Pharmacogenetics and the treatment of cardiovascular disease

Pharmacogenetics and the treatment of cardiovascular diseasePatients with cardiovascular disease, like other patient groups, vary in their response to drugs.This is true both in terms of the response of their disease to treatment and their ability to tolerate medication.Several factors contribute to this variability, including diVerences in body mass, co-existent renal disease, concomitant drug treatment, and the heterogeneous nature of the disease.The Human Genome Project and the general focus of clinical science on genetic determinants of disease has increased interest in the role of genetic factors in determining an individual's response to drugs.Pharmacogenetics is a growing discipline concerned with the eVect of genetic variation on the response to drugs and the extent to which drug treatment can be tailored to the individual according to their genetic makeup. Genetic polymorphismThe idea that the dose of a drug should be adjusted according to the patient's genotype is not new.It is well recognised that polymorphism in genes encoding P450 enzymes, N-acetyltransferase, and other key enzymes of drug metabolism are responsible for major inter-individual diVerences in blood concentrations of certain drugs.Clinically, poor metabolisers may be slow to activate and respond inadequately to some pro-drugs, or exhibit reduced clearance and increased eVects from some pharmacologically active agents, particularly when the latter have a steep dose-response curve or a narrow therapeutic index.For example, the principle route of metabolism of flecainide and propafenone is via cytochrome P450 2D6 and multiple alleles have been identified that impair the activity of the enzyme.Patients with poor CYP450 2D6 activity demonstrate higher blood concentrations of flecainide and propafenone and have more side eVects for a given dose than those with normal enzyme activity.1 2 Awareness of a patient's genotype can protect that patient from certain drugs or their prescription in dangerous doses.Pharmacogenetics extends this approach of tailoring drug development and treatment beyond factors that regulate drug metabolism to other genetically determined variables that may influence the response of a patient to a given drug.Some tentative progress has been made in this direction.Several genetic polymorphisms have been identified that appear to influence the response to pravastatin.3 For example, the Taq1B polymorphism of cholesteryl ester transfer protein (CETP), which has a key role in the metabolism of high density lipoprotein, has been reported to show a dose dependent correlation with severity of coronary atherosclerosis and predict the response to treatment with pravastatin; patients with the B1B1 genotype (homozygous for the restriction site for Taq1) demonstrated more severe disease and responded better to the statin than patients with the B2B2 genotype (homozygous for the absence of the restriction site), with the B1B2 genotype intermediate.4