Cardiovascular disease is a leading cause of death worldwide. Many pharmacologic
therapies are available that aim to reduce the risk of
cardiovascular disease but there is significant inter-individual variation in
drug response, including both efficacy and toxicity. Pharmacogenetics aims to personalize medication choice and dosage to ensure that maximum clinical benefit is achieved whilst side effects are minimized. Over the past decade, our knowledge of pharmacogenetics in cardiovascular
therapies has increased significantly. The
anticoagulant warfarin represents the most advanced application of pharmacogenetics in cardiovascular medicine. Prospective randomized clinical trials are currently underway utilizing dosing algorithms that incorporate genetic polymorphisms in
cytochrome P450 (CYP)2C9 and
vitamin k epoxide reductase (VKORC1) to determine
warfarin dosages. Polymorphisms in
CYP2C9 and VKORC1 account for approximately 40 % of the variance in
warfarin dose. There is currently significant controversy with regards to pharmacogenetic testing in anti-platelet
therapy. Inhibition of platelet aggregation by
aspirin in vitro has been associated with polymorphisms in the
cyclo-oxygenase (COX)-1 gene. However, COX-1 polymorphisms did not affect clinical outcomes in patients prescribed
aspirin therapy. Similarly,
CYP2C19 polymorphisms have been associated with
clopidogrel resistance in vitro, and have shown an association with
stent thrombosis, but not with other cardiovascular outcomes in a consistent manner. Response to
statins has been associated with polymorphisms in the
cholesterol ester transfer protein (CETP),
apolipoprotein E (
APOE), 3-hydroxy-3-methylglutaryl
coenzyme A (
HMG-CoA) reductase, calmin (CLMN) and
apolipoprotein-CI (APOC1) genes. Although these genes contribute to the variation in
lipid levels during
statin therapy, their effects on cardiovascular outcomes requires further investigation. Polymorphisms in the solute carrier
organic anion transporter 1B1 (SLCO1B1) gene is associated with increased
statin exposure and
simvastatin-induced
myopathy.
Angiotensin-converting enzyme (
ACE) inhibitors and β-
adrenoceptor antagonists (β-blockers) are medications that are important in the management of
hypertension and
heart failure. Insertion and deletion polymorphisms in the ACE gene are associated with elevated and reduced serum levels of ACE, respectively. No significant association was reported between the polymorphism and blood pressure reduction in patients treated with
perindopril. However, a pharmacogenetic score incorporating single nucleotide polymorphisms (SNPs) in the
bradykinin type 1 receptor gene and
angiotensin-II type I receptor gene predicted those most likely to benefit and suffer harm from
perindopril therapy. Pharmacogenetic studies into β-blocker
therapy have focused on variations in the β1-adrenoceptor gene and
CYP2D6, but results have been inconsistent. Pharmacogenetic testing for
ACE inhibitor and β-blocker
therapy is not currently used in clinical practice. Despite extensive research, no pharmacogenetic tests are currently in clinical practice for cardiovascular medicines. Much of the research remains in the discovery phase, with researchers struggling to demonstrate clinical utility and validity. This is a problem seen in many areas of
therapeutics and is because of many factors, including poor study design, inadequate sample sizes, lack of replication, and heterogeneity amongst patient populations and phenotypes. In order to progress pharmacogenetics in cardiovascular
therapies, researchers need to utilize next-generation sequencing technologies, develop clear phenotype definitions and engage in multi-center collaborations, not only to obtain larger sample sizes but to replicate associations and confirm results across different ethnic groups.