Cardiovascular pharmacogenomics and individualized drug therapy

Abstract

The goal of individualized drug therapy requires physicians to be able to accurately predict an individual's response to a drug. Both genetic and environmental factors are known to influence drug response. 'Pharmacogenetics' is the study of the role of inheritance in variation in drug response phenotypes. Pharmacogenetics is now moving genome-wide to become 'pharmacogenomics', resulting in the recognition of novel biomarkers for individual variation in drug response. This article reviews the development, promise and challenges facing pharmacogenomics, using examples of drugs used to treat or prevent cardiovascular disease.

Figure 1

Warfarin, which is metabolized by CYP2C9, inhibits the vitamin K cycle via actions on thiol-dependent enzymes, such as vKORC1, that are required for regeneration of active vitamin K. The vitamin K cycle is essential for post-translational gamma-carboxylation of several blood coagulation factors and, therefore, coagulation. Abbreviations: vKORC1, vitamin K epoxide reductase complex 1; CYP2C9, cytochrome P450, family 2, subfamily C, polypeptide 9.

Figure 2

Genome-wide association study data for statin-induced myopathy. a | Association between myopathy and each SNP assayed during the genome-wide association study. The x axis shows the location of each SNP in the gene and the y axis is −log₁₀ of this P value (for example, 6 is P = 10⁻⁶). b | Estimated cumulative risk of myopathy associated with 80 mg of simvastatin daily. Abbreviation: SNP, single nucleotide polymorphism. Copyright © 2008 Massachusetts Medical Society. All rights reserved. The SEARCH Collaborative Group et al. N. Engl. J. Med. 359, 789–799 (2008).

Figure 3

Diagrammatic representation of the use of a cell-line-based model system to identify and validate, both functionally and clinically, pharmacogenomic candidate genes. Permission obtained from Oxford University Press © Wang, L. & Weinshilboum, R. M. Hum. Mol. Genet. 17, R174–R179 (2008).