Pharmacogenomic profiling of ABCB1 and CES1 in atrial fibrillation patients on dabigatran from a multiethnic Malaysian cohort

Abstract

Direct oral anticoagulants (DOACs) are preferred for atrial fibrillation (AF) due to their efficacy and safety, though response variabilities raises concerns about fixed-dose regimens. This study investigates the association between ABCB1 and CES1 genetic polymorphisms with Dabigatran trough drug levels (DL), clotting time (CT), and clinical outcomes in a multiethnic Malaysian cohort. A total of 180 AF patients in Dabigatran were sequenced across the entire length of ABCB1 and CES1 genes using the Illumina MiSeq platform. Trough Dabigatran levels and clotting time were measured by LC-MS/MS and viscoelastic assay (Clotpro®), respectively. Patients were followed up for one year to assess major adverse cardiovascular and cerebrovascular events (MACCE). The mean dabigatran level was 34.7 ± 45.4 ng/ml (CV: 130%), and clotting time was 374.6 ± 207.9 s (CV: 55.5%). Trough levels were significantly correlated with clotting time (r = 0.663, p < 0.001).). Multiple non-coding variants in ABCB1 and CES1 showed nominal associations (unadjusted p < 0.05) with drug level (35 SNPs) and/or clotting time (32 SNPs), although none remained statistically significant after false discovery rate correction. A total of 17 SNPs overlapped, and were associated with both. Overall, these findings suggest that non-coding regulatory variation may contribute to inter-individual variability in dabigatran pharmacokinetics and pharmacodynamics, but the results are exploratory and require replication in larger cohorts. This study highlights the importance of population-specific pharmacogenomic research for future investigations on personalized anticoagulation strategies.