AHNAK2 Polymorphisms rs2582513 and rs10145032 Are Associated with Rivaroxaban Pharmacodynamics and Bleeding Risk: A Two-Stage Multicenter Cohort Study

Abstract Purpose Existing studies have investigated how genetic variations in drug- metabolizing enzymes and transporters affect rivaroxaban concentrations, but the relationship between these variants and bleeding events is unclear. Moreover, other genes related to pharmacodynamics and bleeding risks need further investigation. Additionally, identifying specific genetic loci in healthy populations and validating their clinical impact are key challenges this study faces. Method A multicenter prospective cohort study was conducted to detect genetic polymorphisms and analyze their pharmacodynamic effects on rivaroxaban in healthy individuals. The study then validated these findings by examining clinical outcomes in patients with non-valvular atrial fibrillation (NVAF). Results The findings revealed that specific mutations in the AHNAK nuclear protein 2 (AHNAK2 ) gene, notably rs2582513 and rs10145032 , were correlated with a blunted prolongation of prothrombin time (PT) in healthy individuals undergoing rivaroxaban treatment (p = 0.0003, 0.0004). The ROC curve was employed to assess the predictive capacity of these two single nucleotide polymorphisms (SNPs) for prothrombin time, yielding an area under the curve (AUC) of 0.93. Additionally, these mutations were associated with an elevated risk of bleeding events in clinical patients with atrial fibrillation (AF). When compared to GA/GC and AA carriers, subjects with the GG genotype for AHNAK2 rs2582513/rs10145032 exhibited a statistically significant increase in bleeding events, with a p of 0.03. The ROC curve's AUC for these two SNPs, rs2582513 and rs10145032 , on the AHNAK2 gene in forecasting bleeding events was 0.85. Combined analysis with ABCB1 rs1045642 and CYP3A5 rs776746 improved the AUC for bleeding event prediction to 0.89. Conclusion This study reveals for the first time that mutations in the AHNAK2 gene represent a hypothesis-generating predictive biomarker candidate for anticoagulation therapy. Individuals carrying the GG genotype exhibited weaker PT prolongation after receiving rivaroxaban, yet were associated with higher bleeding risks in clinical patients. These findings should be considered hypothesis-generating and warrant further validation in independent cohorts and functional studies before clinical application.