Pharmacogenomics of cholesterol-lowering therapy.
The prevention of cardiovascular disease is critically dependent on lipid-lowering therapy, including 3-hydroxymethyl-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins), cholesterol absorption inhibitors, bile acid resins, fibrates, and nicotinic acid. Although these drugs are generally well tolerated, severe adverse effects can occur in a minority of patients. Furthermore, a subset of patients does not respond to cholesterol-lowering therapy with a reduction in coronary heart disease progression. Significant progress has been made in the identification of common DNA sequence variations in genes influencing the pharmacokinetics and pharmacodynamics of statins and in disease-modifying genes relevant for coronary heart disease (CHD). Among the most promising candidate genes for pharmacogenomic analysis of statin therapy are HMG-CoA reductase as a direct target gene and other genes modulating lipid and lipoprotein homeostasis. Based on data from pharmacogenetic trials, a combined analysis of multiple genetic variants in several genes is more likely to give significant results than single gene studies in small cohorts. In the future, pharmacogenomic testing may allow risk stratification of patients to avoid serious side effects and enable clinicians to select lipid-lowering drugs with the highest efficacy resulting in the best response to therapy.
Schmitz
Gerd
G
Institute of Clinical Chemistry and Laboratory Medicine, University of Regensburg, Franz-Josef-Straub-Allee 11, 93042 Regensburg, Germany. gerd.schmitz@klinik.uni-regensburg.de
Langmann
Thomas
T
D001057:Apolipoproteins E / Q000235:genetics; D002318:Cardiovascular Diseases / Q000201:enzymology / Q000235:genetics* / Q000517:prevention & control; D002352:Carrier Proteins / Q000235:genetics; D053480:Cholesterol Ester Transfer Proteins; D002986:Clinical Trials as Topic; D020022:Genetic Predisposition to Disease; D006023:Glycoproteins / Q000235:genetics; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000235:genetics; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006937:Hypercholesterolemia / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics*; D009135:Muscular Diseases / Q000235:genetics / Q000503:physiopathology; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic
D001057:Apolipoproteins E; C506642:CETP protein, human; D002352:Carrier Proteins; D053480:Cholesterol Ester Transfer Proteins; D006023:Glycoproteins; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D006903:Hydroxymethylglutaryl CoA Reductases