Our study represents the first report of a strong association between the rs10892151 A allelic variant and the expression, particularly during PI-treatment, of a dyslipidemic phenotype in HIV-infected patients, which includes hypertriglyceridemia and depressed HDL-cholesterol levels.
The high prevalence of lipid disorders among treated HIV-infected patients requires the identification of specific polymorphisms in candidate genes that might predispose to these complications. However, the genetic basis of these metabolic abnormalities remains unclear. Some studies show that variants of apo A-V and C-III, interacting with APOE genotypes, are associated with the severity of antiretroviral treatment-induced dyslipidemia. For instance, the most severe dyslipidemic profiles after PI therapy were obtained in those patients carrying the three APOC3 variations (i.e., at nucleotides -455, -482 and the SstI site) and a non-ε3/ε3 APOE genotype [19–21]. Similarly, Guardiola et al.  indicated that in a cohort of PI treated HIV-infected patients, the -1131C carriers in APOA5 gene experienced marked increases in triglyceride levels (up to 80%) during a 3-year follow-up, while no change was recorded in patients carrying the normal -1131T allele. More recent studies [23, 24] have associated nucleotide variations in resistin and β2 adrenegic receptor (ARβ2) with the occurrence of lipodystrophy. In addition, tumor necrosis factor-α (TNFα) [20, 25, 26] and nuclear transcription-factor sterol response element-binding protein 1c (SREBP1c) [27, 28] have also been shown to affect HIV-induced lipodystrophy, but confirmation is required in long-term prospective studies.
The intriguing results obtained by Pollin et al.  in the polymorphism rs10892151, which is located 800 kb from the APOC3 gene cluster, prompted us to test the presence of a genetic association with lipid outcomes in our patients. In their high-fat feeding intervention study in 809 Old Order Amish individuals, the authors observed that rs10892151 A carriers had lower fasting and post-prandrial serum triglycerides values than non-carriers, and they found a linkage disequilibrium with an APOC3 null mutation, which was likely the result of a founder effect. Conversely, we found that this polymorphism in our study has no effect on circulating apo C-III values in either HIV-infected patients or healthy subjects, indicating that the linkage disequilibrium between this two genetic regions could not be universal.
High serum triglyceride concentration and low HDL-cholesterol values were found in our population, irrespective of the treatment they were assigned (although the effect was notably higher in those patients under PI treatment), but these lipid disorders were not related to a differential or abnormal response to circulating apo C-III levels. In addition, we were not able to identify further associations between the polymorphism and other lipid and inflammatory parameters. However, being a carrier of the rs10892151 A variant was a primary determinant of the course of lipid alterations. During follow-up, these patients consistently showed higher serum triglyceride and cholesterol concentrations, as well as lower HDL-cholesterol levels than those carrying the G/G genotype. This effect was particularly evident in those under PI-treatment, although a residual effect in HDL-cholesterol levels was also evident in those under NNRTI-treatment indicating that the HIV-infection itself may have a considerable impact on lipid concentrations for patients with the G/A genotype. However, further studies in larger populations under other chronic inflammatory stimulus are required to confirm the direction of rs10892151 polymorphism effect and to explain the fact that the observed effects in our study were quite different than expected from HIV negative individuals as previously reported .
Although the design of our study cannot address the mechanism by which antiretroviral treatment and HIV-infection interact with the polymorphism, it could be argued that antiretroviral treatment may interfere in the functioning of lipolytic enzymes, [29, 30] which are regulated by serum apo C-III concentrations, decreasing the catabolism of triglyceride-rich proteins in carriers of the rs10892151 A allele. However it does not explain why antiretroviral treatment and rs10892151 genetic variation have a limited impact on apo C-III levels, probably masked by the concomitant metabolic effects described during HIV infection. Despite the fact that our HIV-infected patients showed higher levels of apo C-III than healthy controls, the described effect was influenced by rs10892151 genotype rather than by serum apo C-III concentration. It is also noteworthy that there is a highly significant gene-nutrient interaction and that dietary manipulation may modulate the effect of polymorphisms on lipid profile .
Another possibility is that antiretroviral treatment may not affect just lipoprotein metabolism, but may exacerbate the chronic inflammatory state by the expression of pro-inflammatory molecules such as TNFα or MCP-1, which have a major role in lipid metabolism and, consequently, in cardiovascular disease [14, 32–34]. However, this hypothesis is not supported by our findings that the plasma MCP-1 and CRP concentrations were essentially the same in both groups of HIV-infected patients as well as in both genotypes.
The peculiar distribution of alleles seriously limits the reach of our conclusions but the differential response and pharmacogenetic implications among patients with different treatment strongly reinforces the need for replication. According to our data, this should be done in a sample with same ethnic origin and a sample size only achievable in multicenter-multicohort studies. The impact of population stratification in this study is unlikely because in our population sample this has been already assessed empirically by analyzing more than 25 unlinked single-nucleotide polymorphisms (SNPs) in several association studies spanning a range of disease states [35–39] and cases selected under the same circumstances.
We also acknowledge that studies assessing only one polymorphism are less robust than those assessing several polymorphisms associated with a plausible role in the pathogenesis of dyslipidemia. Further studies are needed to assess the possibly coordinated association with other well-documented polymorphisms, particularly those involved in metabolism and in molecular targets of antiretroviral drugs in order to uncover a host-related predisposition towards developing metabolic complications. If successful this may aid for specific, individual design of antiretroviral regimens to diminish the rapid emergence of side effects and the consequent deleterious significance.