Current Concepts and State of Knowledge

One thread of the origin of PGx dates back to the 1950s (see Box 1) when pharmacologists began to incorporate genetics into their studies of adverse drug reactions. Examples of classical PGx studies include the observations that at doses tolerated well by others, the muscle relaxant succinylcho-line, the antimalarial drug primaquine and the antituberculosis drug isionazid induced life-threatening effects, such as respiratory arrest, hemolytic anemia and neuropathies, in some patients. By studying families and ethnic populations as well as through careful phenotyping, pharmacologists demonstrated that these unusual drug responses were inherited and due to certain enzyme variations controlled by single-genes. The understanding of the molecular genetic basis for the phenotypes came later, with the development of DNA technology (► Single nucleotide polymorphism testing and, more recently, ► haplotype testing) and in vitro molecular tests allowing the exact identification of the gene sequences responsible for variations in drug responses. The recent flourishing of genomics with development of new technologies such as microarrays has changed the focus of PGx from study of the effect of single gene sequence polymorphisms in two ways. First, the search has broadened to multiple genes (i.e., from monogenic to polygenic traits), and second, gene expression is now known to play an important role in affecting variations in drug responses. Indeed, modern PGx (phar-macogenomics) often uses a reverse approach, studying whether sequence variations and/or gene expression are in anyway related to variations in drug response phenotypes (see methods).

The second thread antecedent to PGx can be traced to the field of behavioral genetics. Studies of behavioral responses to a variety of drugs, often in mice and rats, employed genetically varying populations and consistently found that different genotypes had characteristic, and widely varied, responses to many drugs. Starting in the late 1940s, this field also pioneered the use of selective breeding to create rat and mouse lines with extreme drug responses. The earliest systematic summary of this work was a monograph by Broadhurst (1978). Behavioral genetic studies now also incorporate ► genetically modified animals and the studies of gene-targeted mutant lines and selected lines have contributed much to our understanding in drug action, particularly in the addictions field.

Defining Pharmacogenetics

Pharmacology often divides drug's interactions with the body into their ► pharmacokinetic and ► pharmacody-namic aspects. Pharmacokinetics, sometimes described as what the body does to a drug, incorporates drug absorption, distribution, metabolism, and excretion. Pharmacodynam-ics, described as what a drug does to the body, involves receptor binding, post-receptor effects, and chemical interactions. Drug's pharmacokinetics and pharmocodynamics are both genetically and environmentally influenced. Genes contain information that determine the structure of proteins and any variations in the DNA sequence (mutation) may alter the expression or the function of proteins. DNA mutations that occur at a frequency of 1% or greater are termed polymorphisms. Polymorphisms in genes coding for a protein that carries a drug to its target cells or tissues may cripple the enzyme that activates a drug or aid its removal from the body, and thus may induce pharmaco-kinetic or pharmacodynamic variations leading to individual differences in the response to the drug (see Fig. 1).

The majority of pharmacogenetic studies have focused on drug metabolizing enzymes. For example, ► cytochrome P450 (CYP, P450) is a large superfamily of metabolizing enzymes. Within the CYP2 family, polymorphic CYP2D6 was one of the first and most important drug-metabolizing enzymes to be characterized at the DNA level. By using response to a "marker" drug (i.e., dextromethorphan), four phenotypes maybe described: "poor meta-bolizers," "intermediate metabolizers," "extensive metabolizers," and "ultrarapid metabolizers." Ultrarapid metabolizers have multiple copies of the CYP2D6 gene

Pharmacogenetics. Fig. 1. Schematic representation of how gene variants affect pharmacokinetic and pharmacodynamic factors resulting in potential modifications in the pharmacological effect of drugs (from http://www.pharmgkb.org).

expressed, and greater-than-normal CYP2D6 activity. Therefore, ultrarapid metabolizers may not achieve therapeutic levels with usual doses and may require several doses to show a response. On the other hand, poor metabolizers are at increased risk of toxicity from CYP2D6 substrate drugs (e.g., codeine). In addition to CYP2D6, polymorphisms have now been identified in more than 20 drug metabolizing enzymes in humans. Some of these polymorphisms show different distributions in racial groups and phenotypically relevant consequences from a clinical point of view (see Table 1). More recently, there has been increased recognition in the contribution of genetic variation in proteins involved in drug responses. For example, a polymorphism in the ► serotonin transporter protein that affects serotonin availability in brain has been reported to be associated with a predisposition to depressive illness as well as with therapeutic response to antidepressive or antipsychotic pharmacotherapy.

Box 1. Dates

1949: Initiation of first rat line selected for high alcohol consumption by J Mardones at the University of Chile

(Mardones and Segovia-Riquelme 1983)

1950: Extensive characterization of mouse and rat genetic differences in response to psychoactive drugs.

1957: Delineation of the field of PGx by Motulsky (1957).

1959: Introduction of the term "PGx" by Vogel (1959).

1962: Definitive establishment of the field by Kalow's monograph (Kalow 1962).

1968: Demonstration by Vessel of the general importance of polygenic inheritance in metabolism of many drugs (Vessel and Shapiro 1968).

1990s: Introduction of the term "pharmacogenomics" with emergence of the Human Genome Project.

Methods

PGx may use a phenotype-driven or a genotype-driven approach for understanding the genetic contributions to variations in drug responses in humans and nonhumans. In the phenotype-driven approach (i.e., from phenotype to genotype), once a genetic contribution to the phenotype of interest has been confirmed (with family analysis, animal models analysis and/or linkage studies), genetic markers reliably associated with the phenotype are identified by genome-wide- and/or -candidate-gene approaches. Such studies must first identify the rough genomic locations of causative genetic variation. These locations are called quantitative trait loci (QTL), and QTL-analysis is the first step for identifying the subset of chromosomal areas containing genes responsible for the genetic variation in a specific trait, and to locate these areas on a genomic map. QTL analyzes have been widely used in animal models with inbred and recombinant strains of rats and mice, as well as in lines selectively bred for extremes in response to various

Pharmacogenetics. Table 1. Representative examples of the relation between genetic polymorphisms of drug-metabolizing enzymes with drug responses adapted from Weber (2008).

Gene

Polymorphism

Drug response

CYP2D6(L)

2-13-fold multiplication of gene

Failure to respond to nortryptyline; toxicity to codeine

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