the process searching out
artificial sweeteners, A. L. Fox discovered that some people found the chemical
intensely bitter while others found it tasteless.3 It was not until the 1950s,
however, that certain adverse drug reactions, such as unusually prolonged
respiratory muscle paralysis due to succinylcholine, hemolysis associated with
antimalarial therapy, and isoniazid-induced neurotoxicity, were recognized to
be a consequence of inherited variation in enzyme activities, as reviewed by
Arno Motulsky in 1957.
4
In 1959, Fridriech Vogel coined the term pharmacogenetics to describe the
study of genetically determined variations in drug response, and the first book
on the subject was published in 1962 by Werner Kalow.5 Through a series of
twin studies conducted during the late 1960s and early 1970s, Elliott Vesell
illustrated the importance of genetic variation in drug disposition by observing
that the half-lives of several drugs were more similar in monozygotic twins than
those in dizygotic twins.6 With the discovery of the debrisoquine/sparteine
hydroxylase polymorphism,
7,8
due to inherited defects in the cytochrome P450
2D6 gene (CYP2D6) and mephenytoin hydroxylase deficiency (CYP2C19)9 in
the late 1970s and early 1980s, the importance of genetic polymorphisms in
drug-metabolizing enzymes has become increasingly apparent. This is
particularly true in recent years due to an enhanced awareness of the number of
clinically useful drugs that are metabolized by polymorphically expressed
enzymes and the proportion of treated patients who are affected.
In the 1970s, an increasing appreciation of genetic influences on variability
in drug disposition and response was accompanied by heightened awareness
that environmental factors (e.g., diet, smoking status, concomitant drug or
toxicant exposure), physiologic variables (e.g., age, gender, disease,
pregnancy), and patient compliance also played important roles. Advances in
analytic tools to accurately measure drugs and drug metabolites in biologic
fluids and the development of mathematical models to characterize and predict
changes in drug concentration over time (pharmacokinetics) led to the
application of pharmacokinetic principles to optimize drug therapy in individual
patients. Introduction of therapeutic drug monitoring (TDM) programs was the
first application of personalized medicine—recognition that all patients were
unique and that serum concentration–time data for an individual patient
theoretically could be used to optimize pharmacotherapy was a significant
advance over the concept of “one-dose-fits-all.” However, routine TDM does
not necessarily translate to improved patient outcome in all situations.
10
At a molecular level, the pharmacokinetic properties of a drug are
determined by the genes that control its disposition in the body (e.g., absorption,
distribution, metabolism, excretion), with drug-metabolizing enzymes and drug
transporters assuming particularly important roles. Over the past 25 years, the
functional consequences of genetic variation in several drug-metabolizing
enzymes have been described in individuals representative of different ethnic
groups.11 Whereas the most common clinical manifestation of pharmacogenetic
variability in drug biotransformation is an increased risk of concentrationdependent toxicity due to reduced clearance and drug accumulation, it has
become more apparent in recent years that the concentration–effect relationship
(pharmacodynamics) is perhaps more relevant for optimizing drug efficacy.
Therefore, the pharmacogenetics of drug receptors and other target proteins
involved in signal transduction or disease pathogenesis can also be expected to
contribute significantly to interindividual variability in drug response.
12,13
However, the most important concept is that the pharmacogenetic determinants
of drug response involve multiple genes, and therefore, for a particular
individual, polymorphisms in a single gene are unlikely to be predictive of
response.
In 1987, the term genomics was introduced to describe the study of the
structure and function of the entire complement of genetic material—the genome
—including chromosomes, genes, and DNA.14 In 1990, the Human Genome
Project was initiated as a nearly three billion dollar public investment with the
goal of sequencing the entire complement of human genes by the year 2005 but,
more importantly, with the expectation that decreased morbidity and mortality
through the development of more effective strategies to diagnose, treat, and
prevent human disease would be the return on that investment (Fig. 5.1). The
publicly funded initiative was forced to accelerate its efforts when J. Craig
Venter announced that his company, Celera Genomics, would sequence the
human genome first. The two efforts resulted in simultaneous publication of
initial draft sequences in 2001,
1,15
and the International Human Genome
Sequencing Consortium announced completion of the task on April 15, 2003,
with an estimated accuracy of one error in 100,000 bases.16 The human genome
consists of three gigabases (three billion bases) of DNA sequence that code for
approximately 30,000 genes, far fewer than was originally expected. However,
it appears that this number of genes encodes 100,000 proteins through the
process of alternative splicing whereby a gene’s exons or coding regions are
spliced together in different ways to produce variant messenger RNA (mRNA)
molecules that are translated into different proteins or isoforms of the same
protein. Thus, the vast amounts of genomic data generated by the Human
Genome Project have laid the foundation for an “-omic” revolution that
includes, but is not limited to, the transcriptome, the set of expressed genes
from a genome
17,18
; the proteome, the set of proteins encoded by the genome19;
and the physiome, in which biochemical, biophysical, and anatomic information
from cells, tissues, and organs will be integrated using computational methods
to provide a model of the human body.20 Metabolomics and metabonomics are
related terms that are sometimes used interchangeably in the literature.
Metabolomics refers to the complete set of low-molecular weight molecules
(metabolites) present in a living system (cell, tissue, organ, or organism) at a
particular developmental or pathologic state. Metabonomics has been defined
as the study of how the metabolic profile of biologic systems change in
response to perturbations due to pathophysiologic stimuli, toxic exposures, and
dietary changes, among others.
21,22
Pharmacometabonomics has been defined as
“the prediction of the outcome, efficacy, or toxicity of a drug or xenobiotic
intervention in an individual based on a mathematical model of preintervention
23
Chemogenomics is the application of combinatorial
chemistry to generate libraries of small molecular weight compounds that can
serve both as probes to investigate biologic mechanisms and as lead compounds
for drug development.24 Lipidomics has been defined as the study of “cellular
lipids on a large scale based on analytical chemistry principles.”25 Several
resources that define pharmacogenetics, pharmcogenomics, and to some extent
related “-omics” fields and their potential application to human health and
disease are available on the Internet (Table 5.1).
