AUTHOR=Li Haobo , Zhang Zhu , Weng Haoyi , Qiu Yuting , Zubiaur Pablo , Zhang Yu , Fan Guohui , Yang Peiran , Vuorinen Anna-Leena , Zuo Xianbo , Zhai Zhenguo , Wang Chen 

TITLE=Association between CES1 rs2244613 and the pharmacokinetics and safety of dabigatran: Meta-analysis and quantitative trait loci analysis

JOURNAL=Frontiers in Cardiovascular Medicine

VOLUME=9

YEAR=2022

URL=https://www.frontiersin.org/journals/cardiovascular-medicine/articles/10.3389/fcvm.2022.959916

DOI=10.3389/fcvm.2022.959916

ISSN=2297-055X

ABSTRACT=<sec><title>Objective</title><p>To date, the influence of the carboxylesterase 1 (<italic>CES1</italic>) rs2244613 genotype on the pharmacokinetics (PKs) and safety of dabigatran remains controversial. Hence, a systematic review was performed to study the association between <italic>CES1</italic> rs2244613 genotype and the PKs and safety of dabigatran and <italic>CES1</italic> relative expression.</p></sec><sec><title>Methods</title><p>In addition to the three English databases (Web of Science, PubMed, and Embase), two Chinese databases (CNKI and Wanfang) were thoroughly revised. The mean differences (MD) and corresponding 95% confidence intervals (CI) were applied to evaluate the differences in PKs between the <italic>CES1</italic> rs2244613 genotype. Odds ratio (OR) was used to study the risk for bleeding events between the <italic>CES1</italic> rs2244613 genotypes. Subsequent expression quantitative trait loci (eQTL) analyses were performed to evaluate genotype-specific expressions in human tissues.</p></sec><sec><title>Results</title><p>Ten studies (<italic>n</italic> = 2,777) were included. <italic>CES1</italic> rs2244613 G allele carriers exhibited significantly lower dabigatran trough concentrations compared to T allele carriers (MD: −8.00 ng/mL; 95% CI: −15.08 to −0.92; <italic>p</italic> = 0.03). The risk for bleeding events was significantly lower in carriers of the G allele compared to T allele carriers (OR: 0.65; 95% CI: 0.44–0.96; <italic>p</italic> = 0.03). Subsequent eQTL analysis showed significant genome-wide expressions in two human tissues, whole blood (<italic>p</italic> = 5.1 × 10<sup>–10</sup>) and liver (<italic>p</italic> = 6.2 × 10<sup>–43</sup>).</p></sec><sec><title>Conclusion</title><p>Our meta-analysis indicated a definite relation between the <italic>CES1</italic> rs2244613 genotype and tolerability variations or pharmacokinetic fluctuations. The carriers of T allele showed higher dabigatran concentrations; therefore, they would benefit from a dose reduction.</p></sec><sec><title>Systematic review registration</title><p>[<ext-link ext-link-type="uri" xlink:href="https://inplasy.com/inplasy-2022-6-0027/" xmlns:xlink="http://www.w3.org/1999/xlink">https://inplasy.com/inplasy-2022-6-0027/</ext-link>], identifier [NPLASY202260027].</p></sec>