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

Maryam Hosseindokht1, Mohammadali Boroumand2, Rasoul Salehi1

  • 1Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.

EXCLI Journal
|July 25, 2019
PubMed

Insights

A specific gene variant (rs12458) in the GATA4 gene is linked to a reduced risk of bleeding in patients taking warfarin. This finding may impact warfarin pharmacogenetics and patient safety.

Area of Science:

  • Pharmacogenetics
  • Molecular Biology
  • Clinical Medicine

Background:

  • Warfarin anticoagulation therapy can lead to serious bleeding complications, even within the therapeutic International Normalized Ratio (INR) range.
  • MicroRNAs are increasingly recognized for their role in pharmacogenetics, influencing drug metabolism by regulating target genes.
  • Single-nucleotide polymorphisms (SNPs) in microRNA-binding sites can alter these interactions, potentially affecting drug response and adverse events.

Purpose of the Study:

  • To investigate the association between 3'-untranslated region (3'-UTR) SNPs in warfarin-related genes and bleeding complications in an Iranian population.
  • To identify specific genetic markers that may predict the risk of warfarin-induced bleeding.

Main Methods:

  • Genotyping of 526 patients on warfarin therapy for four selected 3'-UTR SNPs (rs12458 in GATA4, rs7294 in VKORC1, rs1868774 in CALU, and rs34669593 in GGCX) using PCR-RFLP.
  • Analysis of the association between genotypes and the incidence of bleeding complications in patients maintaining a therapeutic INR (2.0-3.5).

Main Results:

  • Patients with the AT or TT genotypes of the rs12458 SNP in the GATA4 gene exhibited a significantly lower risk of bleeding compared to those with the AA genotype (adjusted ORs ranging from 0.416 to 0.478).
  • No significant association was found between the other three studied SNPs (in VKORC1, CALU, and GGCX) and warfarin-related bleeding risk.
  • The findings suggest that rs12458A>T polymorphism in GATA4 may influence warfarin metabolism or response, thereby affecting bleeding risk.

Conclusions:

  • The SNP rs12458A>T in the 3'-UTR of the GATA4 gene is associated with a reduced incidence of warfarin-related bleeding in the studied population.
  • This association is likely mediated by alterations in microRNA binding, potentially affecting warfarin metabolism.
  • Further research is warranted to validate these genetic findings for potential clinical application in warfarin therapy management.
Keywords:
GATA4 geneWarfarinbleedingmicroRNAspolymorphism

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