Chapter 7

### INTRODUCTION

Pharmacogenetics is the study of the genetic basis for variation in drug response. In this broadest sense, pharmacogenetics encompasses pharmacogenomics, which employs tools for surveying the entire genome to assess multigenic determinants of drug response. Prior to the technical advances in genomics of the last decade, pharmacogenetics proceeded using a forward genetic, phenotype-to-genotype approach. Drug response outliers were compared to individuals with "normal" drug response to identify the pharmacologic basis of altered response. An inherited component to response was demonstrated using family studies or imputed through intra- vs. intersubject reproducibility studies. With the explosion of technology in genomics, a reverse genetic, genotype-to-phenotype approach is feasible whereby genomic polymorphisms can serve as the starting point to assess whether genomic variability translates into phenotypic variability.

Individuals differ from each other approximately every 300-1000 nucleotides, with an estimated total of 10 million single nucleotide polymorphisms (SNPs; single base pair substitutions found at frequencies ≥1% in a population) and thousands of copy number variations in the genome (International HapMap et al., 2007; Redon et al., 2006; Stranger et al., 2007). Identifying which of these variants or combinations of variants have functional consequence for drug effects is the task of modern pharmacogenetics.

Historical Context. In the pre-genomics era, the frequency of genetic variation was hypothesized to be relatively uncommon, and the demonstration of inherited drug-response traits applied to a relatively small number of drugs and pathways (Eichelbaum and Gross, 1990; Evans and Relling, 2004; Johnson and Lima, 2003). Historically, uncommon severe drug-induced phenotypes served as the triggers to investigate and document pharmacogenetic phenotypes. Prolonged neuromuscular blockade following normal doses of succinylcholine, neurotoxicity following isoniazid therapy (Hughes et al., 1954), and methemoglobinemia in glucose-6-phosphate dehydrogenase (G6PD) deficiency (Alving et al., 1956) were discovered to have a genetic basis in the first half of the 20th century. In the 1970s and 1980s, debrisoquine hydroxylation and exaggerated hypotensive effects from that drug were related to an autosomal recessive inherited deficiency in the cytochrome P450 isoenzyme 2D6 (CYP2D6) (Evans and Relling, 2004). Since the elucidation of the molecular basis of the phenotypic polymorphism in CYP2D6 (Gonzalez et al., 1988), the molecular bases of many other monogenic pharmacogenetic traits have been identified (Meyer and Zanger, 1997).

#### Importance of Pharmacogenetics to Variability in Drug Response

Drug response is considered to be a gene-by-environment phenotype. That is, an individual's response to a drug depends on the complex interplay between environmental factors and genetic factors (Figure 7–1). Variation in drug response therefore may be explained by variation in environmental and genetic factors, alone or in combination. What proportion of drug-response variability is likely to be genetically determined? Classical family studies provide some information (Weinshilboum and Wang, 2004).

###### Figure 7–1.

Exogenous and endogenous factors contribute to variation in drug ...

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