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

Purpose: Direct oral anticoagulants (DOACs) are used to prevent and treat thromboembolic events in adults. We aimed to investigate whether pharmacogenomic variation contributes to the risk of bleeding during DOAC treatment.

Methods: Cases were recruited from reports of bleeding sent to the Swedish Medical Products Agency (n = 129, 60% men, 93% Swedish, 89% on factor Xa inhibitors) and compared with population controls (n = 4891) and a subset matched for exposure to DOACs (n = 353). We performed a genome-wide association study, with analyses of candidate single nucleotide polymorphisms (SNPs) and candidate gene set analyses.

Results: Forty-four cases had major, 37 minor, and 48 clinically relevant non-major (CRNM) bleeding. When cases were compared with matched controls, BAIAP2L2 rs142001534 was significantly associated with any bleeding and major/CRNM bleeding (P = 4.66 × 10^-8 and P = 3.28 × 10^-8, respectively). The candidate SNP CYP3A5 rs776746 was significantly associated with major and major/CRNM bleeding (P = 0.00020 and P = 0.00025, respectively), and ABCG2 rs2231142 was nominally associated with any bleeding (P = 0.01499). Rare coding variants in the candidate gene VWF were significantly associated with any bleeding (P = 0.00296).

Conclusion: BAIAP2L2, CYP3A5, ABCG2, and VWF may be associated with bleeding in DOAC-treated patients. The risk estimates of the candidate variants in CYP3A5 and ABCG2 were in the same direction as in previous studies. The Von Willebrand Factor gene (VWF) is linked to hereditary bleeding disorders, while there is no previous evidence of bleeding associated with BAIAP2L2.