Beta3-adrenergic receptor polymorphism and the antiretroviral therapy-related lipodystrophy syndrome.

Abstract

The treatment of HIV patients with highly active antiretroviral therapy (HAART) is associated with the occurrence of peripheral lipodystrophy, low total body fat, visceral abdominal fat accumulation, hyperlipidaemia and insulin resistance. This syndrome implies a predisposition for cardiovascular disease, which may become of crucial importance because HIV infection needs lifelong treatment [1]. Some authors [1] report that up to 64% of patients on HIV protease inhibitors, the cornerstone of HAART, may develop lipodystrophy syndrome (LDS). The β3-adrenergic receptor (β3-AR) is mainly expressed in visceral fat in humans and is involved in lipolysis and the regulation of thermogenesis [2]. Recently, a codon 64 TGGtrp to CGGarg (Trp64Arg) mutation in the β3-AR gene was identified [3]. This β3-AR polymorphism has been associated with a syndrome of visceral abdominal obesity, hypertriglyceridaemia, hypercholesterolaemia, insulin resistance and the early onset of non-insulin-dependent diabetes mellitus. Apart from peripheral lipodystrophy, the described syndrome and HAART-associated LDS have much in common. To test the hypothesis that β3-AR polymorphism is associated with the development of LDS we investigated 239 subjects. From a cohort of 135 HIV patients on HAART, 39 HIV patients were selected: 22 with (LDS+) and 17 without (LDS−) the characteristics of LDS. As a control group, we selected 200 non-HIV individuals with normal body composition. Lipodystrophy was defined clinically by physical examination. Demographic and laboratory data for each of the HIV patients are summarized in Table 1. Genomic DNA was extracted from peripheral blood leukocytes and amplified by polymerase chain reaction and subjected to restriction enzyme fragment analysis [3].Table 1: Clinical and laboratory characteristics of HIV patients on highly active antiretroviral therapy with (LDS +) and without (LDS−) lipodystrophy syndrome. In the HIV patient group with lipodystrophy characteristics (LDS+, n = 22), six patients were heterozygous, none was homozygous for the Arg64 allele (6/44 alleles, Arg64 allele frequency 13.6%). In the LDS negative HIV patients (LDS−, n = 17) two were heterozygous, none homozygous (2/34 alleles, 5.9%). In the control group, 19 out of 200 individuals were heterozygous, one was homozygous for the 64Arg allele (21/400 alleles, 5.3%). The difference of 64Arg allele frequencies of LDS+ HIV patients and control individuals was significant (P = 0.04; Fisher's exact test), but the allele frequency of LDS− HIV patients was not different from the control group (P = 0.7). The difference in 64Arg allele frequencies of LDS+ and LDS− HIV patients did not reach a significant level (P = 0.4). The severity of lipodystrophy seems to be predicted by C peptide, fasting triglyceride levels and body weight before the start and by the duration of protease inhibitor therapy, and as yet, no genetic risk factor for the development of the syndrome has been found [1]. It was recently hypothesized that mitochondrial damage in fat tissue, afflicted by long-standing therapy with nucleoside reverse transcriptase inhibitors is a causative factor in lipodystrophy [4]. Mitochondrial dysfunction is known to play a crucial role in apoptotic cell death [5]. Accordingly, one might speculate that HIV protease inhibitors could stimulate apoptosis and prevent the proliferation of peripheral adipocytes, resulting in lipolysis and hyperlipidaemia by interference with the production of an essential regulatory protein. This hypothesis may explain how HIV therapy induces peripheral lipolysis and hyperlipidaemia, but does not explain the characteristic visceral obesity. LDS might be multifactorial, in which various factors in individuals lead to different expression of the components of the syndrome. In this respect, our observation that the Trp64Arg mutation of the β3-adrenergic codon is a genetic risk factor for the development of protease-inhibitor-associated peripheral lipodystrophy is novel. One might speculate that aberrations in β3-AR, resulting in lowered excitability, could lead to a decrease in thermogenesis and lipolysis in visceral adipocytes and thus stimulate the accumulation of abdominal fat. Several studies have associated a codon 64 TGGtrp to CGGarg (Trp64Arg) mutation in the β3-AR gene to a syndrome of visceral obesity [6], lower resting metabolic rates, hypertriglyceridaemia, hypercholesterolaemia, insulin resistance [7] and the early onset of non-insulin-dependent diabetes mellitus [3,8]. We suggest that HIV patients who have this β3-AR polymorphism are more prone to develop the syndrome of peripheral lipodystrophy when using antiretroviral therapy than those who do not. Because of the restricted size of the patient group, further studies are warranted. Harald E. Vonkemana Chris H. H. ten Napela Arletta M. van Oeveren-Dybiczb Istvan Vermesb