Population-specific associations of deleterious rare variants in coding region of P2RY1–P2RY12 purinergic receptor genes in large-vessel ischemic stroke patients

Piotr K. Janicki, Ceren Eyileten, Victor Ruiz-Velasco, Khaled Anwar Sedeek, Justyna Pordzik, Anna Czlonkowska, Iwona Kurkowska-Jastrzebska, Shigekazu Sugino, Yuka Imamura-Kawasawa, Dagmara Mirowska-Guzel, Marek Postula

Research output: Contribution to journalArticle

4 Citations (Scopus)

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.

Original languageEnglish
Article number2678
JournalInternational journal of molecular sciences
Volume18
Issue number12
DOIs
Publication statusPublished - 2017 Dec 11
Externally publishedYes

Keywords

  • Cerebrovascular stroke
  • DNA sequencing
  • Genetic polymorphism
  • Large-vessel ischemic stroke
  • Platelets
  • Polish population
  • Purinergic receptors

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

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  • Cite this

    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. (2017). Population-specific associations of deleterious rare variants in coding region of P2RY1–P2RY12 purinergic receptor genes in large-vessel ischemic stroke patients. International journal of molecular sciences, 18(12), [2678]. https://doi.org/10.3390/ijms18122678