Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Exome-Wide Association Study of candidate pharmacogenes on DOAC haemorrhage

Dmitry A. Sychev
,
Anastasiia A. Buianova
ORCID logo ,
Sherzod P. Abdullaev
* ORCID logo ,
Karin B. Mirzaev
,
Vera A. Belova
ORCID logo ,
Anna O. Shmitko
ORCID logo ,
Valery V. Cheranev
,
Oleg N. Suchalko
,
Lyudmila V. Fedina
ORCID logo ,
Svetlana V. Batyukina
,
Natalia A. Shatalova
ORCID logo ,
Pavel O. Bochkov
ORCID logo ,
Sergey V. Glagolev
,
Denis V. Rebrikov
ORCID logo ,
Dmitriy O. Korostin
ORCID logo
Version 1 : Received: 6 September 2024 / Approved: 9 September 2024 / Online: 10 September 2024 (08:52:42 CEST)

How to cite: Sychev, D. A.; Buianova, A. A.; Abdullaev, S. P.; Mirzaev, K. B.; Belova, V. A.; Shmitko, A. O.; Cheranev, V. V.; Suchalko, O. N.; Fedina, L. V.; Batyukina, S. V.; Shatalova, N. A.; Bochkov, P. O.; Glagolev, S. V.; Rebrikov, D. V.; Korostin, D. O. Exome-Wide Association Study of candidate pharmacogenes on DOAC haemorrhage. Preprints 2024, 2024090734. https://doi.org/10.20944/preprints202409.0734.v1 Sychev, D. A.; Buianova, A. A.; Abdullaev, S. P.; Mirzaev, K. B.; Belova, V. A.; Shmitko, A. O.; Cheranev, V. V.; Suchalko, O. N.; Fedina, L. V.; Batyukina, S. V.; Shatalova, N. A.; Bochkov, P. O.; Glagolev, S. V.; Rebrikov, D. V.; Korostin, D. O. Exome-Wide Association Study of candidate pharmacogenes on DOAC haemorrhage. Preprints 2024, 2024090734. https://doi.org/10.20944/preprints202409.0734.v1

Abstract

Background/Objectives: Direct oral anticoagulants (DOACs) are first-line medications for stroke prevention in non-valvular atrial fibrillation (AF). However, variability in drug response poses risks of hemorrhagic or thromboembolic events. The role of genetics in determining DOAC safety is gaining attention, but evidence linking specific genetic polymorphisms to bleeding risk is lacking. Therefore, the aim of our study was to conduct an Exome-Wide Association Study with 198 non-valvular AF patients treated with rivaroxaban or apixaban, including 97 with bleeding complications and 99 without. Methods: DOAC plasma concentrations, 6-β-hydroxycortisol and cortisol levels in urine were measured for CYP3A4 phenotyping. Sequencing was performed on the DNBSEQ G-400 platform. Single nucleotide variants (SNV) associations with bleeding risk were assessed using logistic regression with additive, dominant, and recessive genetic models. Results: No SNVs reached Bonferroni-corrected significance in any genetic model. Polygenic risk scores (PRS) showed weak predictive ability for bleeding with apixaban. For rivaroxaban, regression indicated that ln Css min/D + 1 index increased with PRS, age, and 6-β-hydroxycortisol/cortisol ratio, but decreased with higher 6-β-hydroxycortisol and coronary heart disease presence. Conclusions: The findings revealed that the residual equilibrium concentration of anticoagulants, including dose-adjusted, cannot alone predict bleeding risk in non-valvular AF patients. No new genetic variants associated with bleeding risk were identified.

Keywords

atrial fibrillation; bleeding; anticoagulation; pharmacogenetics; DOAC; whole-exome sequencing

Subject

Medicine and Pharmacology, Medicine and Pharmacology

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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