Findings from Denver
Three of the studies examined the effects of variation in the genes for apolipoproteins. These compounds are involved in the transport of cholesterol and other materials around the body, with variation in their genes having been linked to hardening of the arteries and blood triglyceride levels.
In one of these studies, investigators focused on six points within the apolipoprotein genes, two in gene E, three in gene C and one in gene A. In a cohort of 370 patients enrolled in a trial comparing ritonavir-boosted lopinavir (Kaletra) with nelfinavir (Viracept), the investigators found that the type of E genes a patient had were associated with changes in blood cholesterol levels. In contrast, variation at one point in the C gene determined the degree to which triglyceride levels rose (Gometz 2006).
The second study examined a range of genes suspected of being involved in determining blood fat levels, which included the apolipoprotein genes. The investigators concluded that patients with a set of particular variants in these genes were linked to higher triglyceride levels in response to ritonavir (Norvir) treatment. However, they also detected a set of genes that was linked to higher levels of high-density lipoprotein (HDL or ‘good’) cholesterol in patients taking non-nucleoside reverse transcriptase inhibitor-based treatment (Arnedo 2006).
Thirdly, Cossarizza et al. found evidence of a link between variation in the apolipoprotein C gene and the risk of the loss of fat from under the skin, due to a possible effect of the gene on the metabolism and death of fat cells or ‘adipocytes’.
This group also confirmed a previously-observed link between variations in the gene FAS-670 and fat loss.
In further study presented in Denver, Ranade et al. examined 285 sites within 137 genes for links with metabolic changes, as part of a larger study comparing various protease inhibitor- and NNRTI-containing HIV treatment regimens. In an analysis of 189 patients, only one of these genetic variations was identified as being linked to changes in blood fat levels, regardless of the patients’ race.
They found that a single variation in the gene for resistin, a hormone released by fat tissue, was linked to the risk of a patient developing elevated blood triglyceride levels or changes in blood cholesterol, as well as changes in resistance to insulin, a marker of the development of diabetes.
Finally, an Italian study found a link between variation in the multidrug resistance-1 (MDR-1) gene. This gene, which is better known through its link with resistance to various drugs including some HIV medications, was found to have a link with the accumulation of fat around the internal organs in patients on HIV therapy, as well as cholesterol levels. While patients with two identical copies of the gene, which produces poly-glycoprotein, were at a reduced risk of fat accumulation, patients with genes that differed at the same point were at an increased risk of developing high triglyceride levels (De Luca 2006).
A series of poster presentations at the Thirteenth Conference on Retroviruses and Opportunistic Infections, held earlier this month in Denver, revealed details of studies linking variations in genes to the risk of patients developing body fat changes or altered blood fat levels as a side-effect of HIV treatment.
Although the study of the interactions between genetics and the actions of drugs or ‘pharmacogenomics’ is complex, these studies may eventually help doctors identify the risk of treatments they are prescribing for a patient, and to tailor the choice of drugs to each patient’s genetic profile.
The five posters presented in Denver, which were also part of a poster discussion session during the conference, all set out to examine the effects of variations in genes in cohorts of HIV-positive patients taking antiretroviral therapy. Since the number of possible variations in the human genome is so large, each study focused on different ‘candidate’ genes, based on knowledge of their function from previous human or animal studies.
These types of study are often criticised as being ‘fishing trips’ that trawl through vast numbers of possible variations to reveal genetic elements that may be linked to drug responses only by statistical fluctuations. However, participants at the poster discussion session heard the investigators defend their studies, after being questioned on their choice of genes for investigation and being asked to explain the biological plausibility of any results they found.
Nevertheless, patients should not expect to see the application of these findings to the HIV clinic for many years, until their findings are confirmed and the predictive value of small changes in the structure of genes are understood in relation to other sources of variation, both genetic and non-genetic.
Ranade K et al. A single nucleotide polymorphism in the resistin gene is associated with adverse metabolic changes on HAART: an exploratory pharmacogenetic association study of A5005s, the metabolic sub-study of ACTG 384. Thirteenth Conference on Retroviruses and Opportunistic Infections, Denver, abstract 763, 2006.
Arnedo M et al. Modeling the influence of polymorphisms of several genes involved in lipid metabolism on the risk of antiretroviral-associated dyslipidemia. Thirteenth Conference on Retroviruses and Opportunistic Infections, Denver, abstract 764, 2006.
De Luca A et al. The effect of polymorphism of the MDR-1 gene on the long-term risk of lipodystrophy and dyslipidemia in HIV-infected patients starting antiretroviral therapy. Thirteenth Conference on Retroviruses and Opportunistic Infections, Denver, abstract 766, 2006.
Cossarizza A et al. FAS-670 and APOC3 polymorphisms as predictors of lipoatrophy in patients receiving antiretroviral therapy. Thirteenth Conference on Retroviruses and Opportunistic Infections, Denver, abstract 767, 2006.
Gometz E et al. Association of lipid changes in HAART-treated individuals with apolipoprotein genotypes. Thirteenth Conference on Retroviruses and Opportunistic Infections, Denver, abstract 768, 2006.