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 theregulation of plasma low-density lipoprotein (LDL) cholesterol by enhancing the degradation ofLDL receptor. Functional variants in PCSK9 have been associated with differences in plasma lipidsand 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 toatorvastatin in Brazilian subjects.METHODS: PCSK9 E670G, I474V, and R46L single nucleotide polymorphisms (SNPs) and plasmalipids were evaluated in 163 hypercholesterolemics (HC) and 171 normolipidemics (NL). HC patientswith indication for cholesterol-lowering drug therapy (n 5 128) 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. Logisticregression analysis showed a trend of association between PCSK9 E670G and hypercholesterolemiaafter adjustment for covariates (P 5 .059). The 670G allele was associated with high basal levels ofLDL cholesterol (P 5 .03) in HC patients using the extreme discordant phenotype method. Noassociation tests were performed for R46L variant because of its very low frequency, whereas theI474V polymorphism and PCSK9 haplotypes were not related to hypercholesterolemia or variabilityon plasma lipids in both NL and HC groups (P ..05). LDL cholesterol reduction in response to atorvastatinwas not influenced by PCSK9 genotypes or haplotypes.CONCLUSIONS: PCSK9 E670G polymorphism but not I474V contributes to the variability onplasma LDL cholesterol levels in hypercholesterolemic subjects. Both PCSK9 variants have no influenceon cholesterol-lowering response to atorvastatin. 2014 National Lipid Association. All rights reserved.