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antimode (arrow). Redrawn with permission from reference 10. Bottom. Change in FEV1 in 1117 participants in 3 different trials of antiasthmatic therapy (inhaled steroids). Although the responses vary markedly, from an apparently deleterious drug effect to a highly beneficial one, there is no antimode. Two distinct processes, either of which can be influenced by genetic factors, underlie the generation of a clinical drug action: delivery to and removal from target sites in plasma on cell surfaces, or within cells (pharmacokinetics) (see Glossary) and interaction with the targets to generate a cellular effect that is translated to clinical effect (pharmacodynamics). Thus, the starting point for many contemporary pharmacogenetic studies is identification of variable drug responses in an individual patient or across a population. Then, an understanding of the underlying pharmacokinetics or pharmacodynamics can be used to identify individual candidate genes (see Glossary) in which variant function may “explain” the variable drug response. An alternate approach, to interrogate many candidate genes or even the whole genome (see Glossary), has emerged more recently and will be discussed further. Some of the earliest findings in pharmacogenetics involve variations in single genes encoding drug-metabolizing enzymes, which can underlie aberrant responses to substrate drugs The highest likelihood of aberrant drug responses occurs when genetically determined reduced function of 1 drug elimination pathway is coupled with the absence of alternate pathways that can readily subserve the same function (15). Individual cases were first identified in patients with clinically dramatic phenotypes (see Glossary) because these patients were homozygous (see Glossary) for loss of function in such alleles *ADD1 = the gene encoding α-adducin; ADRB1 = the gene encoding the β1-adrenergic receptor; ADRB2 = the gene encoding the β2-adrenergic receptor; CRHR1 = the gene encoding corticotrophin-releasing hormone receptor-1; CYP2C19 = the gene encoding the 2C19 cytochrome P450 isoform; CYP2C9 = the gene encoding the 2C9 cytochrome P450 isoform; CYP2D6 = the gene encoding the 2D6 cytochrome P450 isoform; HMG-CoA = 3-hydroxy-3-methylglutaryl coenzyme A; HMGCR = the gene encoding HMG-CoA reductase; MDR1 = the gene encoding P-glycoprotein; RYR1 = the gene encoding the skeletal muscle calcium-release channel; TPMT = the gene encoding thiopurine methyltransferase; UGT1A1 = the gene encoding uridine diphosphate glycosyltransferase 1 family, polypeptide A1; VKORC1 = the gene encoding vitamin K epoxide reductase complex, subunit 1. Coding-Region Variants Changes in DNA sequence that occur in regions that encode protein may lead to changes in the primary amino acid sequence and protein function. A well-studied example that is entering routine clinical practice is the thiopurine methyltransferase (TPMT) gene, whose protein product is responsible for bioinactivation of thiopurines, such as azathioprine or mercaptopurine (1, 16, 17). Rare individuals who are homozygous for loss of function variants are at high risk for bone marrow aplasia during therapy with standard doses, and this is stated in the package label. Ten percent of persons carry a single abnormal allele and are also at increased risk for bone marrow toxicity (18, 19). Conversely, “standard” doses of mercaptopurine that are used in the 90% of patients with functional alleles mutations (see Glossary) may in fact be inadequate for achieving an optimal antileukemic effect (20). The most common mechanism for drug elimination is metabolism by members of the cytochrome P450 (CYP) superfamily. Common coding-region CYP variants that affect drug elimination and responses have now been described. The frequency of many variants varies by ethnicity, and this may be one factor determining ethnic-specific drug responses. Up to 10% of white and African-American persons are homozygous for loss of activity of a cytochrome P450 isoform, which is termed CYP2D6. Persons with this poor-metabolizer genotype have drug accumulation and increased side effects with some antidepressants (21). In addition, persons who
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