Increased burden of rare deleterious variants of the KCNQ1 gene in patients with large‑vessel ischemic stroke

  • Authors:
    • Piotr K. Janicki
    • Ceren Eyileten
    • Victor Ruiz‑Velasco
    • Justyna Pordzik
    • Anna Czlonkowska
    • Iwona Kurkowska‑Jastrzebska
    • Shigekazu Sugino
    • Yuka Imamura Kawasawa
    • Dagmara Mirowska‑Guzel
    • Marek Postula
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  • Published online on: February 25, 2019     https://doi.org/10.3892/mmr.2019.9987
  • Pages: 3263-3272
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Abstract

The impact of rare and damaging variants in genes associated with platelet function in large‑vessel ischemic stroke (LVIS) remains unknown. The aim of this study was to investigate the contribution of some of these variants to the genetic susceptibility to LVIS in Polish patients using a deep re‑sequencing of 54 selected genes, coding for proteins associated with altered platelet function. Targeted pooled re‑sequencing (Illumina HiSeq 2500) was performed on genomic DNA of 500 cases (patients with history of clinically proven diagnosis of LVIS) and 500 age‑, smoking status‑, and sex‑matched controls (no history of any type of stroke), and from the same population as patients with LVIS. After quality control and prioritization based on allele frequency and damaging probability, individual genotyping of all deleterious rare variants was performed in patients from the original cohort, and stratified to concomitant cardiac conditions differing between the study and stroke groups. We demonstrated a statistically significant increase in the number of rare and potentially damaging variants in some of the investigated genes in the LVIS pool (an increase in the genomic variants burden). Furthermore, we identified an association between LVIS and 6 rare functional and damaging variants in the Kv7.1 potassium channel gene (KCNQ1). The predicted functional properties (partial loss‑of function) for the three most damaging variants in KCNQ1 coding locus were further confirmed in vitro by analyzing the membrane potential changes in cell lines co‑transfected heterogeneously with human muscarinic type 1 receptor and wild‑type or mutated KCNQ1 cDNA constructs using fluorescence imaging plate reader. The study demonstrated an increased rare variants burden for 54 genes associated with platelet function, and identified a putative role for rare damaging variants in the KCNQ1 gene on LVIS susceptibility in the Polish population.
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April-2019
Volume 19 Issue 4

Print ISSN: 1791-2997
Online ISSN:1791-3004

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Spandidos Publications style
Janicki PK, Eyileten C, Ruiz‑Velasco V, Pordzik J, Czlonkowska A, Kurkowska‑Jastrzebska I, Sugino S, Imamura Kawasawa Y, Mirowska‑Guzel D, Postula M, Postula M, et al: Increased burden of rare deleterious variants of the KCNQ1 gene in patients with large‑vessel ischemic stroke. Mol Med Rep 19: 3263-3272, 2019.
APA
Janicki, P.K., Eyileten, C., Ruiz‑Velasco, V., Pordzik, J., Czlonkowska, A., Kurkowska‑Jastrzebska, I. ... Postula, M. (2019). Increased burden of rare deleterious variants of the KCNQ1 gene in patients with large‑vessel ischemic stroke. Molecular Medicine Reports, 19, 3263-3272. https://doi.org/10.3892/mmr.2019.9987
MLA
Janicki, P. K., Eyileten, C., Ruiz‑Velasco, V., Pordzik, J., Czlonkowska, A., Kurkowska‑Jastrzebska, I., Sugino, S., Imamura Kawasawa, Y., Mirowska‑Guzel, D., Postula, M."Increased burden of rare deleterious variants of the KCNQ1 gene in patients with large‑vessel ischemic stroke". Molecular Medicine Reports 19.4 (2019): 3263-3272.
Chicago
Janicki, P. K., Eyileten, C., Ruiz‑Velasco, V., Pordzik, J., Czlonkowska, A., Kurkowska‑Jastrzebska, I., Sugino, S., Imamura Kawasawa, Y., Mirowska‑Guzel, D., Postula, M."Increased burden of rare deleterious variants of the KCNQ1 gene in patients with large‑vessel ischemic stroke". Molecular Medicine Reports 19, no. 4 (2019): 3263-3272. https://doi.org/10.3892/mmr.2019.9987