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Role of CES1 and ABCB1 Genetic Polymorphisms on Functional Response to Dabigatran in Patients with Atrial
Luca Cumitini1,2, Giulia Renda3,4, Mara Giordano5,6
1Department of Translational Medicine, University of Eastern Piedmont, 28100 Novara, Italy.
Journal of Clinical Medicine
|May 11, 2024
Summary
The ABCB1 rs4148738 CT genotype is linked to lower dabigatran anticoagulant activity at trough levels in atrial fibrillation patients on higher doses. This finding highlights the impact of genetic variations on drug efficacy.
Area of Science:
- Pharmacogenomics
- Cardiology
- Drug Metabolism
Background:
- Dabigatran etexilate, a direct thrombin inhibitor prodrug, is metabolized by carboxylesterases (CES) and transported by P-glycoprotein (encoded by ABCB1 genes).
- Genetic variations in CES1 and ABCB1 genes may influence dabigatran's pharmacokinetic and pharmacodynamic profile.
- Atrial fibrillation (AF) patients require effective anticoagulation, making understanding drug response variability crucial.
Purpose of the Study:
- To investigate the association between CES1 and ABCB1 single-nucleotide polymorphisms (SNPs) and dabigatran's functional response in AF patients.
- To evaluate the impact of specific SNPs (CES1 rs2244613, CES1 rs8192935, ABCB1 rs4148738) on diluted thrombin time (dTT) and plasma concentrations.
- To analyze these relationships across different dabigatran dosage regimens (110 mg and 150 mg BID).
Main Methods:
- A cohort of 100 consecutive AF patients on dabigatran therapy was recruited from two Italian centers.
- Genetic analysis for CES1 and ABCB1 SNPs was performed on venous blood samples.
- Diluted thrombin time (dTT) and dabigatran plasma concentrations were measured at trough and peak intervals.
Main Results:
- No significant differences in dTT values were observed based on CES1 rs2244613 or CES1 rs8192935 genotypes.
- In patients on the 150 mg dabigatran dose, the ABCB1 rs4148738 CT genotype was associated with significantly lower trough dTT values compared to the wild-type CC genotype (p=0.048).
- The ABCB1 rs4148738 CT genotype showed an odds ratio of 3.21 for having trough dTT values below the median (p=0.042).
Conclusions:
- The ABCB1 rs4148738 CT heterozygous genotype is associated with reduced anticoagulant activity of dabigatran at trough levels in AF patients on the higher 150 mg BID dose.
- This SNP may represent a genetic marker influencing dabigatran's efficacy, particularly in patients requiring higher anticoagulation levels.
- Further research is warranted to explore the clinical implications of this pharmacogenetic finding for personalized anticoagulation therapy.
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