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. 2010 Nov;51(11):3342-9.
doi: 10.1194/jlr.M010009. Epub 2010 Aug 10.

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

Ilaria Guella  1 , Rosanna Asselta, Diego Ardissino, Pier Angelica Merlini, Flora Peyvandi, Sekar Kathiresan, Pier Mannuccio Mannucci, Marco Tubaro, Stefano Duga
Affiliations

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

Ilaria Guella et al. J Lipid Res. 2010 Nov.

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 significantly 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.

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Figures

Fig. 1.
Fig. 1.
Distribution of plasma LDL and total cholesterol levels in the ATVB population according to the presence or absence of the L46 allele. A: Distribution of plasma LDL cholesterol levels among 2,426 subjects who did not carry the L46 allele (top) is compared with the distribution of levels among the 69 individuals heterozygous for the L46 allele (bottom). B: Distribution of plasma total cholesterol levels among 3,368 subjects who did not carry the L46 allele (top) is compared with the distribution of levels among the 85 individuals heterozygous for the L46 allele (bottom).
Fig. 2.
Fig. 2.
Linkage disequilibrium structure of the PCSK9 locus. The gene structure of PCSK9 is drawn to scale; the gene size is indicated by the ruler at the top of the figure. Pairwise LD values [D'/logarithm of odds (LOD)], estimated for the genotyped SNPs, are represented by boxes: dark gray indicates strong LD, light gray intermediate, whereas white denotes no LD. D' values are shown within the boxes; empty cells are in complete LD. The R46L variant (rs11591147) and the rs11206510 polymorphism located in the promoter region are underlined. The haplotype in block 2 slightly associated with MI is also indicated.
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