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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
6 There are several other phenotypes that will be discussed in the chapter,
particularly those that deal with drug targets or pharmacodynamic responses.
The vast majority of drug metabolism pathways are not simply, a single enzyme
resulting in one inactive metabolite that is immediately excreted by the body. Instead,
most drugs utilize multiple metabolizing enzyme pathways, rely on several drug
transporters, and have many metabolites of varying activity. Each of these steps may
be subject to variable gene expression, coupled with indirect genetic and
environmental effects on variables such as disease, weight, nutrition, age, and others.
Add this complexity and it becomes evident how complicated pharmacogenomic
Pharmacogenomics is unique in the field of genetics in that the representation of a
person’s genotype is noted by a “*,” known as a star allele in the literature. For
example, in many situations, the text representation of normal or “wild-type” variant
7 As other alleles are discovered, they are numbered sequentially *2,
*3, etc. Inevitably, as discoveries are sometimes reported simultaneously around the
world, there is occasionally an overlap of star alleles and the variants represented.
There are several worldwide databases for reporting new pharmacogenomic
variants, including the CYP Allele Nomenclature Database
http://www.cypalleles.ki.se/ and the Database of Genomic Variants
http://dgv.tcag.ca/dgv/app/home.
During drug development and postmarketing analysis, it becomes clear that some
patients will have severe adverse drug reactions (including nonresponse) after
receiving the population-derived standard dose. These adverse reactions occur in the
absence of medication error or lack of proper adherence to the drug. The Institute of
Medicine “To Err is Human” report published in 2000 cited over 2 million reported
adverse drug reactions in the United States per year, resulting in approximately
100,000 deaths at a cost of 20.6 billion annually.
It is estimated that 52% of U.S.
adults are taking at least one prescription drug and 12% are taking more than five
prescription drugs. If herbal products and over-the-counter drugs are included, then
the estimates increase to over 80% and 29%, respectively.
adverse drug reactions often go unnoticed and even more frequently unreported,
making the actual numbers likely far higher. The clinical application of
pharmacogenomics not only has allowed us to explain some of these historical
reactions, but also helps clinicians predict who may be at higher risk for developing
an adverse reaction if exposed to a drug or drug class.
reactions has a measureable impact on a patient’s quality of life, decreases overall
health care costs, and lessens the time burden on health care providers managing the
adverse reaction. However, acceptance of clinical pharmacogenomic testing is not
universal and there remains the challenge of conclusively validating the genetic
variant associated with the adverse reaction.
Figure 4-1 Example of a single-nucleotide polymorphism (SNP).
Isoniazid is part of the four-drug regimen used to treat active TB and latent TB
infection because it is bactericidal against Mycobacterium tuberculosis organisms.
One of the most commonly reported side effects leading to premature discontinuation
of the drug is drug-induced liver injury (DILI). Significantly elevated hepatic
enzymes are seen in up to 20% of patients, with progression to hepatitis in a smaller
The metabolism of isoniazid is complex, with a key enzyme within the pathway
being N-acetyltransferase-2 (NAT2).
11 NAT2 acetylates both the parent drug and a
hydrazine metabolite, converting the hydrazine metabolite to acetyl hydrazine
12An alternative metabolic pathway for hydrazine results in a toxic reactive
metabolite. When NAT2 function is decreased, this pathway dominates, resulting in
The production of the NAT2 enzyme is generated from a gene of the same name,
with several known polymorphisms leading to alleles associated with either slow or
rapid acetylation rates. Individuals homozygous for alleles associated with loss of
function are considered “slow acetylators,” those homozygous for alleles associated
with gain of function “rapid acetylators,” and heterozygotes “intermediate
acetylators” (Table 4-1). DILI has been found to be highest in patients who are slow
In addition to isoniazid, NAT2 is also a known acetylator of other
drugs and/or metabolites, although the clinical effects of NAT2 genotype on these
drugs are less well-studied, including: sulfonamides (sulfamethoxazole, metabolites
of sulfasalazine), aromatic and aliphatic amines (procainamide, dapsone, metabolite
The “gene test” mentioned by A.S.’s mother is likely a test for the NAT2 gene. A
variety of pharmacogenomic tests are available to examine SNPs in the NAT2 gene
and assign a patient’s genotype, either as part of a more extensive gene panel or as a
targeted assay. Preemptive NAT2 testing prior to isoniazid therapy is not currently
the standard of care; however, evidence suggests that in some populations with a high
prevalence of DILI in slow acetylators, this may be beneficial.
have been found to have the highest rates of DILI in the setting of a slow acetylator
status (see summary of studies in Table 4-2). Although there are no formal dosing
guidelines set for isoniazid therapy in the context of genotype or acetylator status, a
study completed by Azuma et al. with 155 Japanese TB patients proposed a
modified, genotype-based dosing regimen with successful clinically and statistically
significant outcomes (results summarized in Table 4-3).
There remain several pending questions as to how to most safely and appropriately
incorporate NAT2 genotype results into a widespread clinical application. For
example, pediatric patients such as A.S. offer a unique set of challenges, because
recommended isoniazid starting doses are within a higher range (10–15 mg/kg), and
dose modifications based on genotype have not been studied in this population.
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