Influence of PCSK9 polymorphisms on plasma lipids and response to atorvastatin treatment in Brazilian subjects

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• 作者：Jacqueline M. Anderson ; PharmD^a ; Alvaro Cerda ; PhD^a ; ^b ; Mario H. Hirata ; PhD^a ; Alice C. Rodrigues ; PhD^c ; Egidio L. Dorea ; PhD^d ; Marcia M.S. Bernik ; PhD^d ; Marcelo C. Bertolami ; PhD^e ; Andre A. Faludi ; PhD^e ; Rosario D.C. Hirata ; PhD^a ; ^{rosariohirata@usp.br" class="auth_mail}
• 关键词：Proprotein convertase subtilisin/kexin type 9 (PCSK9) ; Single nucleotide polymorphism ; Cholesterol ; Atorvastatin ; Pharmacogenomics
• 刊名：Journal of Clinical Lipidology
• 出版年：May-June 2014
• 年：2014
• 卷：8
• 期：3
• 页码：256-264
• 全文大小：242 K

文摘

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.