Exome-wide association analysis revealed no single-nucleotide variants reaching Bonferroni-corrected significance for predicting bleeding risk in patients receiving apixaban or rivaroxaban.
Case-Control (n=196)
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Do specific genetic variants or polygenic risk scores predict bleeding events in patients with non-valvular atrial fibrillation receiving apixaban or rivaroxaban?
Exome-wide association analysis did not identify any single-nucleotide variants significantly associated with bleeding risk in patients with non-valvular atrial fibrillation taking apixaban or rivaroxaban.
Background 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. Objectives Although genetic influences on DOACs safety are increasingly recognized, robust evidence directly linking specific polymorphisms to bleeding risk remains limited. Design Multi-center observational case–control study including exome-wide association analysis of 196 non-valvular AF patients treated with rivaroxaban or apixaban, comprising 97 with bleeding complications and 99 without. Methods DOAC plasma concentrations, urinary 6-β-hydroxycortisol and cortisol levels were measured for CYP3A4 phenotyping. Sequencing was performed on the DNBSEQ G-400 platform. Single-nucleotide variant (SNV) associations with bleeding risk were assessed using logistic regression with additive, dominant, and recessive genetic models. Polygenic risk scores (PRSs) were calculated to evaluate cumulative genetic effects. Results No SNVs reached Bonferroni-corrected significance under any model. PRSs showed weak predictive ability for bleeding with apixaban. For rivaroxaban, regression indicated that ln C ss 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. No statistically significant differences were found for the PharmGKB Level 3 variants rs1045642 (rivaroxaban) and rs2231142 (apixaban). Trends toward statistical significance were observed for the rs2472304-G variant in rivaroxaban users, rs6977165-C in apixaban users, and for the CYP3A4*1/*36 diplotype. Conclusion Residual equilibrium concentration of DOACs, including dose-adjusted, did not independently predict bleeding risk in non-valvular AF patients. Variants rs2472304 and rs6977165 may warrant further investigation as potential contributors to bleeding risk.
Сычев et al. (Wed,) conducted a case-control in Non-valvular atrial fibrillation (n=196). Apixaban or Rivaroxaban vs. Patients without bleeding was evaluated on Single-nucleotide variant (SNV) associations with bleeding risk. Exome-wide association analysis revealed no single-nucleotide variants reaching Bonferroni-corrected significance for predicting bleeding risk in patients receiving apixaban or rivaroxaban.