Pharmacogenetics of HMG-CoA reductase inhibitors: exploring the potential for genotype-based individualization of coronary heart disease management

Despite the benefit of statin therapy in the prevention of coronary heart disease, a considerable inter-individual variation exists in its response. It is well recognized that genetic variation can contribute to differences in drug disposition and, consequently, clinical efficacy at the population level. Pharmacogenetics, exploring genetic polymorphisms that influence response to drug therapy, may one day allow the clinician to customize treatment strategies for patients in order to improve the success rate of drug therapies. To date, 41 studies have investigated the relationships between common genetic variants and response to statin therapy in terms of lipid effects and clinical outcomes; 16 candidate genes involved in lipoprotein metabolism and 3 in pharmacokinetics. APOE is the most extensively studied locus, and absolute difference in LDL cholesterol reduction across genotypes remained 3-6%. Moreover, none of the associations was striking enough to justify genetic analysis in clinical practice. Reported data have suggested that larger studies (>1000 participants) or combination analyses with >2 different polymorphisms would enable us to find clinically or biologically meaningful difference, which could be assumed as >10% absolute difference, and that genes influencing cholesterol biosynthesis in the liver, such as ABCG5/G8, CYP7A1, HMGCR, would be good candidates for future studies. (C) 2004 Elsevier Ireland Ltd. All rights reserved.