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Review
. 2011 Apr 19;123(15):1661-70.
doi: 10.1161/CIRCULATIONAHA.109.914820.

Pharmacogenomics: the genetics of variable drug responses

Dan M Roden  1 , Russell A Wilke, Heyo K Kroemer, C Michael Stein
Affiliations
Review

Pharmacogenomics: the genetics of variable drug responses

Dan M Roden et al. Circulation. .
No abstract available

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Figures

Figure 1
Figure 1
High-risk pharmacokinetics. Drugs that are eliminated by a single pathway can generate aberrant responses if that pathway is absent on a genetic basis, or because of co-administration of inhibiting drugs. This figure illustrates the two scenarios underlying such “high-risk” pharmacokinetic situations. One (left) is the administration of a drug that is itself not active but requires drug metabolism to generate an active metabolite; the absence of the pathway can lead to failure to generate the desired drug effect. This is thought to underlie variability in response to clopidogrel, tamoxifen, losartan, and codeine, as described in the text. The second scenario (right) is the administration of a drug eliminated by single pathway. Absence of this pathway will result in accumulation of the parent drug and thus drug-related toxicity. Adapted, by permission.
Figure 2
Figure 2
A framework for analyzing contributions of multiple genes to a clinical phenotype. The example of warfarin maintenance dose requirement is shown here. A. A simple pathway analysis of the key molecular determinants of warfarin response. The drug is administered as a racemate, and most anticoagulant action is mediated by the more potent S-enantiomer. S-warfarin is bioinactivated primarily by CYP2C9. The pharmacologic target for the drug is encoded by VKORC1, important for maintaining active Vitamin K. The role for other drug metabolizing pathways and for other enzymes that influence Vitamin K metabolism (EPHX1, GGCX) are shown in gray. B. Distribution of CYP2C9 and VKORC1 variants as a function of ancestry. For CYP2C9 (top panel), the *1 allele has the highest activity, *2 is a reduction of function variant, and *3 is a near loss of function variant. For the VKORC1 promoter variant shown, the G allele results in greater liver expression than does the A allele. These distributions of genotypes largely explain ancestry-dependent variability in warfarin dosing. C. Contribution of common and rare variants to warfarin dose requirements in a population. The normally-distributed dose requirements predominantly reflect the common variants shown in panel (B). However, individuals with rare VKORC1 coding region variants and individuals with the rare CYP2C9*3/*3 genotype may display unusually high or low dose requirements.
Figure 3
Figure 3
Contrasting approaches to incorporating genomic information into prescribing. The pathway on the left illustrates current practice, genetic testing on an as needed basis. The pathway on the right illustrates how preemptive deposit of genotypic data into a genome-enabled electronic medical record would result rapid and efficient genotype-guided therapy.
See this image and copyright information in PMC

References

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