Association between four microRNA binding site-related polymorphisms and the risk of warfarin-induced bleeding complications

Authors

  • Maryam Hosseindokht Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
  • Mohammadali Boroumand Department of Pathology and Laboratory Medicine, Tehran Heart Center, Tehran University of Medical Sciences, Tehran, Iran
  • Rasoul Salehi Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
  • Ali Mandegary Department of Pharmacology and Toxicology, School of Pharmacy, Kerman University of Medical Sciences, Kerman, Iran; Gastroenterology and Hepatology Research Center, Afzalipour's Hospital, Imam Highway, Kerman, Iran
  • Azita Hajhosseini Talasaz Department of Cardiac Research, Tehran Heart Center, Tehran University of Medical Sciences, Tehran, Iran; Department of Clinical Pharmacy, School of Pharmacy, Tehran University of Medical Sciences
  • Leyla Pourgholi Department of Pathology and Laboratory Medicine, Tehran Heart Center, Tehran University of Medical Sciences, Tehran, Iran
  • Hamed Zare Cellular and Molecular Research Center, Birjand University of Medical Sciences, Birjand, Iran
  • Shayan Ziaee Department of Pathology and Laboratory Medicine, Tehran Heart Center, Tehran University of Medical Sciences, Tehran, Iran
  • Mohammadreza Sharifi Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, 81744-176, Iran, Tel: +983137929037; Fax: +983136688597; E-mail: mo_sharifi@med.mui.ac.ir

DOI:

https://doi.org/10.17179/excli2019-1352

Keywords:

Bleeding; Warfarin; GATA4 gene; microRNAs; Polymorphism

Abstract

Bleeding is the most serious complication of warfarin anticoagulation therapy and is known to occur even at patients with therapeutic international normalized ratio (INR) range. Recently, it has been shown that microRNAs play a significant role in pharmacogenetics by regulating genes that are critical for drug function. Interaction between microRNAs and these target genes could be affected by single-nucleotide polymorphisms (SNPs) located in microRNA-binding sites. This study focused on 3′-untranslated region (3′-UTR) SNPs of the genes involved in the warfarin action and the occurrence of bleeding complications in an Iranian population receiving warfarin. A total of 526 patients under warfarin anticoagulation therapy with responding to the therapeutic dose and maintenance of the INR in the range of 2.0-3.5 in three consecutive blood tests were included in the study. Four selected 3'-UTR SNPs (rs12458, rs7294, rs1868774 and rs34669593 located in GATA4, VKORC1, CALU and GGCX genes, respectively) with the potential to disrupt/eliminate or enhance/create microRNA-binding site were genotyped using a simple PCR-based restriction fragment length polymorphism (PCR-RFLP) method. Patients with the rs12458 AT or TT genotypes of the GATA4 gene had a lower risk of bleeding compared to patients with the AA genotype (adjusted OR: 0.478, 95% CI: 0.285-0.802, P= 0.005, OR: 0.416, 95% CI: 0.192-0.902, P= 0.026, respectively). 3'-UTR polymorphisms in other genes were not significantly associated with the risk of bleeding complications. In conclusion, the SNP rs12458A>T in the 3′UTR region of GATA4 is associated with the incidence of warfarin-related bleeding at target range of INR, likely by altering microRNA binding and warfarin metabolism. Further genetics association studies are needed to validate these findings before they can be implemented in clinical settings.

Published

2019-05-28

How to Cite

Hosseindokht, M., Boroumand, M., Salehi, R., Mandegary, A., Hajhosseini Talasaz, A., Pourgholi, L., … Sharifi, M. (2019). Association between four microRNA binding site-related polymorphisms and the risk of warfarin-induced bleeding complications. EXCLI Journal, 18, 287–299. https://doi.org/10.17179/excli2019-1352

Issue

Section

Original articles