Glutathione S-transferase null and cholesteryl ester transfer protein TaqI B polymorphisms and lipid response to atorvastatin in Greek dyslipidaemic patients.

摘要

Impairment of high-density lipoprotein (HDL) cholesterol efflux capacity, coupled to attenuated antioxidative and anti-inflammatory properties of HDL particles, has been lately recognized as intimately connected to atherogenic dyslipidaemia, a well-established cardiovascular risk factor . Concomitantly, raising HDL-cholesterol (HDL-C) and apolipoprotein A-I (apoA-I) levels has been proposed as a major anti-atherogenic therapeutic target . While 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) are very efficacious in reducing total cholesterol, triacylglycerol, low-density lipoprotein cholesterol (LDL-C) and apolipoprotein B (apoB) levels in dyslipidaemic patients, their effect on HDL-C and apoA-I is moderate at best, and may be dependent on the type of statin used, dosage, duration of treatment, but also, genetic factors . In the past, pharmacogenetic studies of lipid response to statins have focused almost exclusively on polymorphisms of genes related to lipoprotein turnover, with the gene coding for cholesteryl ester transfer protein (CETP) receiving most of the attention [5-7]. Other factors may be involved as well. Oxidative stress has been implicated in the pathophysiology of cardiovascular disease and oxidative modification has been recently reported to impair the lipid-binding capacity of apoA-I, resulting in reduced HDL cholesterol efflux . In addition, the apoA-I gene promoter is known to contain an antioxidant response element and may be responsive to oxidative stress [10]. Because statins are reportedly able to attenuate the production of reactive oxygen species through mechanisms unrelated to their lipid-lowering effect [11], the possibility that genes affecting the antioxidant status of the organism can influence apoA-Iresponse to these drugs is an intriguing and as yet untested hypothesis. On the other hand, such an effect could conceivably be modulated by polymorphisms affecting reverse cholesterol transport - such as CETP TaqI B - especially since a growing body of evidence, from human and animal studies, suggests that there is a functional interaction between apoA-I expression and CETP activity [12-14].