An interaction between apo C-III variants and protease inhibitors contributes to high triglyceride/low HDL levels in treated HIV patients

Background: Long-term therapy with protease inhibitors (PI) is associated with hypertriglyceridaemia, low high-density lipoprotein (HDL) levels and accumulation of apolipoprotein (apo) E- and apo C-III-containing lipoproteins. Objectives: To evaluate the impact, on this dyslipaemic phenotype, of three polymorphisms of the apo C-III gene: two on an insulin response element and one in the 3'-region. Apo E genotypes were evaluated also. Design: Sixty consecutive male patients attending the HIV follow-up consultation were included during a 3-month period. All patients received at least one PI. Apo C-III and apo E genotypes were determined. Besides routine bio-clinical examination, a detailed exploration of lipoproteins and of insulin secretion markers was carried out. Methods: Plasma lipoparticles, insulin, proinsulin and C-peptide were measured by specific immuno-assays. Determination of apo C-III genotypes (-455C/T, -482C/F and Sstl) and of apo E alleles (epsilon2, epsilon3 and epsilon4) were performed by amplification and endonuclease digestion and were confirmed by allele-specific oligonucleotide hybridization. Results: Distribution of apo C-III alleles defined four major haplotyes. Carriers of the -455C variant had 30% lower levels of HDL-cholesterol than non-carriers. Plasma triglycerides increased according to the number of variant alleles. in multivariate analysis, a model including age, body mass index, clinical stage and treatment length, plasma insulin and apo C-III haplotypes explained around 43% of the HDL-cholesterol and triglycerides variability, Measurements of lipids before and after the use of PI demonstrated synergistic effects of the treatment and apo C-III variants on triglyceride levels. Conclusions: Apo C-III polymorphisms might identify a genetic predisposition to develop dyslipidaemia under PI therapy. (C) 2001 Lippincott Williams & Wilkins.