The polymorphisms of both ABCB1 and CES1 genes may lead to a significant association with pharmacokinetic variations and clinical outcomes of dabigatran [8, 19, 22]. 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 metabolite. 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 concentration. 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 Asians. 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 China[6, 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 study. 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 events. Earlier studies have found associations between genetic variability and plasma levels of direct oral anticoagulants[16, 24]. 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 population.
It can be found that the trough and peak concentrations of the ABCB1 rs4148738 TT genotype are significantly higher than those of other genotypes (Table 3). Similarly, the trough and peak concentrations of the ABCB1 rs1045642 GG genotype are also significantly higher than those of other genotypes, and the trend is very obvious. However, no statistical difference was shown due to the limited sample size. The genetic polymorphism of CES1 rs8192935 was associated with any bleeding event. However, due to the limited sample size and the large coefficient of variation of blood drug concentration, there was no correlation between CES1 rs8192935 polymorphisms and peak-to-trough concentrations.
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.