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      The Influence of OLR1 and PCSK9 Gene Polymorphisms on Ischemic Stroke: Evidence from a Meta-Analysis

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          Abstract

          Both OLR1 and PCSK9 genes are associated with atherosclerosis, cardiovascular disease and ischemic stroke. The overall prevalence of PCSK9 rs505151 and OLR1 rs11053646 variants in ischemic stroke were 0.005 and 0.116, respectively. However, to date, association between these polymorphisms and ischemic stroke remains inconclusive. Therefore, this first meta-analysis was carried out to clarify the presumed influence of these polymorphisms on ischemic stroke. All eligible case-control and cohort studies that met the search terms were retrieved in multiple databases. Demographic and genotyping data were extracted from each study, and the meta-analysis was performed using RevMan 5.3 and Metafor R 3.2.1. The pooled odd ratios (ORs) and 95% confidence intervals (CIs) were calculated using both fixed- and random-effect models. Seven case-control studies encompassing 1897 cases and 2119 controls were critically evaluated. Pooled results from the genetic models indicated that OLR1 rs11053646 dominant (OR = 1.33, 95%  CI:1.11–1.58) and co-dominant models (OR = 1.24, 95%  CI:1.02–1.51) were significantly associated with ischemic stroke. For the PCSK9 rs505151 polymorphism, the OR of co-dominant model (OR = 1.36, 95%  CI:1.01–1.58) was found to be higher among ischemic stroke patients. In conclusion, the current meta-analysis highlighted that variant allele of OLR1 rs11053646 G > C and PCSK9 rs505151 A > G may contribute to the susceptibility risk of ischemic stroke.

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          Binding of proprotein convertase subtilisin/kexin type 9 to epidermal growth factor-like repeat A of low density lipoprotein receptor decreases receptor recycling and increases degradation.

          Proprotein convertase subtilisin/kexin type 9 (PCSK9) promotes degradation of hepatic low density lipoprotein receptors (LDLR), the major route of clearance of circulating cholesterol. Gain-of-function mutations in PCSK9 cause hypercholesterolemia and premature atherosclerosis, whereas loss-of-function mutations result in hypocholesterolemia and protection from heart disease. Recombinant human PCSK9 binds the LDLR on the surface of cultured hepatocytes and promotes degradation of the receptor after internalization. Here we localized the site of binding of PCSK9 within the extracellular domain of the LDLR and determined the fate of the receptor after PCSK9 binding. Recombinant human PCSK9 interacted in a sequence-specific manner with the first epidermal growth factor-like repeat (EGF-A) in the EGF homology domain of the human LDLR. Similar binding specificity was observed between PCSK9 and purified EGF-A. Binding to EGF-A was calcium-dependent and increased dramatically with reduction in pH from 7 to 5.2. The addition of PCSK9, but not heat-inactivated PCSK9, to the medium of cultured hepatocytes resulted in redistribution of the receptor from the plasma membrane to lysosomes. These data are consistent with a model in which PCSK9 binding to EGF-A interferes with an acid-dependent conformational change required for receptor recycling. As a consequence, the LDLR is rerouted from the endosome to the lysosome where it is degraded.
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            Cross-talk between LOX-1 and PCSK9 in vascular tissues.

            Lectin-like ox-LDL receptor-1 (LOX-1) plays an important role in inflammatory diseases, such as atherosclerosis. Proprotein convertase subtilisin/kexin type 9 (PCSK9) modulates LDL receptor degradation and influences serum LDL levels. The present study was designed to investigate the possible interaction between PCSK9 and LOX-1.
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              The proprotein convertases, 20 years later.

              The proprotein convertases (PCs) are secretory mammalian serine proteinases related to bacterial subtilisin-like enzymes. The family of PCs comprises nine members, PC1/3, PC2, furin, PC4, PC5/6, PACE4, PC7, SKI-1/S1P, and PCSK9 (Fig. 3.1). While the first seven PCs cleave after single or paired basic residues, the last two cleave at non-basic residues and the last one PCSK9 only cleaves one substrate, itself, for its activation. The targets and substrates of these convertases are very varied covering many aspects of cellular biology and communication. While it took more than 22 years to begin to identify the first member in 1989-1990, in less than 14 years they were all characterized. So where are we 20 years later in 2011? We have now reached a level of maturity needed to begin to unravel the mechanisms behind the complex physiological functions of these PCs both in health and disease states. We are still far away from comprehensively understanding the various ramifications of their roles and to identify their physiological substrates unequivocally. How do these enzymes function in vivo? Are there other partners to be identified that would modulate their activity and/or cellular localization? Would non-toxic inhibitors/silencers of some PCs provide alternative therapies to control some pathologies and improve human health? Are there human SNPs or mutations in these PCs that correlate with disease, and can these help define the finesses of their functions and/or cellular sorting? The more we know about a given field, the more questions will arise, until we are convinced that we have cornered the important angles. And yet the future may well reserve for us many surprises that may allow new leaps in our understanding of the fascinating biology of these phylogenetically ancient eukaryotic proteases (Fig. 3.2) implicated in health and disease, which traffic through the cells via multiple sorting pathways (Fig. 3.3).
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                Author and article information

                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group
                2045-2322
                15 December 2015
                2015
                : 5
                : 18224
                Affiliations
                [1 ]Institute of Bioproduct Development and Department of Bioprocess Engineering, Faculty of Chemical Engineering, Universiti Teknologi Malaysia , 81300 Johor, Malaysia
                [2 ]Genomics Research Centre, Institute of Health and Biomedical Innovation, Queensland University of Technology , Musk Avenue, Kelvin Grove, QLD 4059, Australia
                [3 ]Innovation Centre in Agritechnology, Universiti Teknologi Malaysia , 81300 Johor, Malaysia
                [4 ]Department of Medicine, Taiping Hospital , Jalan Tamingsari, 34000 Taiping, Perak, Malaysia
                [5 ]Medical Department and Clinical Research Centre, Hospital Seberang Jaya , Jalan Tun Hussein Onn, 13700 Seberang Jaya, Pulau Pinang, Malaysia
                [6 ]Centre for Biodiversity Research, Universiti Tunku Abdul Rahman , Bandar Barat, 31900 Kampar, Perak, Malaysia
                [7 ]Department of Biological Science, Faculty of Science, Universiti Tunku Abdul Rahman , Bandar Barat, 31900 Kampar, Perak, Malaysia
                Author notes
                Article
                srep18224
                10.1038/srep18224
                4678327
                26666837
                e10d6fef-4527-40fe-a4f7-d039b430bbf1
                Copyright © 2015, Macmillan Publishers Limited

                This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

                History
                : 13 August 2015
                : 16 November 2015
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