Genetic causes

Some people may have a genetic predisposition to elevated lipid levels, and/or to the development of ART-induced lipoatrophy. Apolipoprotein E2 is strongly associated with high triglycerides, as well as LDL-B phenotype, (which is also associated with obesity or a sedentary lifestyle, and with Syndrome X, in HIV-negative people). LDL-B is predictive of atherosclerosis (hardening of the arteries), and can be reduced by diet and exercise in HIV-negative people.

High triglyceride levels and low HDL cholesterol levels have been associated with genetic variations. Specifically, polymorphisms in the Apo C-III gene, which governs the production of very low density lipoprotein (VLDL) cholesterol (the carriers of triglycerides) are associated with higher triglyceride and lower HDL levels in men receiving protease inhibitors.¹ These polymorphisms are associated with higher average triglyceride and plasma lipoprotein levels in most studies in the general population, and commencing PI therapy results in a more pronounced increase in triglyceride levels in people with some of the polymorphisms. In HIV-positive men, elevated ApoC-III and triglyceride levels were associated with PI or NNRTI treatment by one group,² whilst another group found that women with lipid abnormalities had higher levels of ApoC-III production, which would interfere with normal hydrolysis of triglycerides. A third group has shown that PI or NNRTI treatment reduces APoB - VLDL cholesterol clearance, leading to increased triglyceride levels.

Studies have also investigated variations in the genes that regulate the production of paraoxonase-1 (PON1), an enzyme that preserves HDL and LDL cholesterol from peroxidation. (Lipid peroxidation is one mechanism through which cardiovascular disease is thought to develop.) In a case-control study of patients with lipodystrophy, metabolic disorders, a positive cardiovascular risk or atherosclerosis compared to HIV-positive patients without any of these conditions, the H7 haplotype of PON1 was associated with greater increases in CD4 cell count, higher levels of HDL cholesterol and apolipoprotein A1, lower triglyceride levels and lower rates of subclinical arteriosclerosis.³

High levels of a metabolic amino acid called homocysteine are also a risk factor for cardiovascular disease. Several studies have reported high homocysteine levels among some people on HAART.^{4 5} Folate supplements readily reverse elevations in homocysteine.

At least one study⁶ has found that the presence of a specific allele (HLA-B*4001) among the HLA genes is strongly associated with the development of d4T (stavudine, Zerit)-associated lipoatrophy. (See Lipoatrophy in Effect of genetic variation on side-effects of HIV drugs.)