Discussion
The polymorphisms of both ABCB1 and CES1 genes may lead to a significant
association with pharmacokinetic variations and clinical outcomes of
dabigatran 8,16,17. In this study, we found that the
CES1 SNP rs8192935 was associated with the plasma concentrations of
dabigatran (P =0.013). For the trough levels, carriers of the G
allele had increased trough plasma concentrations of dabigatran compared
to the noncarriers. The ABCB1 SNPs rs4148738 and rs1045642 were
associated with a higher risk for major bleeding in patients receiving
dabigatran treatment. However, no significant difference was observed in
ischemic events or minor bleeding events among variant genotypes of the
ABCB1 SNPs and the CES1 SNPs.
CES1 is responsible for the biotransformation of dabigatran etexilate
into the active metabolite13. Genome-wide association
analysis identified that the CES1 SNP rs2244613 is associated with
trough dabigatran blood concentration, while rs8192935 and rs4148738 are
modestly associated with peak dabigatran blood
concentration7. A Chinese patient case report showed
that the impacts on dabigatran concentrations related to rs2244613 and
rs8192935 may be greater than previously postulated, especially in
Asians5. Thus, more studies should be conducted in the
Chinese population.
Our results showed that the CES1 SNP rs8192935 significantly influenced
dabigatran trough concentrations in the Chinese population, and carriers
of the G allele had increased trough plasma concentrations of dabigatran
compared to noncarriers. This result is in accordance with a previous
study in Italy and China6,13. To the best of our
knowledge, only one study conducted in China indicated the effect of
genetic associations of dabigatran along with the bleeding risk for
individuals, but it failed to elucidate major bleeding and
thromboembolic events of this variability due to the small number of
patients enrolled in the study6. Our results
reverified the importance of the CES1 SNP rs8192935 with larger enrolled
patient numbers and included ischemic events, major bleeding events and
minor bleeding events in further studies. However, the CES1 SNP
rs8192935 showed no significant difference in ischemic events or minor
bleeding events at the 1.5-year follow-up.
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
events18. Earlier studies have found associations
between genetic variability and plasma levels of direct oral
anticoagulants19,20. ABCB1 SNP 1045642 is associated
with a reduced risk for thromboembolic outcomes, while rs4148738 is
associated with a lower risk for bleeding events in apixaban users. For
the ABCB1 polymorphisms rs4148738 and rs1045642, no significant
association was previously found with dabigatran PK/PD in the Chinese
population6.
In our study, no significant associations were found between the plasma
concentrations of dabigatran and ABCB1 polymorphisms. The results are in
accordance with a previous study in China. However, the ABCB1 SNPs
rs4148738 and rs1045642 were detected to have significant associations
with a higher risk for major bleeding in patients receiving dabigatran
treatment in the Chinese population for the first time. However, they
showed no significant difference in ischemic events or minor bleeding
events at the 1.5-year follow-up. Since our research has a longer
follow-up and we have a strict selection criterion for the patients,
further research should be conducted in the future.