RXRc gene variants are associated with HIV lipodystrophy Sudeep P. Pushpakom a,b , Andrew Owen b , David J. Back b and Munir Pirmohamed a,b HIV lipodystrophy (HIVLD), associated with combination antiretroviral therapy (cART), leads to metabolic and cardiovascular diseases. Nuclear receptors play a central role in lipid homoeostasis and drug disposition; their genetic variants may predispose an individual to the development of HIVLD. DNA samples obtained from cART-treated HIV-positive patients with (HIVLD + ; 124) and without (HIVLD – ; 56) HIVLD were genotyped for 77 single nucleotide polymorphisms in nine nuclear receptor genes. Statistical analysis was carried out using Haploview software and by logistic regression. Three single nucleotide polymorphisms in RXRc (rs2134095, rs113471, rs2194899) and its haplotypes (HIVLD + , 54%; HIVLD – , 40.6%; P = 0.02) showed significant association with HIVLD. Multivariate analysis identified time since diagnosis (P = 0.001) and carriage of the RXRc haplotype (P = 0.02) to be independently associated with HIVLD. Genetic variation in RXRc, a common binding partner of nuclear receptors that modulate lipid homoeostasis and drug disposition, may contribute to the development of HIVLD in cART-treated HIV patients. These results need replication in other cohorts. Pharmacogenetics and Genomics 23:438–441  c 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins. Pharmacogenetics and Genomics 2013, 23:438–441 Keywords: gene variation, HIV lipodystrophy, HIV-associated lipodystrophy, nuclear receptors, pharmacogenetics, RXR, single nucleotide polymorphisms a NIHR Biomedical Research Centre, Royal Liverpool Hospital and b Department of Molecular and Clinical Pharmacology, The Wolfson Centre for Personalised Medicine, University of Liverpool, Liverpool, UK Correspondence to Sudeep P. Pushpakom, MPharm, PhD, Department of Molecular and Clinical Pharmacology, The Wolfson Centre for Personalised Medicine, University of Liverpool, Block A, Waterhouse Buildings, 1-5 Brownlow Street, Liverpool L69 3GL, UK Tel: + 44 151 795 5404; fax: + 44 151 794 5540; e-mail: sudeepp@liv.ac.uk Received 15 November 2012 Accepted 1 May 2013 Introduction HIV lipodystrophy (HIVLD) is an important adverse effect of combination antiretroviral therapy (cART) with a prevalence of 38.8% [1]; it is also a risk factor for type 2 diabetes and cardiovascular disease [1]. HIVLD is characterized by abnormal body fat redistribution (lipo- atrophy, visceral lipid hypertrophy), insulin resistance and dyslipidemia. A role for genetic factors has been suggested in HIVLD pathogenesis; however, there are few data on this. HIV treatment is life-long; it is therefore important to identify the potential predisposing factors for HIVLD. Nuclear receptors are ligand-activated transcription factors that play a central role in maintaining cellular and whole-body lipid homoeostases. Liver X receptors (LXRa, LXRb), peroxisome proliferator-activated recep- tors (PPARa, PPARg), the farnesoid X receptor (FXR) and their common binding partner, retinoid X receptors (RXRa, RXRb and RXRg), regulate the activation of genes involved in cholesterol transport, cholesterol efflux and high-density lipoprotein metabolism [2]. FXR and LXR together regulate the cellular lipid content by activation of SREBP1c, a master regulator of de-novo lipogenesis [3]. They also regulate the peripheral tissue uptake and efflux of lipids and their reverse transport into the intestinal enterocytes before their secretion into bile or conversion into bile acids. Nuclear receptors also regulate the expression of drug disposition genes [4]. The pregnane X receptor (PXR) regulates the expression of CYP3A4, ABCC2 and ABCB1, all of which are involved in antiretroviral drug disposition. The constitutive androstane receptor (CAR) regulates UGT1A1 and ABCC2 [4]; FXR regulates CYP3A4 and ABCC2; and hepatocyte nuclear factor 4a (HNF4a) is a critical determinant of PXR-mediated and CAR-mediated induction [4]. Table 1 details various gene targets of nuclear receptors. Single nucleotide polymorphisms (SNPs) in nuclear receptor genes could therefore influence the control of lipid homoeostasis and/or affect antiretroviral drug disposition, accentuating toxicity and thereby contributing to the development of HIVLD. We genotyped nine nuclear receptors to investigate whether their gene variants contributed to HIVLD. Patients and methods Patients Demographic and clinical characteristics of the study population have been published previously [5]. Local research ethics committee approvals and written in- formed consent from all patients were obtained. The diagnosis of HIVLD was based either on the clinician’s confirmation of the patient’s self-report or on the clinician’s observation alone after the initiation of Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (www.pharmacogeneticsandgenomics.com). 438 Short communication 1744-6872  c 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins DOI: 10.1097/FPC.0b013e328362cfc6 Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.