ORIGINAL ARTICLE ESR1 polymorphisms and statin therapy: a sex-specific approach L Smiderle 1 , M Fiegenbaum 1,2 , MH Hutz 3 , CR Van Der Sand 4 , LC Van Der Sand 4 , MEW Ferreira 4 , RC Pires 4 and S Almeida 1,2 Lipid-lowering therapy has shown a high degree of variability in clinical response and there is evidence that the variability in drug response between individuals is due to genetic factors. Thirteen single nucleotide polymorphisms (SNPs) within the ESR1 gene were evaluated with basal lipid and lipoprotein levels, as well as response to lipid-lowering therapy, in 495 hypercholesterolemic individuals of European descent receiving simvastatin or atorvastatin. Significant associations were detected between rs4870061 (P = 0.040, corrected P-value (PC) = 0.440), rs1801132 (P = 0.002, PC = 0.022) and the SNP rs3020314 (P = 0.013, PC = 0.143) with triglyceride (TG) baseline levels. The rs4870061 was also associated with high-density lipoprotein cholesterol (HDL-C) baseline levels (P = 0.045, PC = 0.495). Regarding statin efficacy, rs2234693 C/C was associated with greater HDL-C increase (P = 0.037; PC = 0.407) and rs3798577 T allele was associated with greater total cholesterol (TC) reduction (P = 0.019; PC = 0.209) and greater TG reduction (P = 0.026; PC = 0.286). These associations suggest that ESR1 polymorphisms are in part responsible for the TC, HDL-C and TG variation levels and this effect may be sex-specific. The Pharmacogenomics Journal advance online publication, 25 August 2015; doi:10.1038/tpj.2015.60 INTRODUCTION Statin therapy shows high efficacy in reducing total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and triglycerides (TG). 1 However, there is a high degree of variability in the clinical response to statins, 2 and many studies have indicated that this variability is due to genetic factors. 2–4 It is estimated that the variability in drug disposition and effect is 20–95% dependent on genetic background 5 and that a significant proportion of basal high-density lipoprotein cholesterol (HDL-C) variability is due to genetic factors. 6 Candidate genes that regulate the pharmacokinetic and pharmaco- dynamic properties of statins are promising targets. The pharma- cokinetic and pharmacodynamic pathways that regulate statin have been extensively studied; 3,7–16 however, this only explains a small part of the observed variation in statin response. Estrogens are important regulators of metabolic homeostasis and lipid metabolism that act through cognate nuclear hormone receptors. The estrogen receptors (ERα and β) are ligand-activated transcription factors that regulate many genomic events. 17 When ERα is activated, transcription complexes are recruited to estrogen- responsive genes, where they act to initiate transcription or modify the local chromatin structure, 18 ultimately leading to activation of the estrogen response. ERα has been demonstrated to influence the expression of proteins involved in the regulation of plasma lipid metabolism such as apolipoprotein E 19 and LDL receptor. 20 ERα is encoded by ESR1, 21 and several single nucleotide polymorphisms (SNPs) have been involved in mediating the effects of estrogen on LDL-C, HDL-C and TG metabolism. 22–24 Men and women show significant differences with regard to the risk of cardiovascular disease (CVD) development, 25 which may be the result of sex-specific differences in gene regulatory mechanisms, particularly those governed by the response to sex hormones. 26,27 A review from Yoon 28 suggests that sexual dimorphism and the ERs (α and β) are involved in the response to lipid-lowering therapy. To our knowledge, there is only one study in the literature evaluating ESR1 polymorphisms and response to statin therapy. Kajinami et al. 7 tested two ESR1 polymorphisms (rs2234693 and rs9340799) in the context of atorvastatin (10 mg) response in hypercholesterolemic patients and observed a sex-specific association with HDL-C levels. Thus, the study of polymorphisms in ER genes may help determine the role of genetic variability in the response to lipid-lowering therapy. Additionally, this approach might identify potential sex-specific characteristics involved in pharmacological efficacy. The present work evaluates the association of ESR1 polymor- phisms with baseline lipid and lipoprotein levels and with the efficacy of atorvastatin/simvastatin lipid-lowering therapy in a patient cohort of European descent from Porto Alegre, the southernmost city of Brazil. METHODS Patients This prospective cohort study was conducted with 495 hypercholesterolemic patients (331 women and 164 men) receiving simvastatin or atorvastatin. The inclusion criteria were the use of simvastatin or atorvastatin and European ascendancy (ascertained by skin color and morphological characteristics). The exclusion criteria were: age lower than 20 years, TG concentration of 4.52 mmol l - 1 or higher, altered thyroid-stimulating hormone levels, impaired hepatic or renal function, an unstable or uncontrolled clinically significant disease and had previously undergone therapy with other lipid- lowering drugs within less than 6 months. Physical examinations, clinical 1 Programa de Pós-Graduação em Ciências da Saúde, Universidade Federal de Ciências da Saúde de Porto Alegre – UFCSPA, Porto Alegre, Brazil; 2 Departamento de Ciências Básicas da Saúde, Universidade Federal de Ciências da Saúde de Porto Alegre – UFCSPA, Porto Alegre, Brazil; 3 Departamento de Genética, Universidade Federal do Rio Grande do Sul – UFRGS, Porto Alegre, Brazil and 4 Centro de Diagnóstico Cardiológico, Porto Alegre, Brazil. Correspondence: Professor S Almeida, Programa de Pós-Graduação em Ciências da Saúde, Universidade Federal de Ciências da Saúde de Porto Alegre – UFCSPA, Rua: Sarmento Leite 245 – sala 309, Porto Alegre 90050-170, Brazil. E-mail: silvana.almeida@pq.cnpq.br Received 23 April 2015; revised 28 June 2015; accepted 1 July 2015 The Pharmacogenomics Journal (2015), 1 – 7 © 2015 Macmillan Publishers Limited All rights reserved 1470-269X/15 www.nature.com/tpj