Introduction : Dabigatran is a direct oral anticoagulant associated with a high incidence of gastrointestinal bleeding, which presents a significant clinical concern. Genetic polymorphisms in the enzymes responsible for drug absorption (ABCB1) and activation (CES1) may influence dabigatran’s pharmacokinetics, potentially altering drug concentration and therapeutic response. The current systematic review and meta-analysis aim to identify genetic variants correlated with dabigatran exposure and evaluate their importance. Methods We systematically searched PubMed, Web of Science, Scopus, Cochrane Library, and Embase to identify studies on dabigatran pharmacogenomics. The review included observational and clinical studies that met eligibility criteria. RevMan 5.4 was used to conduct the meta-analysis. Quality assessment was done using ROB 2.0 and NOS tools. Results Out of 1336 records retrieved, 1008 were screened, resulting in 16 studies included in the systematic review and 9 in the meta-analysis. Data from 3834 participants (61.8% males) were reviewed. For the ABCB1 polymorphism rs4148738, both CT and TT genotypes decreased C trough compared to CC genotype (MD = − 9.82, 95% CI [− 17.65, − 1.99], P = 0.01) and (MD= − 7.69, 95% CI [− 15.54, 0.16], P = 0.05), respectively. While CES1 rs8192935 GG increased C max compared to AA (MD = 22.66, 95% CI [5.04, 40.27], P = 0.01). For CES1 rs2244613 AA, both C max and C trough exhibited higher levels compared to GG (MD = 13.58, 95% CI [− 0.08,27.25], P = 0.05) and (MD = 13.41, 95% CI [8.05,18.77], P < 0.01), respectively. Also, compared to GG the heterozygote type GA increased the C max (MD = 32.02, 95%CI [16.54,47.5], P < 0.01). Bleeding risk did not significantly differ across ABCB1 rs1045642, ABCB1 rs4148738 and CES1 rs8192935 polymorphisms. Only CES1 rs2244613 T allele showed significant effect on bleeding (OR = 2.43, P = 0.002). Stroke incidence did not differ across ABCB1 rs4148738, CES1 rs2244613, and CES1 rs8192935 genotypes. Conclusion ABCB1 rs4148738 T allele reduced dabigatran trough levels, while CES1 rs8192935 GG increased peak levels. CES1 rs2244613 TT raised both peak and trough levels, and its T allele was linked to higher bleeding risk. No consistent associations were found for other variants. These findings highlight CES1 rs2244613 as a key contributor to variability in dabigatran response, warranting further large-scale studies to confirm its role in personalized anticoagulation therapy.

The role of ABCB1 and CES1 genotypes on the efficacy and safety of dabigatran: a systematic review and meta-analysis

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2025年10月22日

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Weam Aldiban,
Nada G. Hamam,
Nereen A. Almosilhy,
Kholoud Elsamman,
Mohamed Wagdy,
Doaa Mashaly,
Suhel F. Batarseh,
Youssef El-Sherif,
Basma Badrawy Khalefa,
Zina Otmani

摘要

Introduction

: Dabigatran is a direct oral anticoagulant associated with a high incidence of gastrointestinal bleeding, which presents a significant clinical concern. Genetic polymorphisms in the enzymes responsible for drug absorption (ABCB1) and activation (CES1) may influence dabigatran’s pharmacokinetics, potentially altering drug concentration and therapeutic response. The current systematic review and meta-analysis aim to identify genetic variants correlated with dabigatran exposure and evaluate their importance.

Methods

We systematically searched PubMed, Web of Science, Scopus, Cochrane Library, and Embase to identify studies on dabigatran pharmacogenomics. The review included observational and clinical studies that met eligibility criteria. RevMan 5.4 was used to conduct the meta-analysis. Quality assessment was done using ROB 2.0 and NOS tools.

Results

Out of 1336 records retrieved, 1008 were screened, resulting in 16 studies included in the systematic review and 9 in the meta-analysis. Data from 3834 participants (61.8% males) were reviewed. For the ABCB1 polymorphism rs4148738, both CT and TT genotypes decreased C _trough compared to CC genotype (MD = − 9.82, 95% CI [− 17.65, − 1.99], P = 0.01) and (MD= − 7.69, 95% CI [− 15.54, 0.16], P = 0.05), respectively. While CES1 rs8192935 GG increased C _max compared to AA (MD = 22.66, 95% CI [5.04, 40.27], P = 0.01). For CES1 rs2244613 AA, both C _max and C _trough exhibited higher levels compared to GG (MD = 13.58, 95% CI [− 0.08,27.25], P = 0.05) and (MD = 13.41, 95% CI [8.05,18.77], P < 0.01), respectively. Also, compared to GG the heterozygote type GA increased the C _max (MD = 32.02, 95%CI [16.54,47.5], P < 0.01). Bleeding risk did not significantly differ across ABCB1 rs1045642, ABCB1 rs4148738 and CES1 rs8192935 polymorphisms. Only CES1 rs2244613 T allele showed significant effect on bleeding (OR = 2.43, P = 0.002). Stroke incidence did not differ across ABCB1 rs4148738, CES1 rs2244613, and CES1 rs8192935 genotypes.

Conclusion

ABCB1 rs4148738 T allele reduced dabigatran trough levels, while CES1 rs8192935 GG increased peak levels. CES1 rs2244613 TT raised both peak and trough levels, and its T allele was linked to higher bleeding risk. No consistent associations were found for other variants. These findings highlight CES1 rs2244613 as a key contributor to variability in dabigatran response, warranting further large-scale studies to confirm its role in personalized anticoagulation therapy.