Role of CES1 and ABCB1 Genetic Polymorphisms on Functional Response to Dabigatran in Patients with Atrial Fibrillation

Author:

Cumitini Luca12ORCID,Renda Giulia34ORCID,Giordano Mara56ORCID,Rolla Roberta56ORCID,Shail Tarek12,Sacchetti Sara56ORCID,Iezzi Lorena34,Giacomini Luca56ORCID,Zanotti Valentina56,Auciello Raffaella7,Angilletta Ilaria34,Foglietta Melissa3,Zucchelli Mirco48ORCID,Antonucci Ivana49,Stuppia Liborio49,Gallina Sabina34ORCID,Dianzani Umberto56,Patti Giuseppe12ORCID

Affiliation:

1. Department of Translational Medicine, University of Eastern Piedmont, 28100 Novara, Italy

2. Division of Cardiology, AOU Maggiore della Carità, 28100 Novara, Italy

3. Institute of Cardiology, Department of Neuroscience, Imaging and Clinical Sciences, G. d’Annunzio University of Chieti-Pescara, 66100 Chieti, Italy

4. Center for Advanced Studies and Technology (CAST), G. d’Annunzio University of Chieti-Pescara, 66100 Chieti, Italy

5. Department of Health Sciences, University of Eastern Piedmont, 28100 Novara, Italy

6. Clinical Biochemistry, AOU Maggiore della Carità, 28100 Novara, Italy

7. Department of Clinical Pathology, Renzetti Hospital, Lanciano (Chieti), 66034 Lanciano, Italy

8. Department of Innovative Technologies in Medicine, G. d’Annunzio University of Chieti-Pescara, 66100 Chieti, Italy

9. Department of Psychological, Health and Territory Sciences, G. d’Annunzio University of Chieti-Pescara, 66100 Chieti, Italy

Abstract

Background: Dabigatran etexilate is a pro-drug hydrolyzed into dabigatran by carboxylesterases (CES) and is a substrate of the P-Glycoprotein encoded by the adenosine-triphosphate-binding cassette sub-family B member (ABCB)1 genes. We evaluated the functional response to dabigatran according to different CES1 and ABCB1 single-nucleotide polymorphisms (SNPs) in patients with atrial fibrillation (AF). Methods: A total of 100 consecutive patients with AF taking dabigatran were enrolled by two Italian centers. A venous blood sample was drawn for genetic determinations, as well as a measurement of the diluted thrombin time (dTT) and drug plasma concentrations, at the trough and peak. The main objective was the relationship between the dTT values and CES1 rs2244613, CES1 rs8192935 and ABCB1 rs4148738 SNP while on two different dabigatran doses (110 and 150 mg BID). Results: A total of 43 patients were on a 110 mg dabigatran dose and 57 on 150 mg. The DTT values at the trough and at peak were not different among patients with different CES1 rs2244613 and CES1 rs8192935 genotypes, regardless of the dabigatran dose. In patients on 150 mg dabigatran, the dTT values at the trough were 77 (44–111) ng/mL in patients with the ABCB1 rs4148738 heterozygous CT genotype vs. 127 (85–147) ng/mL in the wild-type CC genotype vs. 110 (47–159) ng/mL in the mutant trait TT genotype (p = 0.048). In patients with the ABCB1 rs4148738 CT genotype, OR for having dTT values at a trough below the median was 3.21, 95% CI 1.04–9.88 (p = 0.042). Conclusions: ABCB1 rs4148738 CT heterozygous is associated with the reduced anticoagulant activity of dabigatran at the trough in patients receiving the higher dose regimen.

Publisher

MDPI AG

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