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Population-Specific Associations of Deleterious Rare Variants in Coding Region of P2RY1–P2RY12 Purinergic Receptor Genes in Large-Vessel Ischemic Stroke Patients

The contribution of low-frequency and damaging genetic variants associated with platelet function to ischemic stroke (IS) susceptibility remains unknown. We employed a deep re-sequencing approach in Polish patients in order to investigate the contribution of rare variants (minor allele frequency, MA...

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Autores principales: Janicki, Piotr K., Eyileten, Ceren, Ruiz-Velasco, Victor, Sedeek, Khaled Anwar, Pordzik, Justyna, Czlonkowska, Anna, Kurkowska-Jastrzebska, Iwona, Sugino, Shigekazu, Imamura-Kawasawa, Yuka, Mirowska-Guzel, Dagmara, Postula, Marek
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5751280/
https://www.ncbi.nlm.nih.gov/pubmed/29232918
http://dx.doi.org/10.3390/ijms18122678
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author Janicki, Piotr K.
Eyileten, Ceren
Ruiz-Velasco, Victor
Sedeek, Khaled Anwar
Pordzik, Justyna
Czlonkowska, Anna
Kurkowska-Jastrzebska, Iwona
Sugino, Shigekazu
Imamura-Kawasawa, Yuka
Mirowska-Guzel, Dagmara
Postula, Marek
author_facet Janicki, Piotr K.
Eyileten, Ceren
Ruiz-Velasco, Victor
Sedeek, Khaled Anwar
Pordzik, Justyna
Czlonkowska, Anna
Kurkowska-Jastrzebska, Iwona
Sugino, Shigekazu
Imamura-Kawasawa, Yuka
Mirowska-Guzel, Dagmara
Postula, Marek
author_sort Janicki, Piotr K.
collection PubMed
description The contribution of low-frequency and damaging genetic variants associated with platelet function to ischemic stroke (IS) susceptibility remains unknown. We employed a deep re-sequencing approach in Polish patients in order to investigate the contribution of rare variants (minor allele frequency, MAF < 1%) to the IS genetic susceptibility in this population. The genes selected for re-sequencing consisted of 26 genes coding for proteins associated with the surface membrane of platelets. Targeted pooled re-sequencing (Illumina HiSeq 2500) was performed on genomic DNA of 500 cases (patients with history of clinically proven diagnosis of large-vessel IS) and 500 controls. After quality control and prioritization based on allele frequency and damaging probability, follow-up individual genotyping of deleterious rare variants was performed in patients from the original cohort. Gene-based analyses identified an association between IS and 6 rare functional and damaging variants in the purinergic genes (P2RY1 and P2RY12 locus). The predicted properties of the most damaging rare variants in P2RY1 and P2RY12 were confirmed by using mouse fibroblast cell cultures transfected with plasmid constructs containing cDNA of mutated variants (FLIPR on FlexStation3). This study identified a putative role for rare variants in P2RY1 and P2RY12 genes involved in platelet reactivity on large-vessel IS susceptibility in a Polish population.
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spelling pubmed-57512802018-01-08 Population-Specific Associations of Deleterious Rare Variants in Coding Region of P2RY1–P2RY12 Purinergic Receptor Genes in Large-Vessel Ischemic Stroke Patients Janicki, Piotr K. Eyileten, Ceren Ruiz-Velasco, Victor Sedeek, Khaled Anwar Pordzik, Justyna Czlonkowska, Anna Kurkowska-Jastrzebska, Iwona Sugino, Shigekazu Imamura-Kawasawa, Yuka Mirowska-Guzel, Dagmara Postula, Marek Int J Mol Sci Article The contribution of low-frequency and damaging genetic variants associated with platelet function to ischemic stroke (IS) susceptibility remains unknown. We employed a deep re-sequencing approach in Polish patients in order to investigate the contribution of rare variants (minor allele frequency, MAF < 1%) to the IS genetic susceptibility in this population. The genes selected for re-sequencing consisted of 26 genes coding for proteins associated with the surface membrane of platelets. Targeted pooled re-sequencing (Illumina HiSeq 2500) was performed on genomic DNA of 500 cases (patients with history of clinically proven diagnosis of large-vessel IS) and 500 controls. After quality control and prioritization based on allele frequency and damaging probability, follow-up individual genotyping of deleterious rare variants was performed in patients from the original cohort. Gene-based analyses identified an association between IS and 6 rare functional and damaging variants in the purinergic genes (P2RY1 and P2RY12 locus). The predicted properties of the most damaging rare variants in P2RY1 and P2RY12 were confirmed by using mouse fibroblast cell cultures transfected with plasmid constructs containing cDNA of mutated variants (FLIPR on FlexStation3). This study identified a putative role for rare variants in P2RY1 and P2RY12 genes involved in platelet reactivity on large-vessel IS susceptibility in a Polish population. MDPI 2017-12-11 /pmc/articles/PMC5751280/ /pubmed/29232918 http://dx.doi.org/10.3390/ijms18122678 Text en © 2017 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Janicki, Piotr K.
Eyileten, Ceren
Ruiz-Velasco, Victor
Sedeek, Khaled Anwar
Pordzik, Justyna
Czlonkowska, Anna
Kurkowska-Jastrzebska, Iwona
Sugino, Shigekazu
Imamura-Kawasawa, Yuka
Mirowska-Guzel, Dagmara
Postula, Marek
Population-Specific Associations of Deleterious Rare Variants in Coding Region of P2RY1–P2RY12 Purinergic Receptor Genes in Large-Vessel Ischemic Stroke Patients
title Population-Specific Associations of Deleterious Rare Variants in Coding Region of P2RY1–P2RY12 Purinergic Receptor Genes in Large-Vessel Ischemic Stroke Patients
title_full Population-Specific Associations of Deleterious Rare Variants in Coding Region of P2RY1–P2RY12 Purinergic Receptor Genes in Large-Vessel Ischemic Stroke Patients
title_fullStr Population-Specific Associations of Deleterious Rare Variants in Coding Region of P2RY1–P2RY12 Purinergic Receptor Genes in Large-Vessel Ischemic Stroke Patients
title_full_unstemmed Population-Specific Associations of Deleterious Rare Variants in Coding Region of P2RY1–P2RY12 Purinergic Receptor Genes in Large-Vessel Ischemic Stroke Patients
title_short Population-Specific Associations of Deleterious Rare Variants in Coding Region of P2RY1–P2RY12 Purinergic Receptor Genes in Large-Vessel Ischemic Stroke Patients
title_sort population-specific associations of deleterious rare variants in coding region of p2ry1–p2ry12 purinergic receptor genes in large-vessel ischemic stroke patients
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5751280/
https://www.ncbi.nlm.nih.gov/pubmed/29232918
http://dx.doi.org/10.3390/ijms18122678
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