title: Clinical implications of pharmacogenetic variation on the effects of statins.
abstract: The last decade has seen an increase in the trend of HMG-CoA reductase inhibitor (statin) usage in the Western world, which does not come as a surprise noting that the latest American Heart Association heart and stroke statistics indicate an alarming prevalence of 80  million Americans (one in three) with one or more forms of diagnosed cardiovascular disease (CVD). Meta-analysis of several large-scale, randomized clinical trials has demonstrated statins to be efficacious in significantly reducing CVD-associated mortality in both primary and secondary prevention. Despite their proven efficacy, statins have also gained attention with respect to adverse drug reactions (ADRs) of muscle myopathy, derangements in hepatic function and even ADRs classified as psychiatric in nature. The depletion of cholesterol within the myocyte cell wall and/or the depletion of key intermediates within the cholesterol synthesis pathway are hypothesized as possible mechanisms of statin-associated ADRs. However, pharmacogenetic variability may also be a risk factor for ADRs and can include, for example, enzymes, transporters, cell membrane receptors, intracellular receptors or components of ion channels that contribute to the pharmacokinetics or pharmacodynamics of response to a particular drug. The cytochrome P450 (CYP) enzymatic pathways that comprise the polymorphic genes, CYP2D6, CYP3A4 and CYP3A5, and also a hepatic transporter, solute carrier organic anion transporter (SLCO1B1), which is a single nucleotide polymorphism discovered to be associated with statin-induced myopathy through a genome-wide association study, are discussed with respect to their effect on altering the pharmacokinetic profile of statin metabolism. Variants of the Apolipoprotein E (APO-E) gene, polymorphisms in the cholesteryl ester transfer protein (CETP) gene, the HMG-CoA reductase gene and other proteins are discussed with respect to altering the pharmacodynamic profile of statins. Pharmacogenetics and its application in medicine to individualize drug therapy has been previously shown to be clinically and economically beneficial through quality-adjusted life-year assessment. Therefore, polymorphisms affecting the pharmacokinetic and pharmacodynamic profiles of statins, which are widely used in therapy, with their potential application in the personalized prescribing of statin therapy, need further research. In this review, we update the recent literature with respect to genetic polymorphisms that may influence the pharmacokinetics and pharmacodynamics of statin therapy, and consider the relevance of these findings to the efficacy of treatment, prevention of ADRs and what this may mean for patient tolerance and compliance.
authors.affiliation: Department of Pharmacology and Toxicology, School of Medical Sciences, University of Otago, Dunedin, New Zealand. simran.maggo@otago.ac.nz
authors.forename: Simran D S
authors.initials: SD
authors.lastname: Maggo
authors.forename: Martin A
authors.initials: MA
authors.lastname: Kennedy
authors.forename: David W J
authors.initials: DW
authors.lastname: Clark
mesh_terms: D000818:Animals; D002318:Cardiovascular Diseases / Q000209:etiology / Q000401:mortality / Q000517:prevention & control*; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D003577:Cytochrome P-450 Enzyme System