Effects of PCSK9 genetic variants on plasma LDL cholesterol levels and risk of premature myocardial infarction in the Italian population

Ilaria Guella, Rosanna Asselta, Diego Ardissino, Pier Angelica Merlini, Flora Peyvandi, Sekar Kathiresan, Pier Mannuccio Mannucci, Marco Tubaro, Stefano Duga

Research output: Contribution to journalArticlepeer-review

Abstract

The R46L variant in the proprotein-convertase subtilisin-kexin type 9 (PCSK9) gene was associated with reduced levels of LDL and total cholesterol and with a lower risk of coronary artery disease. We investigated the association of R46L with myocardial infarction (MI) in 1,880 Italian patients with premature MI and 1,880 controls. A trend toward a protective effect of the L46 allele was observed [odds ratio (OR) = 0.75, 95% confidence interval (CI) = 0.49-1.13; P = 0.17], although the association with MI was not significant. This is probably due to the combined effect of the low frequency of R46L among Italians and of the young age of the analyzed cohort for whom the impact of coronary atherosclerosis is less important. This hypothesis was indirectly confirmed by the significant association found after including 1,056 additional older controls (OR = 0.67, 95% CI = 0.46-0.97; P = 0.036). LDL cholesterol was signifi-cantly lower in L46 carriers (116.2 ± 34.7 mg/dl) than in noncarriers (137.4 ± 47.3 mg/dl; P = 0.00022); a similar reduction was observed for total cholesterol (191.7 ± 37.7 vs. 211.7 ± 49 mg/dl; P = 0.00019). Analysis of 23 additional polymorphisms in the PCSK9 region identified another single nucleotide polymorphism (SNP) (rs11206510) associated with cholesterol levels. We confirmed that the L46 allele not only decreases LDL cholesterol but also protects against MI. Moreover, we replicated the association of total and LDL cholesterol with the SNP rs11206510.

Original languageEnglish
Pages (from-to)3342-3349
Number of pages8
JournalJournal of Lipid Research
Volume51
Issue number11
DOIs
Publication statusPublished - Nov 2010

Keywords

  • Association study
  • Low density lipoprotein
  • Proprotein-convertase subtilisin-kexin type 9 genetic variants

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Endocrinology

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