title: Impact of 3'UTR genetic variants in PCSK9 and LDLR genes on plasma lipid traits and response to atorvastatin in Brazilian subjects: a pilot study.
abstract: BACKGROUND
  Hypercholesterolemia is a complex trait, resulting from a genetic interaction with lifestyle habits. Polymorphisms are a major source of genetic heterogeneity, and variations in 2 key cholesterol homeostasis genes; low-density lipoprotein receptor (LDLR) and proprotein convertase subtilisin/kexin type-9 (PCSK9), lead to dyslipidemia. So, we investigated the relation of 2 variants located in the 3'-UTR (3'-untranslated region) of LDLR (rs14158, G>A) and PCSK9 (rs17111557, C>T) with lipid profile and atorvastatin response.
  
  
  METHODS
  SNP influence on lipid profile was assessed in hypercholesterolemic patients (HC; n = 89) using atorvastatin (10 mg/day/4 weeks) and in normolipidemic subjects (NL; n = 171). Genotyping was completed through real-time PCR using TaqMan assays.
  
  
  RESULTS
  rs14158 G allele was higher in HC than in NL group (P = 0.043). NL subjects carrying the T allele of the PCSK9 variant had lower high-density lipoprotein cholesterol (HDL-c) than C allele carriers (P = 0.009). There was no association between LDLR and PCSK9 SNPs and atorvastatin response. Additionally, the PCSK9 variant creates a microRNA interaction site, which could implicate an epigenetic mechanism in PCSK9-dependent HDL-C regulation.
  
  
  CONCLUSIONS
  The rs14158 SNP contributes to hypercholesterolemia. Also, a putative microRNA regulation may influence HDL-C variability observed in rs17111557 carriers. Cholesterol-lowering response to atorvastatin is not influenced by LDLR and PCSK9 variants.
authors.affiliation: School of Pharmaceutical Sciences, University of Sao Paulo São Paulo, Brazil ; Center of Molecular Biology and Pharmacogenetics, Scientific and Technological Bioresource Nucleus (BIOREN), Universidad de La Frontera Temuco, Chile.
authors.forename: Tomás
authors.initials: T
authors.lastname: Zambrano
authors.affiliation: School of Pharmaceutical Sciences, University of Sao Paulo São Paulo, Brazil.
authors.forename: Mario Hiroyuki
authors.initials: MH
authors.lastname: Hirata
authors.affiliation: School of Pharmaceutical Sciences, University of Sao Paulo São Paulo, Brazil ; Center of Molecular Biology and Pharmacogenetics, Scientific and Technological Bioresource Nucleus (BIOREN), Universidad de La Frontera Temuco, Chile.
authors.forename: Álvaro
authors.initials: Á
authors.lastname: Cerda
authors.affiliation: University Hospital, University of Sao Paulo São Paulo, Brazil.
authors.forename: Egidio L
authors.initials: EL
authors.lastname: Dorea
authors.affiliation: University Hospital, University of Sao Paulo São Paulo, Brazil.
authors.forename: Gelba A
authors.initials: GA
authors.lastname: Pinto
authors.affiliation: University Hospital, University of Sao Paulo São Paulo, Brazil.
authors.forename: Maria C
authors.initials: MC
authors.lastname: Gusukuma
authors.affiliation: Institute Dante Pazzanese of Cardiology Sao Paulo, Brazil.
authors.forename: Marcelo C
authors.initials: MC
authors.lastname: Bertolami
authors.affiliation: Center of Molecular Biology and Pharmacogenetics, Scientific and Technological Bioresource Nucleus (BIOREN), Universidad de La Frontera Temuco, Chile.
authors.forename: Luis A
authors.initials: LA
authors.lastname: Salazar
authors.affiliation: School of Pharmaceutical Sciences, University of Sao Paulo São Paulo, Brazil.
authors.forename: Rosario Dominguez Crespo
authors.initials: RD
authors.lastname: Hirata
keywords: Atorvastatin; LDLR; PCSK9; cholesterol; microRNAs; polymorphism