The previous chapter discussed mechanisms underlying variability in drug action, highlighting pharmacokinetic and pharmacodynamic pathways to beneficial and adverse drug events. Work in the past several decades has defined how genetic variation can play a prominent role in modulating these pathways. Initial studies described unusual drug responses due to single genetic variants in individual subjects, defining the field of pharmacogenetics. A more recent view extends this idea to multiple genetic variants across populations, and the term “pharmacogenomics” is often used. Understanding the role of genetic variation in drug response could improve the use of current drugs, avoid drug use in those at increased risk for adverse drug reactions (ADRs), guide development of new drugs, and even be used as a lens through which to understand mechanisms of diseases themselves. This chapter will outline the principles of pharmacogenomics, the evidence as currently available that genetic factors play a role in variable drug actions, and areas of controversy and ongoing work.
PRINCIPLES OF GENETIC VARIATION AND DRUG RESPONSE
A goal of traditional Mendelian genetics is to identify DNA variants associated with a distinct phenotype in multiple related family members (See Also Chaps. 466 and 467). However, it is unusual for a drug response phenotype to be accurately measured in more than one family member, let alone across a kindred. Some clinical studies have examined drug disposition traits (such as urinary drug excretion after a fixed test dose) in twins and have, in some instances, shown greater concordance in monozygotic compared to dizygotic pairs, supporting a genetic contribution to the trait under study. However, in general, non-family-based approaches are usually used to identify and validate DNA variants contributing to variable drug actions. Both candidate gene and genome-wide studies have been used, and as with any genomic study, results require replication before they should be accepted as valid.
Types of Genetic Variants Influencing Drug Response
The most common type of genetic variant is a single nucleotide polymorphism (SNP), and nonsynonymous SNPs (i.e., those that alter primary amino acid sequence encoded by a gene) are a common cause of variant function in genes regulating drug responses, often termed pharmacogenes (Table 68-1). Small insertions and deletions can similarly alter protein function or lead to functionally important splice variation. Examples of synonymous coding region variants altering pharmacogene function have also been described; the postulated mechanism is an alteration in the rate of RNA translation, and hence in folding of the nascent protein. Variation in pharmacogene promoters has been described, and copy number variation (gene deletion or multiple copies of the same gene) is also well described.
TABLE 68-1Examples of Genetic Variation and Ancestry ||Download (.pdf) TABLE 68-1 Examples of Genetic Variation and Ancestry
|STRUCTURAL VARIANT ||EXAMPLE ||FUNCTIONAL EFFECT ||MINOR ALLELE FREQUENCY (%)a |
|COMMON NAME ||dbSNP ||EUROPEAN ||AFRICAN...|