The importance of plasma cholesterol reduction in the attenuation of cardiovascular (CV) risk has been clearly demonstrated in large clinical trials using statins. However, despite the clear risks of hyperlipidaemia and the proven benefits of lipid-lowering therapies, only a minority of patients currently achieve recommended low-density lipoprotein (LDL) cholesterol treatment goals in clinical practice.1,2 More patients are being treated for lipid reduction than ever before, but there remains a substantial degree of undertreatment. This is due to a number of factors, including patient non-compliance, tolerability issues, variable physician follow-up, patients not receiving adequate dosages of the lipid-lowering drugs available and the drugs themselves not being optimal.
Statins are widely prescribed and are established as first-line therapy for the primary and secondary prevention of coronary artery disease. However, the benefit of treatment varies between patients. Genetic variation can contribute to inter-individual variations in the clinical efficacy of drug therapy, and significant progress has been made in identifying common genetic polymorphisms that influence responsiveness to statin therapy. To date, more than 30 candidate genes related to the pharmacokinetics and pharmacodynamics of statins have been investigated as potential determinants of drug responsiveness in terms of LDL cholesterol lowering.3
An important link also exists between dietary cholesterol absorption and cholesterol production. Inhibiting cholesterol synthesis with statins increases cholesterol absorption, and decreasing cholesterol absorption increases cholesterol synthesis. This partially explains why it is difficult to achieve LDL targets in many patients. The intestinal pool of cholesterol is also an important source of blood cholesterol and is derived from biliary secretion and the diet. Approximately half of intestinal cholesterol is absorbed into the bloodstream. The absorption of excess cholesterol can increase the amount of cholesterol stored in the liver, resulting in increased very-low-density lipoprotein (VLDL) secretion and LDL cholesterol formation and downregulation of LDL receptor activity, leading to increased plasma LDL cholesterol levels. Genetic variation at gene loci that affect intestinal cholesterol absorption include apolipoprotein (apo) E4; adenosine triphosphate-binding cassette transporters G5 and G8; cholesterol production such as 3-hydroxy-3-methylglutaryl co-enzyme A (HMGCoa) reductase; and lipoprotein catabolism such as apoB and the LDL receptor. All may play a role in modulating responsiveness as well as genes involved in the metabolism of statins such as cytochrome P450.3
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