Pharmacogenomics: application to the management of cardiovascular disease

Abstract

The past decade has seen substantial advances in cardiovascular pharmacogenomics. Genetic determinants of response to clopidogrel and warfarin have been defined, resulting in changes to the product labels for these drugs that suggest the use of genetic information as a guide for therapy. Genetic tests are available, as are guidelines for incorporation of genetic information into patient-care decisions. These guidelines and the literature supporting them are reviewed herein. Significant advances have also been made in the pharmacogenomics of statin-induced myopathy and the response to β-blockers in heart failure, although the clinical applications of these findings are less clear. Other areas hold promise, including the pharmacogenomics of antihypertensive drugs, aspirin, and drug-induced long-QT syndrome (diLQTS). The potential value of pharmacogenomics in the discovery and development of new drugs is also described. In summary, pharmacogenomics has current applications in the management of cardiovascular disease, with clinically relevant data continuing to mount.

Figure 1

Clinical Pharmacogenetics Implementation Consortium guidelines for initiating antiplatelet therapy in patients with coronary disease based on cytochrome P450 2C19 genotype. ACS, acute coronary syndrome; CYP2C19, cytochrome P450 2C19; PCI, percutaneous coronary intervention. Adapted from ref. .

Figure 2

Median warfarin dose requirements in Asians, Caucasians, and African Americans, overall and by VKORC1 genotype; based on data from the International Warfarin Pharmacogenetics Consortium. The cyan bars indicate the median warfarin dose in each racial group, overall. The yellow, blue, and pink bars show the dose within each racial group by the VKORC1 −1639 AA, AG, and GG genotypes, respectively. As shown, the overall warfarin dose requirements are lower in Asians and higher in African Americans, compared with Caucasians. This racial difference in dose is largely explained by a higher frequency of the VKORC1 −1639 AA (low-dose) genotype in Asians, AG (intermediate-dose) genotype in Caucasians, and GG (high-dose) genotype in African Americans, resulting in similar doses by race within genotype. wk, week. Prepared from data in ref. .

Figure 3

Percentage of patients whose actual warfarin dose fell within 20% of the predicted dose according to either the clinical or the pharmacogenetic dosing algorithm derived by the International Warfarin Pharmacogenetics Consortium (IWPC). The pharmacogenetic algorithm was more predictive of the actual dose requirements for those requiring ≤21 mg/week or ≥49 mg/week of warfarin. For individuals requiring intermediate doses, the clinical and pharmacogenetic algorithms were similarly predictive of the dose requirements. The percentages of patients in each dosage group are shown at the bottom. wk, week. Adapted from ref. .

Figure 4

Schematic representation of adrenergic receptor signaling in the heart. α1AR, α1-adrenergic receptors; α2AR, α2-adrenergic receptors; AC, adenylyl cyclase; β1AR, β1-adrenergic receptors; β2AR, β2-adrenergic receptors; cAMP, cyclic adenosyl monophosphate; DAG, diacylglycerol; EPI, epinephrine; Gα_s, G-protein α subunit, stimulatory; Gα_i, G-protein α subunit, inhibitory; Gα_qG-protein a subunit q; GRK, G-protein receptor kinase; IP₃, inositol triphosphate; NE, norepinephrine; PLC, phospholipase C. From ref. .