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

Concepts in Pharmacogenomics and Personalized Medicine
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patient genotypes and phenotypes. Variations in a gene may impact either the pharmacokinetics
(PK) or pharmacodynamics (PD) of a drug, which in turn affects
clinical outcomes. PK is the process by which a drug is absorbed, distributed, metabolized,
and excreted by the body (ADME); in essence, “what the body does to the
drug?” PD is the effect of a drug on the body; in other words, “what the drug does to
the body?” These factors can potentially determine the efficacy or toxicity of a drug;
for example, a polymorphism may lead to increased drug plasma concentrations,
which, in turn, translates to increased drug effectiveness or adverse effects.
Pharmacogenetics is defined as “the study of genetic causes of individual variations
in drug response.” 1 Pharmacogenomics is defined as “the genome-wide analysis
of genetic determinants of drug efficacy and toxicity.” 2 Although the terms may
be used interchangeably, we use the term pharmacogenomics in this chapter.
The purpose of this chapter is to provide an overview of the drugs whose pharmacogenomic
applications could demonstrate their place in the prediction of drug
efficacy, toxicity, and dosing. We review six important drugs as they relate to each
category: omeprazole (efficacy), trastuzumab (efficacy), abacavir (toxicity), codeine
(toxicity), carbamazepine (toxicity), and warfarin (dosing). Although these six examples
vary in levels of evidence and recommendations for testing in clinical practice,
they portray the current state of clinical applications (or lack thereof) in real-world
practice. For each drug, we present a clinical case scenario, background of the drug,
gene/allele of interest and functional effect, clinical relevance and testing availability,
and recommendations. At the end of this chapter, we discuss several challenges in
implementing pharmacogenomic testing in clinical practice, including availability
of tests, generalizability of scientific evidence, and knowledge and education of
healthcare professionals.
Definitions
A polymorphism is defined as a DNA sequence variant present in >1% of the general
population. 3 If a DNA sequence variant is present in <1% of the population,
it is defined as a mutation. An allele refers to two different versions, or alternate
sequences, of the same gene localized at any position on a chromosome. Within
a gene, variations of an individual nucleotide can be considered alleles. Alleles
include the wild type: that is, the usual sequence, mutations, and polymorphisms of
a given gene. Since humans are diploid organisms, there are two alleles (one from
each parent) of each gene. Each person carries a set of two alleles of each gene,
and this is defined as the genotype. A phenotype is the set of characteristics or the
clinical presentation of an individual, which results from the particular genotype.
For example, variations in the cytochrome P450 (CYP) genes may result in the
contrasting phenotypes of ultrarapid metabolizers (UMs) and poor metabolizers
(PMs) of the affected drug. A haplotype is a set of alleles at multiple, neighboring
positions that coexist on the same chromosome. These alleles may be in separate
locations within a single gene or among different genes. Neighboring alleles
(located near one another) are physically tethered and usually inherited as a set
that prevents their separation during inheritance. One individual inherits two copies
of a haplotype.