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are poor metabolizers do not metabolize codeine to its active metabolite morphine and thus have reduced analgesia (22). An important implication of the identification of highly variable CYP2D6 activity is that new drug candidates that are eliminated predominantly by this enzyme are often not further developed (23, 24). In contrast to CYP2D6, the poor metabolizer trait for a different CYP, CYP2C19, is more common in Asian persons, and persons with this genotype have higher drug concentrations and a greater cure rate of Helicobacter pylori infections during therapy with the CYP2C19 substrate omeprazole (25). DNA Variants in Noncoding Regions Only a small fraction of the human genome encodes proteins. One important role of noncoding DNA is to regulate the amount of messenger RNA (mRNA) transcribed, and thus protein generated, in the basal state or in response to many environmental stimuli. Sequence variants in regulatory regions that result in altered amounts of otherwise normally functioning protein can underlie abnormal drug responses. A good example is the repeat polymorphism (see Glossary) in the promoter of UGT1A1, which encodes the glucuronosyltransferase responsible for conjugation of bilirubin and many drugs. The most common hypofunctional allele, termed UGT1A1*28, is an insertion of 2 extra base pairs (TA) in a key regulatory region of the gene, resulting in decreased protein expression. Impaired elimination of bilirubin by this mechanism is the cause of the Gilbert syndrome. UGT1A1 is responsible for the metabolism of SN-38, the active metabolite of the anticancer drug irinotecan, and persons who are homozygous for UGT1A1*28 are at increased risk for serious adverse effects of the drug (26). This effect is of sufficient clinical importance that it is now described on the irinotecan product label (27, 28). Commercial tests for variants in TPMT, CYP2D6, CYP2C19, and UGT1A1 are now available (29). Variable Drug Transport Drug entry into and removal from cells are often active processes, accomplished by specific drug transport molecules (30, 31), and variants in the genes encoding these transporters have been implicated in variable drug responses. Thus, normal function of the drug efflux transporter P-glycoprotein is required for the biliary excretion of digoxin, and a common P-glycoprotein polymorphism has been associated with variable serum digoxin (32, 33). Similarly, polymorphisms in an organic anion (uptake) transporter have been implicated in the efficacy and some adverse effects of statins (34). Genetically Determined Pharmacodynamics Variability in the Genes Encoding Drug Targets Drugs can produce highly variable effects, even in the absence of substantial variability in drug concentrations at target sites. This pharmacodynamic variability tends to be drug- or disease-specific, in contrast to pharmacokinetic variability that often extends across many drugs and disease processes. One obvious set of genes in which variants might account for such pharmacodynamic variability is those encoding drug targets. Thus, a plausible candidate gene for modulating variability in response to β2-agonists in asthma is the β2-receptor, and such variants in this gene have been reported (35). Variants in multiple genes can contribute to variable drug actions, and recent studies with warfarin are an excellent example. Previous work had identified variable metabolism by CYP2C9 as a major contributor to variable responses to the drug (36). In 2004, coding-region mutations in VKORC1, encoding a subunit of the vitamin K epoxide reductase complex (the pharmacologic target for the drug), were found to cause a rare syndrome of warfarin resistance (37). Subsequently, common variants in VKORC1 have been found to account for a much greater fraction of variability in warfarin response (21%) than do variants in CYP2C9 (6%) (38). The CYP2C9 variants are in the coding region and alter enzyme activity, whereas the VKORC1 variants are noncoding and are thought to alter expression of the protein. The mechanisms underlying the remaining variability in warfarin effect have not been elucidated. Variability in the
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