Pharmacogenetics and pharmacogenomics in cardiovascular medicine and surgery

Abstract

Cardiovascular disease is a principal cause of global morbidity and mortality. Multiple drugs are used clinically to improve the population-level prognosis of cardiovascular conditions. However, there is a noticeable difference in the response of individual patients to a given drug, observed in both intermediate phenotypes (e.g. platelet function tests) and clinical outcomes. The aetiology underlying this drug response interindividual variation is multifactorial, incompletely understood, but is comprised from demographic, clinical, environmental and genetic factors. Pharmacogenomics aims to understand the genomic determinants of drug response, and to translate findings into clinical practice to reduce adverse drug reactions and/ or improve drug effectiveness through genotype-informed dose and/or drug selection. Pharmacogenomic associations have been implemented for a few drugs after they have been licensed (e.g. abacavir in HIV disease), and there is a growing array of newly developed therapeutics that require a genomic companion diagnostic test, particularly in oncology. However, pharmacogenomics is yet to be adopted into widespread cardiovascular clinical practice. Several obstacles, including evidential, logistical, financial, and knowledge-based, have been identified. Nevertheless, substantive progress has been made, and early adopter sites are pioneering cardiovascular pharmacogenomics in practice. There is an undeniable large genomic influence affecting warfarin response, and strong evidence of pharmacogenomic associations with simvastatin myopathy, and stent thrombosis on clopidogrel. Variants that modulate responses to beta blockers, antiarrhythmics and angiotensin-converting enzyme inhibitors are also being identified. The integration of genomics into systems pharmacology approaches may further resolve interindividual drug response variability; the prospects are good, but the challenges are prodigious.