title: Influence of PCSK9 polymorphisms on plasma lipids and response to atorvastatin treatment in Brazilian subjects.
abstract: BACKGROUND
  The proprotein convertase subtilisin/kexin type 9 (PCSK9) has a key role in the regulation of plasma low-density lipoprotein (LDL) cholesterol by enhancing the degradation of LDL receptor. Functional variants in PCSK9 have been associated with differences in plasma lipids and may contribute to the variability of the response to cholesterol-lowering drugs.
  
  
  OBJECTIVE
  To investigate the influence of PCSK9 variants on plasma lipid profile and response to atorvastatin in Brazilian subjects.
  
  
  METHODS
  PCSK9 E670G, I474V, and R46L single nucleotide polymorphisms (SNPs) and plasma lipids were evaluated in 163 hypercholesterolemics (HC) and 171 normolipidemics (NL). HC patients with indication for cholesterol-lowering drug therapy (n = 128) were treated with atorvastatin (10 mg/d/4 wk). PCSK9 SNPs were analyzed by real time polymerase chain reaction.
  
  
  RESULTS
  Frequencies of the PCSK9 SNPs were similar between the HC and NL groups. Logistic regression analysis showed a trend of association between PCSK9 E670G and hypercholesterolemia after adjustment for covariates (P = .059). The 670G allele was associated with high basal levels of LDL cholesterol (P = .03) in HC patients using the extreme discordant phenotype method. No association tests were performed for R46L variant because of its very low frequency, whereas the I474V polymorphism and PCSK9 haplotypes were not related to hypercholesterolemia or variability on plasma lipids in both NL and HC groups (P > .05). LDL cholesterol reduction in response to atorvastatin was not influenced by PCSK9 genotypes or haplotypes.
  
  
  CONCLUSIONS
  PCSK9 E670G polymorphism but not I474V contributes to the variability on plasma LDL cholesterol levels in hypercholesterolemic subjects. Both PCSK9 variants have no influence on cholesterol-lowering response to atorvastatin.
authors.affiliation: School of Pharmaceutical Sciences, University of Sao Paulo, Av. Prof. Lineu Prestes, 580, B17, Sao Paulo 05508-000, SP, Brazil.
authors.forename: Jacqueline M
authors.initials: JM
authors.lastname: Anderson
authors.affiliation: School of Pharmaceutical Sciences, University of Sao Paulo, Av. Prof. Lineu Prestes, 580, B17, Sao Paulo 05508-000, SP, Brazil; Center of Molecular Biology and Pharmacogenetics, Scientific and Technological Bioresource Nucleus, Universidad de la Frontera, Temuco, Chile.
authors.forename: Alvaro
authors.initials: A
authors.lastname: Cerda
authors.affiliation: School of Pharmaceutical Sciences, University of Sao Paulo, Av. Prof. Lineu Prestes, 580, B17, Sao Paulo 05508-000, SP, Brazil.
authors.forename: Mario H
authors.initials: MH
authors.lastname: Hirata
authors.affiliation: Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, SP, Brazil.
authors.forename: Alice C
authors.initials: AC
authors.lastname: Rodrigues
authors.affiliation: University Hospital, University of Sao Paulo, Sao Paulo, SP, Brazil.
authors.forename: Egidio L
authors.initials: EL
authors.lastname: Dorea
authors.affiliation: University Hospital, University of Sao Paulo, Sao Paulo, SP, Brazil.
authors.forename: Marcia M S
authors.initials: MM
authors.lastname: Bernik
authors.affiliation: Dante Pazzanese Institute of Cardiology, Sao Paulo, SP, Brazil.
authors.forename: Marcelo C
authors.initials: MC
authors.lastname: Bertolami
authors.affiliation: Dante Pazzanese Institute of Cardiology, Sao Paulo, SP, Brazil.
authors.forename: Andre A
authors.initials: AA
authors.lastname: Faludi
authors.affiliation: School of Pharmaceutical Sciences, University of Sao Paulo, Av. Prof. Lineu Prestes, 580, B17, Sao Paulo 05508-000, SP, Brazil. Electronic address: rosariohirata@usp.br.
authors.forename: Rosario D C
authors.initials: RD
authors.lastname: Hirata
mesh_terms: D000328:Adult; D000368:Aged; D000069059:Atorvastatin; D054316:Biomarkers, Pharmacological / Q000378:metabolism*; D001938:Brazil; D008078:Cholesterol, LDL / Q000378:metabolism*; D005260:Female; D006538:Heptanoic Acids / Q000008:administration & dosage; D006801:Humans; D006937:Hypercholesterolemia / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases / Q000235:genetics* / Q000378:metabolism; D011758:Pyrroles / Q000008:administration & dosage; D012697:Serine Endopeptidases / Q000235:genetics* / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D054316:Biomarkers, Pharmacological; D008078:Cholesterol, LDL; D006538:Heptanoic Acids; D011758:Pyrroles; D000069059:Atorvastatin; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases
keywords: Atorvastatin; Cholesterol; Pharmacogenomics; Proprotein convertase subtilisin/kexin type 9 (PCSK9); Single nucleotide polymorphism