Abstract
Background/PurposeGenetic variation in proprotein convertase subtilisin/kexin type 9 (PCSK9) gene has been recently identified as an important determinant of plasma LDL-cholesterol and severity of coronary heart disease. We studied whether the PCSK9 gene is linked to the risk of ischemic stroke (IS) and with the development of intracranial atherosclerosis.Methods/ResultsThe pivotal E670G polymorphism, tagging an important haplotype of the PCSK9 gene, was genotyped in two independent studies. The Belgium Stroke Study included 237 middle aged (45–60) Belgian patients, with small-vessel occlusion (SVO) and large-vessel atherosclerosis stroke (LVA), and 326 gender and ethnicity matched controls (>60 yrs) without a history of stroke. In multivariate analysis the minor allele (G) carriers appeared as a significant predictor of LVA (OR = 3.52, 95% CI 1.25–9.85; p = 0.017). In a Finnish crossectional population based consecutive autopsy series of 604 males and females (mean age 62.5 years), G-allele carriers tended to have more severe allele copy number-dependent (p = 0.095) atherosclerosis in the circle of Willis and in its branches.ConclusionOur findings in this unique combination of clinical and autopsy data, provide evidence that PCSK9 gene associates with the risk of LVA stroke subtype, and suggest that the risk is mediated by the severity of intracranial atherosclerosis.
Highlights
Familial predisposition has a modest effect (odds ratio (OR) 1.3– 1.76) to the risk of stroke in general [1]
The main observation of this study was that the E670G SNP of Proprotein convertase subtilisin/kexin type 9 (PCSK9) gene associated significantly with large-vessel atherosclerosis (LVA) stroke risk in the Belgian population
The same allele tended to associate with increased atherosclerosis of the large intracerebral arteries in an independent Finnish autopsy study, with a gene dose effect
Summary
Familial predisposition has a modest effect (odds ratio (OR) 1.3– 1.76) to the risk of stroke in general [1]. Proprotein convertase subtilisin/kexin type 9 (PCSK9), a serine protease, has recently gain a lot of attention because of its major role in regulation of plasma low density lipoprotein (LDL) cholesterol levels [5] [6] [7] [8] [9] [10] and in determining coronary heart disease (CHD) risk [6] [11] [12]. PCSK9 promotes degradation of the low density lipoprotein receptors (LDLR) in liver through an unknown posttranscriptional mechanism [13] In the large long-term Atherosclerosis Risk in Communities study, some sequence variations of the PCSK9 gene associated both with low LDL cholesterol levels and reduced incidence of coronary events [6]. The G allele has been observed to relate to polygenic hypercholesterolemia in men [14]
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