Expanding role of pharmacogenomics in the management of cardiovascular disorders.

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.