Genetic variants influenced the risk of bleeding and pharmacodynamics of rivaroxaban in patients with nonvalvular atrial fibrillation: A multicentre prospective cohort study

Abstract

Introduction Individual variability of rivaroxaban was observed in clinical application. This study aimed to identify genetic variants associated with the variability of pharmacodynamics and bleeding risk of rivaroxbaban in patients with nonvalvular atrial fibrillation (NVAF). Materials and Methods From June 2017, and July 2019, this study enrolled 257 patients with NVAF receiving rivaroxaban. Pharmacodynamics was assessed by determining anti‐Factor Xa (anti‐FXa) level 3 h after rivaroxaban administration as peak concentration. Whole‐exome sequencing was performed to detected single nucleotide polymorphisms (SNPs). This study was registered (NCT03161496). Results The bleeding events within 12 months were significantly related to the peak anti‐FXa level (p = .027). SUSD3 rs76292544 was associated with 12‐month bleeding events (odds ratio [OR]: 4.20, 95% confidence interval [CI]: 2.17–8.14, p = 6.43×10−5). Five SNPs including NCMAP rs4553122 (p = 2.29×10−5), PRF1 rs885821 (p = 7.02×10−5), PRKAG2 rs12703159 (p = 7.97×10−5), PRKAG2 rs13224758 (p = 8.70×10−5), and POU2F3 rs2298579 (p = 8.24×10−5) were associated with peak anti‐FXa level. Genetic variants of 52 SNPs from 36 genes including GOT2 rs14221 and MMP13 rs640198 were potentially related to 12‐month bleeding events caused by rivaroxaban's efficacy. Conclusions Peak anti‐FXa level was associated with risk of bleeding events in patients with NVAF receiving rivaroxaban. SUSD3 rs76292544 was suggestively associated with 12‐month bleeding events and five SNPs (NCMAP rs4553122, PRF1 rs885821, PRKAG2 rs12703159, rs13224758 and POU2F3 rs2298579) were suggestively associated with peak anti‐FXa level.

Unraveling genetic contributors to bleeding events induced by rivaroxaban treatment

“…In this issue of Clinical and Translational Medicine, the multicenter prospective cohort study focused on genetic polymorphisms, researchers identified 18 SNPs from 14 genes (including COL6A3 , NCAM2 , MMP3 , VCAN , JCAD ) as promising biomarkers for understanding the adverse effects of rivaroxaban. These candidate genes were found to influence multiple regulatory factors associated with bleeding events 18 …”

“…13 For example, specific genotypes of ABCB1 rs3842 and APOB rs13306198 variants have been linked to an increased risk of bleeding events in patients receiving DOACs. 14 In addition to ABCB1, emerging risk factors such as AKR7A3 and ABCA6 were observed; however, the role of genetic variations in bleeding events by rivaroxaban treatment remains unclear and has drawn limited attention [15][16][17][18] (Table 1). In this issue of Clinical and Translational Medicine, the multicenter prospective cohort study focused on genetic polymorphisms, researchers identified 18 SNPs from 14 genes (including COL6A3, NCAM2, MMP3, VCAN, JCAD) as promis-ing biomarkers for understanding the adverse effects of rivaroxaban.…”

“…These candidate genes were found to influence multiple regulatory factors associated with bleeding events. 18 COL6A3 encodes collagen VI, a cell-binding protein that plays a crucial role in the blood coagulation cascade. MARCH1 is a member of the MARCH family of membrane-bound E3 ubiquitin ligases, responsible for the ubiquitination of specific proteins such as major histocompatibility complex class II proteins.…”