Apolipoprotein A-V Genetic Variation and Plasma Lipoprotein Response to Fibrates

Abstract

The field of pharmacogenetics has begun to reveal solid evidence for the relationship between interindividual variability in response to drug treatment and one’s genetic background. In the lipoprotein field, response to statin treatment and the severity of adverse events from statin treatment has been linked to genetic variation. Now, new evidence of a relationship between apolipoprotein A-V genetic variation and plasma lipoprotein response to fibrates has been found. See page 1417 The field of pharmacogenetics promises to explain interindividual variability in response to both beneficial and adverse effects of medications.1–3 In theory, interindividual differences in drug response could be the result of functional polymorphisms in the human genome that encode differences in: (1) gene products that act within pathophysiological pathways underlying the disease whose natural history is being targeted by the drug; (2) pharmacokinetic activity of drug transporters or of processing or metabolizing enzymes; and (3) pharmacodynamics of gene products expressed as carriers or receptors for drug molecules. In the lipoprotein field, inhibitors of 3-hydroxy-3-methylglutaryl (HMG)-coenzyme A (CoA) (HMG-CoA) reductase (“statins”) have been studied pharmacogenetically, with genotypes of many common DNA polymorphisms associated with variation in plasma low-density lipoprotein (LDL) cholesterol responsiveness (reviewed by Kajinami et al1). The associated genes typically encode proteins that are involved in cholesterol biosynthesis, such as HMG-CoA reductase, in plasma LDL metabolism, such as the LDL receptor, apolipoprotein (apo) E and B, and in drug metabolism, such as certain cytochrome P450 enzymes.1 Furthermore, the severity of adverse events from statin treatment, such as myopathy, could be determined in part by interindividual variation in genes involved in ubiquitination.4 Similarly, plasma LDL cholesterol response to the cholesterol absorption inhibitor ezetimibe has been associated with variation in Niemann-Pick C like protein 1 (NPC1L1), the presumed target of ezetimibe (reviewed by Huff et al5 …