Genome-wide association study of direct oral anticoagulants and their relation to bleeding

Area of Science:

• Pharmacogenomics
• Thromboembolism Treatment
• Bleeding Risk Assessment

Background:

• Direct oral anticoagulants (DOACs) are widely prescribed for preventing and treating thromboembolic events.
• Individual variability in DOAC response and adverse events, such as bleeding, necessitates further investigation into contributing factors.
• Pharmacogenomic factors are increasingly recognized for their role in drug efficacy and safety.

Purpose of the Study:

• To investigate the potential contribution of pharmacogenomic variations to the risk of bleeding in patients treated with DOACs.
• To identify specific genetic variants associated with increased bleeding risk during DOAC therapy.

Main Methods:

• A case-control study design was employed, comparing patients who experienced bleeding events during DOAC treatment with population and DOAC-matched controls.
• Genome-wide association studies (GWAS) were conducted, alongside analyses of candidate single nucleotide polymorphisms (SNPs) and candidate gene sets.
• Data were sourced from bleeding event reports submitted to the Swedish Medical Products Agency.

Main Results:

• The BAIAP2L2 rs142001534 SNP showed a significant association with any bleeding and major/clinically relevant non-major (CRNM) bleeding.
• The CYP3A5 rs776746 SNP was significantly associated with major and major/CRNM bleeding.
• Rare coding variants in the Von Willebrand Factor (VWF) gene were significantly associated with any bleeding, while ABCG2 rs2231142 showed a nominal association with any bleeding.

Conclusions:

• Genetic variations in BAIAP2L2, CYP3A5, ABCG2, and VWF may be associated with an increased risk of bleeding in patients receiving DOACs.
• Findings for CYP3A5 and ABCG2 variants align with previous research.
• The study highlights potential genetic markers for personalized DOAC therapy to mitigate bleeding risks.