Polymorphisms in LPL, CETP, and HL Protect HIV-Infected Patients from Atherogenic Dyslipidemia in an Allele-Dose-Dependent Manner Montse Guardiola, 1 Patricia Echeverria, 2 Marta Gonza ´ lez, 1 Joan C. Vallve ´, 1 Jordi Puig, 2 Bonaventura Clotet, 2 Josep Ribalta, 1 and Euge ` nia Negredo 2,3 Abstract HIV-infected patients treated with highly active antiretroviral therapy (HAART) may be predisposed to a lipid profile, associated with increased cardiovascular risk, derived from having high triglycerides (TG) and low high-density lipoprotein cholesterol (HDLc) levels. We propose that genetic variability leaves some HIV- infected patients more predisposed to this lipid profile than others. We performed a cross-sectional, observa- tional study including 321 antiretroviral-treated HIV-infected patients classified as normolipidemic (n = 173) or presenting with high TG (‡1.7 mmol/liter) and low HDLc [ < 1.02 (men) or 1.28 mmol/liter (women)] (n = 148) to investigate the impact of 13 polymorphisms of 9 genes affecting lipid metabolism (APOA5, APOC3, LPL, CETP, HL, MTP, APOE, LRP5, and VLDLR genes). The polymorphism rs328 in LPL was 40% significantly more frequent in normolipidemics ( p = 0.018), and in the same group, polymorphisms rs708272 in CETP and rs1800588 in HL were 10% significantly more frequent ( p = 0.037 for both polymorphisms). Patients who presented a combination of one to six alleles from these polymorphisms had 10% increased HDLc levels [1.13 (0.40) vs. 1.24 (0.23) mmol/liter, p = 0.002] and a trend toward lower triglycerides [2.23 (2.34) vs. 1.89 (1.24) mmol/liter] and lower remnant-like particle cholesterol (RLPc) [16.41 (11.42) vs. 12.99 (11.69) mmol/liter]. This effect was dependent on the number of protective alleles and independent of the regimen administered. Polymorphisms in LPL, CETP, and HL protect HIV-infected patients from developing the dyslipidemia derived from high TG and low HDLc levels in a dose-dependent manner. Introduction I n HIV-infected patients, dyslipidemia is to a significant extent attributed to the adverse effects of highly active antiretroviral therapy (HAART). Not all antiretroviral drugs have the same impact on metabolic parameters. 1–6 Increased triglycerides (TG) together with decreased high-density li- poprotein cholesterol (HDLc) are characteristically observed in HIV patients undergoing HAART receiving protease in- hibitors (PIs). 7 PIs are the antiretroviral drugs most associated with cardiovascular events, which mainly occur secondary to lipid profile abnormalities. 8 Epidemiological evidence supports the concept of an in- verse relationship between plasma TG and HDLc levels 9 as well as the importance of this tandem on cardiovascular risk. 10 TG is the driving force of this atherogenic profile. It starts with decreased fatty acid trapping in adipose tissue, which induces increased hepatic synthesis and secretion of TG-rich particles, the very-low-density lipoproteins (VLDLs). 11 These VLDLs are larger, contain more TG, and possess a greater content of apoCIII, the inhibitor of lipoprotein lipase (LPL), compared to apoCII, resulting in reduced LPL activ- ity, and consequently less TG hydrolysis. 12 The resulting lipoprotein particles are poorly recognized by both the low- density lipoprotein-receptor (LDLR) and LRP (LDLR- related protein), which are responsible for their clearance from the circulation. 13 This increases the time that these li- poproteins remain in circulation and allows for the formation of more remnant-like particles (RLPs). Due to the actions of cholesteryl ester transfer protein (CETP) and hepatic lipase 1 Unitat de Recerca en Lı ´pids i Arteriosclerosi, CIBER de Diabetes y Enfermedades Metabo ´licas Asociadas (CIBERDEM), Institut d’Investigacio ´ Sanita `ria Pere Virgili, Universitat Rovira i Virgili, Reus, Spain. 2 Fundacio ´ Lluita contra la Sida, Hospital Universitari Germans Trias i Pujol, Badalona, Universitat Auto `noma de Barcelona, Barcelona, Spain. 3 Universitat de Vic-Universitat Central de Barcelona, Barcelona, Spain. AIDS RESEARCH AND HUMAN RETROVIRUSES Volume 31, Number 00, 2015 ª Mary Ann Liebert, Inc. DOI: 10.1089/aid.2015.0061 1 AID-2015-0061-ver9-Guardiola_1P Type: research-article AID-2015-0061-ver9-Guardiola_1P.3d 07/04/15 11:55am Page 1