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Int. J. Mol. Sci. 2017, 18(12), 2678; doi:10.3390/ijms18122678

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

1
Perioperative Genomics Laboratory, Penn State College of Medicine, Hershey, PA 17033, USA
2
Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Center for Preclinical Research and Technology CEPT, 02-097 Warsaw, Poland
3
Department of Anesthesiology and Perioperative Medicine, Penn State College of Medicine, Hershey, PA 17033, USA
4
2nd Department of Neurology, Institute of Psychiatry and Neurology, 02-957 Warsaw, Poland
5
Genome Sciences Facility, Penn State College of Medicine, Hershey, PA 17033, USA
*
Author to whom correspondence should be addressed.
Received: 20 September 2017 / Revised: 5 December 2017 / Accepted: 7 December 2017 / Published: 11 December 2017
(This article belongs to the Special Issue Molecular Pharmacology and Pathology of Strokes)
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Abstract

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. View Full-Text
Keywords: DNA sequencing; platelets; genetic polymorphism; cerebrovascular stroke; purinergic receptors; large-vessel ischemic stroke; Polish population DNA sequencing; platelets; genetic polymorphism; cerebrovascular stroke; purinergic receptors; large-vessel ischemic stroke; Polish population
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Janicki, P.K.; Eyileten, C.; Ruiz-Velasco, V.; Sedeek, K.A.; Pordzik, J.; Czlonkowska, A.; Kurkowska-Jastrzebska, I.; Sugino, S.; Imamura-Kawasawa, Y.; Mirowska-Guzel, D.; Postula, M. Population-Specific Associations of Deleterious Rare Variants in Coding Region of P2RY1–P2RY12 Purinergic Receptor Genes in Large-Vessel Ischemic Stroke Patients. Int. J. Mol. Sci. 2017, 18, 2678.

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