An Exploratory Association Analysis of ABCB1 rs1045642 and ABCB1 rs4148738 with Non-Major Bleeding Risk in Atrial Fibrillation Patients Treated with Dabigatran or Apixaban

Abstract

(1) Background: The approach of bleeding complications in patients treated with non-vitamin K oral anticoagulants (NOACs) represents an important issue in clinical practice. Both dabigatran and apixaban are substrates for P-glycoprotein and, therefore, ABCB1 gene variations may be useful in individualizing NOACs treatment, especially in high-risk patients. (2) Methods: ABCB1 rs1045642 and rs4148738 were determined in 218 atrial fibrillation patients treated with dabigatran or apixaban (70.94 ± 9.04 years; 51.83% men). (3) Results: Non-major bleeding appeared in 7.34% NOACs–treated patients. The logistic tested models based on the four genetic models revealed no significant association between the variant genotype of two ABCB1 SNPs and the risk of bleeding (p > 0.05). Among the four two-locus haplotypes, TA and CA haplotypes had the highest frequency in NOACs-treated patients with bleeding, involving a possible positive association with the susceptibility of bleeding complications (OR = 1.04 and OR = 1.91, respectively). The logistic model found no significant association of estimated haplotypes with bleeding (p > 0.05) except for the TG haplotype which had a trend toward statistical significance (p = 0.092). Among the risk factors for bleeding, only age > 70 years and stroke/TIA showed a tendency toward statistical significance. (4) Conclusions: We found no significant associations between the studied ABCB1 variant genotypes with non-major bleeding risk in NOACs-treated patients. A trend of association between TG haplotype with bleeding risk was observed, implying a protective role of this haplotype against bleeding in patients treated with dabigatran or apixaban.

Pharmacogenetics of Bleeding and Thromboembolic Events in Direct Oral Anticoagulant Users

“…We also found an association of the ABCB1 c.2482‐2236G>A SNV with a decreased bleeding risk in apixaban users. This variant has been found to be associated with bleeding in one earlier study, 10 while other studies have not been able to confirm the association 19,34 …”

“…This variant has been found to be associated with bleeding in one earlier study, 10 while other studies have not been able to confirm the association. 19,34 So far, the most extensive investigation of the pharmacogenomics of DOACs has been the genome-wide association study of Paré et al focusing on dabigatran users. 13 The study found association of the CES1 rs2244613 SNV with a decreased risk of bleeding.…”

“…For the SNV association analysis, we primarily used the dominant genetic model 34 comparing the noncarriers (no variant alleles) with carriers (one or two variant alleles). We repeated the analysis by using the recessive genetic model comparing homozygous subjects having two variant alleles with subjects having only one variant allele or no variant alleles.…”

The impact of ABCB1 and CES1 polymorphisms on the safety of dabigatran in patients with non-valvular atrial fibrillation

“…Dabigatran etexilate is a substrate of P-glycoprotein encoded by the ABCB1 gene. ABCB1 variants are potential factors affecting thromboembolic events in dabigatran users and bleeding events 18 . Earlier studies have found associations between genetic variability and plasma levels of direct oral anticoagulants 19,20 .…”

The impact of ABCB1 and CES1 polymorphisms on the safety of dabigatran in patients with non-valvular atrial fibrillation

“…Dabigatran etexilate is a substrate of P-glycoprotein encoded by the ABCB1 gene. ABCB1 variants are potential factors affecting thromboembolic events in dabigatran users and bleeding events [27]. Earlier studies have found associations between genetic variability and plasma levels of direct oral anticoagulants [17,28].…”