Pharmacogenetics and cardiovascular disease--implications for personalized medicine

Abstract

The past decade has seen tremendous advances in our understanding of the genetic factors influencing response to a variety of drugs, including those targeted at treatment of cardiovascular diseases. In the case of clopidogrel, warfarin, and statins, the literature has become sufficiently strong that guidelines are now available describing the use of genetic information to guide treatment with these therapies, and some health centers are using this information in the care of their patients. There are many challenges in moving from research data to translation to practice; we discuss some of these barriers and the approaches some health systems are taking to overcome them. The body of literature that has led to the clinical implementation of CYP2C19 genotyping for clopidogrel, VKORC1, CYP2C9; and CYP4F2 for warfarin; and SLCO1B1 for statins is comprehensively described. We also provide clarity for other genes that have been extensively studied relative to these drugs, but for which the data are conflicting. Finally, we comment briefly on pharmacogenetics of other cardiovascular drugs and highlight β-blockers as the drug class with strong data that has not yet seen clinical implementation. It is anticipated that genetic information will increasingly be available on patients, and it is important to identify those examples where the evidence is sufficiently robust and predictive to use genetic information to guide clinical decisions. The review herein provides several examples of the accumulation of evidence and eventual clinical translation in cardiovascular pharmacogenetics.

Fig. 1.

Clopidogrel pharmacokinetic and target pathway. ABCB1, ATP-binding cassette, subfamily B, member 1, encodes P-glycoprotein; CES1, carboxylesterase 1; CYPXXX, gene name and encoded proteins for the various cytochrome P450 enyzmes involved in metabolism of clopidogrel; P2RY12, purinergic receptor P2Y12; PON1, paroxonase 1. Copyright to the Pharmacogenomics Knowledge Base (PharmGKB), with permission given by PharmGKB and Stanford University to reproduce this figure.

Fig. 2.

Warfarin pharmacokinetic and pharmacodynamic pathway. CYP2C9, cytochrome P450 2C9, metabolizes the more potent S-enantiomer of warfarin; VKORC1, vitamin K epoxide reductase complex 1, target site for warfarin; CYP4F2, cytochrome P450 4F2, metabolizes vitamin K. The genes for proteins shown in boxes are the primary genes influencing warfarin dose requirements.