Effects of PCSK9 variants on common carotid artery intima media thickness and relation to ApoE alleles.
BACKGROUND
PCSK9 plays a key role in plasma cholesterol metabolism by modulating the expression of LDL receptors.


OBJECTIVE
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+/-0.102mm vs. 0.652+/-0.092mm, 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.
Norata
Giuseppe Danilo
GD
Department of Pharmacological Sciences, Università degli Studi di Milano, Via Balzaretti 9, Milan, Italy. Danilo.Norata@unimi.it
Garlaschelli
Katia
K
Grigore
Liliana
L
Raselli
Sara
S
Tramontana
Simona
S
Meneghetti
Fiorella
F
Artali
Roberto
R
Noto
Davide
D
Cefalù
Angelo Baldassare
AB
Buccianti
Gherardo
G
Averna
Maurizio
M
Catapano
Alberico Luigi
AL
D000483:Alleles; D001057:Apolipoproteins E / Q000235:genetics*; D017536:Carotid Artery, Common / Q000473:pathology*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases / Q000235:genetics*; D017539:Tunica Intima / Q000473:pathology*; D017540:Tunica Media / Q000473:pathology*
D001057:Apolipoproteins E; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases