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Pharmacogenomics is a single and important element of the broader
concept of personalized medicine, which incorporates a variety of
factors, both genetic and nongenetic, to guide targeted and individualized
Pharmacogenomic effects can be both pharmacokinetic and
pharmacodynamic in nature. Pharmacokinetic effects are observed
when variants affect the absorption, distribution, metabolism, or
excretion of a drug. Pharmacodynamic polymorphisms may result in
variable amounts of drug target enzymes or receptors as well as
possible changes in the drug target shape. These variations may render
therapy ineffective or necessitate dose changes in certain affected
DNA polymorphisms in drug-metabolizing enzymes can result in gain of
function, loss of function, or no effect on function of the enzyme
produced. In some cases, significant toxicity can result.
Drug transport proteins and binding targets can also be affected by
HLA genes are unique in that the presence of a variant does not impact
the metabolism of a drug, but instead may indicate the likelihood of the
development of a serious or life-threatening reaction.
Test interpretation is crucial to the practical application of
pharmacogenomic data. In particular, CYP2D6 is a well-described
cytochrome P450 enzyme responsible for approximately 25% of all drug
metabolism. However, CYP2D6 is a complicated gene locus subject to
multiple variants, pseudogene interference, and copy number variation.
Age-based development adds a level of complexity when assessing
pharmacogenomic markers in pediatric patients. Many of the
pharmacogenomic dosing guidelines have not been validated in infants
Implementation of pharmacogenomics into practice currently faces many
challenges including: the appropriate determination of when and whom
to test; storage, analysis, and security of genetic data; and
considerations for implementing pharmacogenomic data and
recommendations into practice.
“Pharmacogenomics” is the study and application of gene expression on drug
pharmacokinetics and pharmacodynamics. This term is often used interchangeably
with “pharmacogenetics.” In the strictest of definitions, “pharmacogenetics” is used
in the context of a drug response to a single gene, whereas “pharmacogenomics”
refers to the broader study of the full genomic impact on drug behavior.
genetic variants are very specific to the individual, the use of pharmacogenomics in
clinical practice has become a core component of the personalized medicine and
Ironically, the study of pharmacogenomics is not
new. There are cases in the literature from the 1950s and 1960s describing the
influence of a person’s genetics on drug toxicity.
cheaper, faster deoxyribonucleic acid (DNA) sequencing techniques, the study of
pharmacogenomics has exploded. In recent years, we have been able to begin
transitioning that knowledge from the research realm to the clinic, although not
A brief review of the basics of human genetics in the context of application to
pharmacogenomics will be discussed in this chapter. Students are encouraged to
utilize the selected references provided for this chapter for further review if needed.
Although somatic “tumor” genetics, or the study of the mutations found in cancer
cells, is a very timely and important consideration in antineoplastic drug selection
and the treatment of oncologic processes, this chapter will primarily focus on the
germline mutations in human DNA affecting drug absorption, distribution,
Human DNA is composed of 3 billion nucleotide base pairs, arranged on 46
chromosomes. There is significant variation in the genetic code from one person to
another, creating what makes each of us unique—such as brown eyes, red hair,
height, and heritable diseases. Included in the unique variations are changes in our
ability to process medications. These differences are largely a result of variants in
the nucleotide sequence on the genes responsible. The four nucleotides that make up
the genes are adenine (A), guanine (G), cytosine (C), and thymine (T).
In most cases, but not all, two copies of each gene are present, one inherited from
the mother and one from the father. Each copy is referred to as an “allele.” If both the
maternal and paternal alleles are the same, then the individual is considered
homozygous for that allele or gene. If the parental copies differ, then the patient is
considered to be heterozygous. Genes code for the production of proteins, such as
enzymes, the structural components of cells, hormones, antibodies, and transport
molecules. In pharmacogenomics, the gene and the enzyme often share the same name.
For example, the gene that codes for cytochrome P450 CYP3A4 is known as
CYP3A4 and the gene that codes for thiopurinemethyltransferase (TPMT) is known
When there is a change in the sequence or code, it is referred to as a variant. A
change in a single base pair is commonly referred to as a single-nucleotide
polymorphism or SNP (pronounced “snip”) (Fig.4-1). Although the formal definition
requires the variant to occur in at least 1% of the population, common usage does not
differentiate on the basis of population frequency. A SNP that changes the function of
the gene product is referred to as a mutation, and although not all SNPs are mutations,
the terms are often used interchangeably. The location of the SNP is designated by a
reference sequence number abbreviated “rsID.” Many of the pharmacogenetic
variants discussed in this chapter are SNPs and were originally found through
genome-wide association studies (GWAS). Most GWAS are usually constructed to
find common SNPs in a group of patients with the condition of interest and then
subsequently define a level of association. These SNPs are responsible for 90% of
pharmacogenetic variability and can result in gain of function (greater production of
enzyme, or higher enzyme activity, than normal) or loss of function (decreased or no
production of enzyme compared to normal).
3 Other changes can include deletions or
insertions of larger segments of DNA and are commonly referred to as “indels.” In
many cases, indels terminate production of the protein.
In some cases, a change in a single allele is sufficient to affect drug metabolism.
This occurs in dominant disorders. These occur because new mutations are passed
from one individual to the next. Whether the ancestors exhibited symptoms or not
likely depends on their own history and, of course, may not be known. In other cases,
both copies of the gene must be defective in order for there to be a functional
consequence. This occurs in recessive disorders, in which the parents are typically
unaffected heterozygous carriers. One in four of their children will be at risk for
inheriting the change and potentially exhibiting symptoms. As discussed earlier, this
child may be homozygous if both parents have the same SNP, or it may be as a
compound heterozygote, if each parent has a different dysfunctional SNP or mutation
in the specific gene. Typically, in recessive disorders, there is otherwise no family
history of any affected individual.
The resultant call or read of the variants gives us a genotype. The phenotype refers
to the expression of that genotype. In some cases, this is visible, such as skin color or
another physical characteristic. In other cases it is invisible, such as blood type or a
less than normal amount of a Human Cytochrome P450 (CYP450) metabolizing
enzyme. In the context of pharmacogenomics and the metabolizing enzymes, patients
are often classified as having a phenotype of ultrarapid metabolizer, extensive
metabolizers, intermediate metabolizers, or poor metabolizers based on their
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