Effects of PCSK9 variants on common carotid artery intima media thickness and relation to ApoE alleles

Giuseppe Danilo Norata, Katia Garlaschelli, Liliana Grigore, Sara Raselli, Simona Tramontana, Fiorella Meneghetti, Roberto Artali, Davide Noto, Angelo Baldassare Cefalù, Gherardo Buccianti, Maurizio Averna, Alberico Luigi Catapano

Research output: Contribution to journalArticle

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Abstract

Background: PCSK9 plays a key role in plasma cholesterol metabolism by modulating the expression of LDL receptors. Objective and methods: In this study we investigated the effects of two common polymorphism of the PCSK9 gene (E670G and I474V) on the intima media thickness of the common carotid artery and the possible relation with polymorphisms of apolipoprotein E in 1541 middle aged subjects selected from the general population enrolled in the PLIC study and confirmed the major findings in a second free-living population enrolled in the Ventimiglia study. Results: 670G carriers showed significantly increased plasma total cholesterol, LDL-cholesterol, and Apo levels B while no significant differences were observed between carriers of the I474V SNP. IMT was significantly increased in 670G carriers compared to individuals homozygous for the E allele (0.640 ± 0.102 mm vs. 0.652 ± 0.092 mm, P <0.05). The presence of the 670G allele was also significantly associated with a greater progression of IMT compared to 670EE subjects. Plasma total cholesterol, LDL-cholesterol, apolipoprotein B, and IMT significantly increased from ApoE2;PCSK9-670EE carriers to ApoE4-PCSK9-670G carriers, while no significant differences were observed when the presence of the ApoE alleles was combined with that of the PCSK9 I474V SNP. In silico analysis on wild type and 670G variant showed several structural differences on the interactions of the loops of the "V" domain. Conclusions: The E670G polymorphism of the PCSK9 gene is associated with increased IMT progression in the general population. When the presence of 670G allele is stratified according to the ApoE gene alleles, ApoE2;PCSK9-670EE carriers show a more favorable plasma lipid profile and decreased IMT compared to ApoE4-PCSK9-670G carriers.

Original languageEnglish
Pages (from-to)177-182
Number of pages6
JournalAtherosclerosis
Volume208
Issue number1
DOIs
Publication statusPublished - Jan 2010

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Carotid Intima-Media Thickness
Common Carotid Artery
Apolipoproteins E
Alleles
Apolipoprotein E2
Apolipoprotein E4
Cholesterol
Apolipoproteins B
LDL Cholesterol
Single Nucleotide Polymorphism
Population
Genes
LDL Receptors
Computer Simulation
Lipids

Keywords

  • IMT
  • In silico modeling
  • Molecular genetics
  • PCSK9

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Effects of PCSK9 variants on common carotid artery intima media thickness and relation to ApoE alleles. / Norata, Giuseppe Danilo; Garlaschelli, Katia; Grigore, Liliana; Raselli, Sara; Tramontana, Simona; Meneghetti, Fiorella; Artali, Roberto; Noto, Davide; Cefalù, Angelo Baldassare; Buccianti, Gherardo; Averna, Maurizio; Catapano, Alberico Luigi.

In: Atherosclerosis, Vol. 208, No. 1, 01.2010, p. 177-182.

Research output: Contribution to journalArticle

Norata, GD, Garlaschelli, K, Grigore, L, Raselli, S, Tramontana, S, Meneghetti, F, Artali, R, Noto, D, Cefalù, AB, Buccianti, G, Averna, M & Catapano, AL 2010, 'Effects of PCSK9 variants on common carotid artery intima media thickness and relation to ApoE alleles', Atherosclerosis, vol. 208, no. 1, pp. 177-182. https://doi.org/10.1016/j.atherosclerosis.2009.06.023
Norata, Giuseppe Danilo ; Garlaschelli, Katia ; Grigore, Liliana ; Raselli, Sara ; Tramontana, Simona ; Meneghetti, Fiorella ; Artali, Roberto ; Noto, Davide ; Cefalù, Angelo Baldassare ; Buccianti, Gherardo ; Averna, Maurizio ; Catapano, Alberico Luigi. / Effects of PCSK9 variants on common carotid artery intima media thickness and relation to ApoE alleles. In: Atherosclerosis. 2010 ; Vol. 208, No. 1. pp. 177-182.
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abstract = "Background: PCSK9 plays a key role in plasma cholesterol metabolism by modulating the expression of LDL receptors. Objective and methods: In this study we investigated the effects of two common polymorphism of the PCSK9 gene (E670G and I474V) on the intima media thickness of the common carotid artery and the possible relation with polymorphisms of apolipoprotein E in 1541 middle aged subjects selected from the general population enrolled in the PLIC study and confirmed the major findings in a second free-living population enrolled in the Ventimiglia study. Results: 670G carriers showed significantly increased plasma total cholesterol, LDL-cholesterol, and Apo levels B while no significant differences were observed between carriers of the I474V SNP. IMT was significantly increased in 670G carriers compared to individuals homozygous for the E allele (0.640 ± 0.102 mm vs. 0.652 ± 0.092 mm, P <0.05). The presence of the 670G allele was also significantly associated with a greater progression of IMT compared to 670EE subjects. Plasma total cholesterol, LDL-cholesterol, apolipoprotein B, and IMT significantly increased from ApoE2;PCSK9-670EE carriers to ApoE4-PCSK9-670G carriers, while no significant differences were observed when the presence of the ApoE alleles was combined with that of the PCSK9 I474V SNP. In silico analysis on wild type and 670G variant showed several structural differences on the interactions of the loops of the {"}V{"} domain. Conclusions: The E670G polymorphism of the PCSK9 gene is associated with increased IMT progression in the general population. When the presence of 670G allele is stratified according to the ApoE gene alleles, ApoE2;PCSK9-670EE carriers show a more favorable plasma lipid profile and decreased IMT compared to ApoE4-PCSK9-670G carriers.",
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AU - Grigore, Liliana

AU - Raselli, Sara

AU - Tramontana, Simona

AU - Meneghetti, Fiorella

AU - Artali, Roberto

AU - Noto, Davide

AU - Cefalù, Angelo Baldassare

AU - Buccianti, Gherardo

AU - Averna, Maurizio

AU - Catapano, Alberico Luigi

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AB - Background: PCSK9 plays a key role in plasma cholesterol metabolism by modulating the expression of LDL receptors. Objective and methods: In this study we investigated the effects of two common polymorphism of the PCSK9 gene (E670G and I474V) on the intima media thickness of the common carotid artery and the possible relation with polymorphisms of apolipoprotein E in 1541 middle aged subjects selected from the general population enrolled in the PLIC study and confirmed the major findings in a second free-living population enrolled in the Ventimiglia study. Results: 670G carriers showed significantly increased plasma total cholesterol, LDL-cholesterol, and Apo levels B while no significant differences were observed between carriers of the I474V SNP. IMT was significantly increased in 670G carriers compared to individuals homozygous for the E allele (0.640 ± 0.102 mm vs. 0.652 ± 0.092 mm, P <0.05). The presence of the 670G allele was also significantly associated with a greater progression of IMT compared to 670EE subjects. Plasma total cholesterol, LDL-cholesterol, apolipoprotein B, and IMT significantly increased from ApoE2;PCSK9-670EE carriers to ApoE4-PCSK9-670G carriers, while no significant differences were observed when the presence of the ApoE alleles was combined with that of the PCSK9 I474V SNP. In silico analysis on wild type and 670G variant showed several structural differences on the interactions of the loops of the "V" domain. Conclusions: The E670G polymorphism of the PCSK9 gene is associated with increased IMT progression in the general population. When the presence of 670G allele is stratified according to the ApoE gene alleles, ApoE2;PCSK9-670EE carriers show a more favorable plasma lipid profile and decreased IMT compared to ApoE4-PCSK9-670G carriers.

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