Genetic Factors May Influence Fat Loss and Accumulation in People with HIV

By Liz Highleyman

Body fat changes and other metabolic complications (collectively known as HIV lipodystrophy syndrome) are a growing concern for people with HIV, especially those on HAART.

Lipodystrophy has been linked to antiretroviral therapy and HIV infection itself, but these manifestations do not occur in all treated individuals, and the underlying mechanisms and risk factors are poorly understood. Two recently published studies suggest that human genetic variations may play a role.

Study 1

In the first study, published in the August 20, 2008 issue of AIDS, researchers investigated the role of genetic variations in influencing the risk of metabolic complications associated with HAART.

They performed a cluster analysis of metabolic traits of 189 patients enrolled in ACTG 5005s, the metabolic substudy of the ACTG 384 clinical trial, which compared regimens containing efavirenz (Sustiva) versus nelfinavir (Viracept) and zidovudine/lamivudine (AZT/3TC; Retrovir/Epivir) versus stavudine/didanosine (d4T/ddI; Zerit/Videx) in treatment-naive HIV patients.

In all, the researchers evaluated nearly 300 single nucleotide polymorphisms (SNPs), or variations at specific positions, in 135 candidate genes to determine their association with metabolic conditions.

Results

• They identified a subgroup of patients that had a normal metabolic profile at baseline, but developed significantly elevated lipids and insulin resistance after starting HAART.

• This high-risk subgroup also experienced significant body composition changes, particularly limb fat loss (lipoatrophy).

• Gene analysis revealed that a SNP in resistin -- a gene previously implicated in obesity and insulin resistance -- was significantly more common in the high-risk group (P = 0.0003).

Based on these results, the study authors concluded, "Genetic variation in resistin is associated with metabolic complications caused by HAART."

Resistin, a hormone produced by adipose tissue, has previously been implicated in obesity and insulin resistance. In experiments in mice, increased resistin was associated with abnormal glucose tolerance, while animals lacking resistin had lower fasting blood glucose.

A specific resistin SNP called rs1862513 was previously linked to increased body mass index and diabetes in humans. While this particular SNP was not significantly associated with lipodystrophy in the current study, 2 flanking SNPs, rs321975 and rs3760678, were significantly more common in the high-risk group.

Speculating on the mechanism underlying their findings, the authors wrote in their discussion, "One possibility is that HIV-positive patients on HAART who are in a chronic inflammatory state might have increased resistin, as resistin gene expression can be induced by the proinflammatory molecules lipopolysaccharide and TNF-alpha."

"Given the link between inflammation and resistin levels and genotypes," they continued, "it will be important in future studies of patients treated with HAART to determine circulating levels of inflammatory molecules including TNF-alpha, its soluble receptor, and C-reactive protein in addition to resistin."

They went on to note that this study suggests potential strategies for managing lipodystrophy in high-risk individuals. Since increased resistin is associated with obesity and insulin resistance, they wrote, agents that reduce resistin -- including the PPAR-gamma agonists pioglitazone (Actos) and rosiglitazone (Avandia) -- "could potentially have a beneficial impact on HAART-induced lipodystrophy."

Bristol-Myers Squibb R&D, Princeton, NJ; University of Pennsylvania, Philadelphia, PA; University of California, San Francisco, CA; University College Dublin, Dublin, Ireland; Harvard Medical School, Boston, MA; Indiana University School of Medicine, Indianapolis, IN.

Study 2

In the second study, published in the September 12, 2008 issue of AIDS, researchers with the Italian ICoNA study team evaluated the influence of genetic polymorphisms on antiretroviral therapy-associated lipodystrophy.

The analysis included 255 participants in the ICoNA cohort. The researchers assessed the distribution and association with lipoatrophy and fat accumulation of several polymorphisms previously implicated in lipid and glucose metabolism and apoptosis (programmed cell death), including Fas-670 AG, ApoC3-455 CT, ApoC3-482 CT, the C161T silent substitution in the PPAR-gamma gene, the adrenergic beta-3 receptor (AR-beta-3) codon 64 TC variant, and 2 polymorphisms in the adrenergic beta-2 receptor (AR-beta-2) codons 16 AG and 27 CG.

Results

• In a multivariate model -- after adjusting for sex, age, HIV exposure, current HIV viral load, hepatitis C status, type of antiretroviral therapy, and duration of HAART -- the following genotypes were protective against lipoatrophy:

• ApoC3-455 CC (adjusted relative risk [ARR] 0.2 vs CT/TT; P = 0.037);

• AR-beta-3 codon 64 TT (ARR 0.39 vs TC/CC; P = 0.066);

• Fas-670 GG (ARR 0.51 vs AG/AA; P = 0.053).

• The AR-beta-2 codon 27 CC genotype was protective against fat accumulation.

• Conversely, the AR-beta-2 codon 16 AA genotype was associated with a higher risk of fat accumulation (ARR 3.72 vs AG/GG; P = 0.0026).

"Our study suggests that genetic polymorphisms of genes involved in apoptosis and adipocyte metabolism are significantly related to antiretroviral-associated lipodystrophy," the study authors concluded. "Particularly, we evidenced a role for ApoC3-455 in lipoatrophy and for the two variants of AR-beta-2 in fat accumulation."

In their discussion, they noted that other researchers have also reported a correlation between the ApoC3 variants and unfavorable lipid profiles and lipoatrophy in people with HIV. The Fas-670 A-G mutation, they suggested, might limit apoptosis of fat cells, thereby protecting against lipoatrophy.

"Given the high prevalence of the polymorphisms analyzed and the increasing literature reports showing an association between some of these with lipodystrophy, and also the relative low cost and feasibility of gene testing, it might be useful to determine the genetic predisposition of each single HIV-1-positive patient starting antiretroviral therapy," the authors suggested. In so doing, "it could be possible to design individual regimens for each patient in order to avoid the rapid emergence of side effects and take adequate measures to delay their appearance."

Department of Clinical Sciences, 'Luigi Sacco' Hospital, University of Milan, Milan, Italy; Department of Biomedical Sciences, University of Modena and Reggio Emilia, Modena, Italy; Department of Medicine, Surgery, and Dentistry, 'San Paolo' Hospital, University of Milan, Milan, Italy; Royal Free and University College Medical School, London, UK; Infectious Diseases Clinic, S.M. Annunziata Hospital, Antella, Firenze, Italy; Clinic of Infectious and Tropical Diseases, University of Modena and Reggio Emilia, Modena, Italy.

9/16/08

References

K Ranade, W Geese, M Noor, and others. Genetic analysis implicates resistin in HIV lipodystrophy. AIDS 22(13): 1561-1568. August 20, 2008.
(Abstract).

B Zanone Poma, A Riva, M Nasi, Milenab, and others (for the ICONA Foundation Study Group). Genetic polymorphisms differently influencing the emergence of atrophy and fat accumulation in HIV-related lipodystrophy. AIDS 22(14): 1769-1778. September 12, 2008. (Abstract).