Antiretroviral Therapy and Dyslipidaemia: Unlocking the Code

D yslipidaemia, characterised by elevated total cholesterol, elevated non–high density lipoprotein (HDL) cholesterol, low HDL cholesterol, and elevated triglycerides, is common in patients with HIV who are treated with long-term antiretroviral therapy (ART) [1]. Although multiple factors infl uence lipid levels in patients treated with ART, exposure to protease inhibitors (PI) is thought to play an important role in the development of dyslipidaemia [2,3]. Data showing a relationship between length of exposure to ART and increased incidence of cardiovascular events [4] have heightened concern that ART-associated dyslipidaemia will result in increased rates of cardiovascular disease among ART-treated patients with HIV. The pathogenesis underlying ART-associated dyslipidaemia is thought to be related to drug-induced effects at the subcellular or molecular level [5–7]. This pathogenic mechanism, together with the interindividual variability in the prevalence and severity of ART-associated dyslipidaemia, suggests an important role for genetic factors in the pathogenesis of this dyslipidaemia. Small variations in genetic sequence, or single-nucleotide polymorphisms (SNPs), are common in the human genome [8]; many adverse drug reactions occur in response to drugs that are metabolised by enzymes known to contain functionally relevant polymorphisms [9]. Determining the effect of SNPs or groups of SNPs (halotypes) on an individual's response to either drugs or disease may help to limit these adverse drug reactions. This area has become a focal point of translational molecular research. Apolipoproteins (apo) are important components of circulating lipoproteins. ApoC-III, a 79–amino acid glycoprotein synthesised in the liver and small intestine, is a major constituent of chylomicrons and very low density lipoproteins (VLDLs), both of which are triglyceride-rich lipoproteins. ApoC-III regulates the synthesis and catabolism of VLDL, an important contributor to plasma triglyceride concentrations [10]. In human studies, levels of apoC-III showed a positive correlation with plasma triglycerides, and higher apoC-III concentrations have been associated with recurrent cardiovascular events [11]. In studies of people with HIV, apoC-III levels showed a positive correlation with triglyceride concentrations in males with HIV [12], and apoC-III levels in males treated with PI were two to three times higher than controls [13]. Regulation of apoC-III occurs at the level of its transcription. Insulin interacts with an insulin-responsive element in the promoter region of apoC-III, resulting in down regulation of apoC-III expression [10]. Within the insulin-responsive element, the presence of two apoC-III polymorphisms, −455T/C and −482C/T, affects the ability of insulin to down-regulate apoC-III expression in vitro [14]. These polymorphisms are common in …