The impact of ABCB1 and CES1 polymorphisms on the safety of dabigatran in patients with non-valvular atrial fibrillation

The impact of ABCB1 and CES1 polymorphisms on the safety of dabigatran in patients with non-valvular atrial fibrillation | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article The impact of ABCB1 and CES1 polymorphisms on the safety of dabigatran in patients with non-valvular atrial fibrillation Zhu Zhu, Chenyue Qian, Cunjing Su, Hong Tao, Jiaojiao Mao, Zhening Guo, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-1544590/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 11 You are reading this latest preprint version Abstract Aims: This study aimed to analyze associations between genetic variants and plasma concentrations along with clinical outcomes in dabigatran in patients with non-valvular atrial fibrillation (NVAF). Methods: We conducted a prospective study and enrolled NVAF patients treated with dabigatran in the real world. A total of 86 patients treated with 110 mg DE twice daily were recruited for this study. Blood samples were obtained from each patient and used for genotyping and determination of plasma dabigatran concentration. All bleeding and thromboembolic complications were recorded during the 1.5 years of follow-up. Results: Eighty-three patients provided samples at the trough plasma level of dabigatran, and 58 patients provided samples at the peak plasma level of dabigatran. There was a significant association between the CES1 SNP rs8192935 and trough plasma concentrations of dabigatran ( P =0.013). The ABCB1 SNP c.2482-2236G>A (rs4148738) was associated with major bleeding events in the addictive model ( P =0.046, OR=3.29) and dominant model ( P =0.040, OR=8.17). Additionally, the ABCB1 SNP c.3435C>T (rs1045642) was associated with the incidence of major bleeding events in the addictive model ( P =0.043, OR=3.34) and dominant model ( P =0.046, OR=7.77). However, no significant associations were found between all the SNPs and the incidence of minor bleeding events. Conclusions: Our results indicated that the CES1 polymorphism rs8192935 was associated with trough plasma concentrations of dabigatran. Carriers of the G allele had increased trough plasma concentrations of dabigatran compared to noncarriers. The ABCB1 polymorphisms rs4148738 and rs1045642 were associated with an increased risk for major bleeding events for the first time in a Chinese population. Dabigatran ABCB1 CES1 Single nucleotide polymorphisms. Introduction Non-valvular atrial fibrillation (NVAF) is the most common cardiac arrhythmia and is associated with an increased risk of ischemic stroke globally[ 1 , 2 ]. Dabigatran etexilate (DE) is a novel non-vitamin K antagonist oral anticoagulant (NOAC) that is widely used in NVAF patients to prevent the formation of thrombus[ 3 , 4 ]. DE was given in fixed-dose treatments without coagulation monitoring, which was shown to be more effective and safer for patients than vitamin K antagonists[ 3 ]. The effect of genetic factors on the pharmacokinetics of active dabigatran metabolites has been investigated in several studies[ 5 – 10 ]. Furthermore, dabigatran was also observed to cause clinical bleeding, which is closely associated with genetic polymorphisms[ 6 , 7 , 10 ]. The major genetic determinants involved in the metabolism of DE are the carboxylesterase 1 (CES1) and ATP binding cassette subfamily B member 1 (ABCB1) genes[ 11 – 13 ]. Single nucleotide polymorphisms (SNPs) of CES1 and ABCB1 have shown a significant effect on dabigatran dosing variations and their safety parameters. However, few studies have examined Asian populations that differ in the risk of bleeding and genetic polymorphisms under anticoagulant therapy conditions, and the genetic impact on dabigatran PK/PD in Chinese or Asian populations remains unclear[ 12 ]. The only study conducted at Zhongshan Hospital 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[ 6 ]. To date, very few pharmacogenetic studies on dabigatran in Asian patients have been published, and the evidence level of these associations is low. Therefore, the purpose of our study was to identify the impact of gene polymorphisms on the plasma concentration and clinical events of dabigatran in Chinese patients treated with DE for NVAF. Methods Study population This was a prospective study performed in the atrial fibrillation (AF) clinic of the Second Affiliated Hospital of Soochow University in China between January 2018 and June 2019. A total of 86 patients treated with 110 mg DE twice daily were recruited for this study. All patients included in our study had received dabigatran for at least 18 continuous months and visited the clinic at least once a month for long-term follow-up. This study was approved by the Ethics Review Board of the Second Affiliated Hospital of Soochow University (approval number JD-LK-2018-069-01) and was performed in accordance with the Declaration of Helsinki. All patients signed informed consent prior to this study. The inclusion criteria were[ 14 ]: (1) diagnosed with NVAF; (2) receiving anticoagulant therapy with oral DE for a minimum of eighteen months; and (3) provided at least one valid blood sample for SNP detection. We excluded patients who were pregnant, younger than 18 years of age, suffered severe vascular heart disease, severe liver damage or cancer, had prior kidney transplant or long-term dialysis, or were unable to fulfill the follow-up visits. Baseline characteristics were collected for all enrolled patients (shown in Table 1 ). All bleeding and thromboembolic complications were recorded during the 1.5 years of follow-up. Major bleeding was defined as a reduction in the hemoglobin level of at least 20 g/L, transfusion of at least 2 U blood, or symptomatic bleeding in a critical area or organ. All other bleeding was considered minor[ 14 , 15 ]. Any bleeding events were composed of major and minor bleeding events. Table 1 Demographics and clinical characteristics of dabigatran-treated patients enrolled in this study Variables Characteristics of the study population (n = 86) Male, n(%) 49(56.98) Age(years), mean(SD) 72.15 ± 9.17 BMI(kg/m2), mean(SD) 25.01 ± 3.76 Creatinine clearance, mL/min 70.44 ± 26.81 CHA2DS2-VASc, mean(SD) 3.41 ± 1.69 HAS-BLED, mean(SD) 1.15 ± 0.88 AST(U/L), mean(SD) 22.84 ± 11.91 ALT(U/L), mean(SD) 23.14 ± 16.55 History of hypertension, n(%) 62(72.09) History of stroke, n(%) 14(16.28) History of diabetes mellitus, n(%) 23(26.74) Aspirin use, n(%) 3(3.49) Clopidogrel use, n(%) 3(3.49) Amiodarone use, n(%) 4(4.65) Trough concentration(ng/mL), mean(SD) 51.32 ± 38.63 (n = 83) Peak concentration(ng/mL), mean(SD) 101.12 ± 56.3 (n = 58) Any ischemic event, n(%) 9(10.47) Any bleeding, n(%) 17(19.77) Major bleeding, n(%) 4(4.65) Minor bleeding, n(%) 13(15.12) Selection Of Snps And Genotyping A total of 86 patients treated with 110 mg DE twice daily were recruited for this study. Peripheral blood samples (3 mL) were collected in EDTA anticoagulant tubes for each patient. Genomic DNA was extracted using a Genomic DNA Purification Kit according to standard protocols. Genotyping of each polymorphism in the ABCB1 and CES1 genes was carried out by the MassARRAY® MALDI-TOF System. Four SNPs in 2 genes (ABCB1 and CES1) were selected from the National Center for Biotechnology Information (NCBI) database (Table 2 ). All of the SNPs satisfied the following criteria: (1) SNPs that are associated with cardiac arrhythmia occurrence or development according to the results of existing research[ 16 – 21 ]; (2) SNPs that may influence the function or expression of ABCB1 and CES1 by NCBI; and (3) minor allele frequency (MAF) ≥ 5% in the Chinese Han population. Table 2 Allele frequencies by loci for ABCB1 and CES1 in the subjects Gene SNP Genotype N(%) Minor allele MAF(%) HWE, p value ABCB1 rs4148738 CC 18(16.1) C 39.7 0.9 CT 53(47.3) TT 41(36.6) rs1045642 AA 18(16.1) A 37.9 0.45 AG 49(43.8) GG 45(40.2) CES1 rs2244613 GG 43(38.4) T 40.2 0.25 GT 48(42.8) TT 21(18.8) rs8192935 AA 65(58.0) G 22.8 0.33 AG 43(38.4) GG 4(3.6) Abbreviations: SNP, single nucleotide polymorphism; MAF, minor allele frequency; HWE, Hardy-Weinberg equilibrium Measurement Of Dabigatran Plasma Concentration A total of 3 ml of peripheral blood was collected from each patient, and those collected 12 hours after the previous dose were considered at the trough plasma level of dabigatran, while those obtained 2 hours after the dose were considered at the peak level. Blood samples containing dabigatran were obtained from whole blood by centrifugation at 3000 rpm at 4°C for 5 min and stored at -80°C for further detection. The plasma concentration of DE was detected by UPLC–MS/MS as described previously[ 14 ]. Statistical analysis The chi-squared test was used to evaluate the Hardy-Weinberg equilibrium or allele frequencies of all SNPs. Unconditional logistic regression was conducted to calculate the adjusted odds ratio (OR) and 95% confidence intervals (95% CI). The association analysis was tested using logistic regression analysis with Plink under additive, dominant, and recessive models. The test of significance was set at two-tailed P = 0.05. Results A total of 86 patients treated with 110 mg DE twice daily were recruited for this study. All subjects were Chinese and had a mean (SD) age of 72.15 ± 9.17 at the time of recruitment. Four SNPs were genotyped in these subjects, and all SNPs conformed to Hardy-Weinberg equilibrium (P > 0 05) (shown in Table 2 ). Eighty-three patients provided samples at the trough plasma level of dabigatran, and 58 patients provided samples at the peak plasma level of dabigatran. Peak and trough plasma concentrations of different genotypes are shown in Table 3 . Table 3 Association between single nucleotide polymorphisms and peak and trough plasma concentrations of dabigatran Gene SNP Genotype Trough (ng/mL) Peak (ng/mL) ABCB1 rs4148738 CC N = 13 46.20 ± 31.10 N = 10 82.30 ± 58.66 CT N = 45 48.80 ± 42.93 N = 26 97.33 ± 60.65 TT N = 25 58.52 ± 34.93 N = 22 114.16 ± 50.35 P value 0.535 0.310 rs2032582 AT N = 17 43.12 ± 34.16 N = 6 87.89 ± 54.86 CC N = 11 45.95 ± 31.91 N = 9 109.01 ± 41.55 AA N = 13 46.20 ± 31.10 N = 10 82.30 ± 58.66 AC N = 28 52.26 ± 47.74 N = 20 100.16 ± 63.34 TT N = 4 65.23 ± 34.14 N = 3 154.06 ± 74.07 CT N = 10 69.66 ± 37.17 N = 10 106.83 ± 50.45 P value 0.568 0.520 rs1045642 AA N = 13 43.01 ± 32.90 N = 11 75.55 ± 59.19 AG N = 41 51.24 ± 44.78 N = 23 99.44 ± 51.85 GG N = 29 55.17 ± 32.39 N = 24 114.45 ± 58.29 P value 0.650 0.169 CES1 rs2244613 GG N = 32 44.21 ± 30.20 N = 20 89.16 ± 57.00 GT N = 37 58.03 ± 45.72 N = 28 113.09 ± 58.86 TT N = 14 49.86 ± 36.21 N = 10 91.54 ± 48.04 P value 0.338 0.304 rs8192935 AA N = 45 42.73 ± 29.04 N = 31 89.58 ± 54.35 AG N = 36 58.66 ± 45.46 N = 25 112.23 ± 58.03 GG N = 2 112.69 ± 40.63 N = 2 141.08 ± 63.29 P value 0.013 * 0.202 Data are expressed as the mean ± standard deviation There was a significant association between the CES1 SNP rs8192935 and trough 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. No significant association was observed between other SNPs and the plasma concentration of dabigatran (Table 3 ). In an exploratory analysis, ischemic and bleeding events related to patients treated with DE were compared among different genotypes of ABCB1 and CES1 (Table 4 ). Clinical outcomes, including ischemic events and bleeding events, were recorded throughout the 1.5-year follow-up. All bleeding events were composed of major and minor bleeding events. Table 4 Association between single nucleotide polymorphisms and ischemic events and bleeding in all subjects. Gene SNP Mod Stroke/SEE Any Bleeding Major bleeding Minor bleeding OR (95%CI) P OR (95%CI) P OR (95%CI) P OR (95%CI) P ABCB1 rs4148738 Add 1.52 (0.62 ~ 3.70) 0.359 2.29 (1.05 ~ 5.01) 0.038 * 3.29 (1.02 ~ 10.59) 0.046 * 1.59 (0.73 ~ 3.44) 0.240 Dom 1.50 (0.63 ~ 3.60) 0.360 2.30 (1.06 ~ 4.96) 0.035 * 8.17 (1.10 ~ 60.88) 0.040 * 1.61 (0.74 ~ 3.49) 0.225 Rec 1.65 (0.65 ~ 4.15) 0.290 2.19 (1.00 ~ 4.76) 0.048 * 2.55 (0.93 ~ 7.03) 0.070 1.56 (0.71 ~ 3.42) 0.266 rs1045642 Add 1.45 (0.60 ~ 3.49) 0.404 2.31 (1.06 ~ 5.03) 0.034 * 3.34 (1.04 ~ 10.74) 0.043 * 1.61 (0.74 ~ 3.50) 0.230 Dom 1.47 (0.61 ~ 3.52) 0.388 2.27 (1.06 ~ 4.87) 0.034 * 7.77 (1.03 ~ 58.39) 0.046 * 1.62 (0.74 ~ 3.49) 0.225 Rec 1.52 (0.62 ~ 3.74) 0.362 2.20 (1.00 ~ 4.82) 0.049 * 2.50 (0.89 ~ 7.00) 0.083 1.57 (0.72 ~ 3.46) 0.260 CES1 rs2244613 Add 1.55 (0.63 ~ 3.79) 0.339 2.30 (1.05 ~ 5.04) 0.038 * 2.62 (0.95 ~ 7.21) 0.062 1.61 (0.74 ~ 3.50) 0.225 Dom 1.50 (0.63 ~ 3.60) 0.360 2.28 (1.04 ~ 5.00) 0.038 * 2.61 (0.94 ~ 7.24) 0.066 1.62 (0.74 ~ 3.51) 0.227 Rec 1.54 (0.63 ~ 3.77) 0.342 2.33 (1.06 ~ 5.14) 0.035 * 2.67 (0.97 ~ 7.33) 0.058 1.63 (0.75 ~ 3.55) 0.216 rs8192935 Add 1.67 (0.65 ~ 4.29) 0.290 2.26 (1.03 ~ 4.96) 0.042 * 2.50 (0.88 ~ 7.05) 0.084 1.61 (0.74 ~ 3.53) 0.232 Dom 1.67 (0.65 ~ 4.31) 0.290 2.31 (1.04 ~ 5.10) 0.039 * 2.39 (0.83 ~ 6.83) 0.105 1.67 (0.75 ~ 3.74) 0.209 Rec 1.54 (0.63 ~ 3.75) 0.348 2.42 (1.08 ~ 5.42) 0.031 * 2.65 (0.96 ~ 7.34) 0.060 1.72 (0.77 ~ 3.79) 0.180 SEE: systemic embolic events; ADD: additive model; DOM: dominant model; REC: recessive model; additive model: comparing the minor allele with major allele subjects; dominant model: comparing carriers of the minor allele with the major homozygous subjects; recessive model: comparing carriers of the major allele with the minor homozygous subjects. Overall, the incidence of ischemic events (stroke/SEE) in the included population was 10.47%. The incidence of ischemic events did not vary considerably among genotypes of ABCB1 or CES1. The incidence of any bleeding event in the included population was 19.77%. There was a significant association between all the SNPs and the incidence of any bleeding event (Table 4 ). Further analysis showed that there was a significant association between the ABCB1 SNP c.2482-2236G > A (rs4148738) and major bleeding events in the addictive model ( P = 0.046, OR = 3.29) and dominant model ( P = 0.040, OR = 8.17). Additionally, the ABCB1 SNP c.3435C > T (rs1045642) was associated with the incidence of major bleeding events in the addictive model ( P = 0.043, OR = 3.34) and dominant model ( P = 0.046, OR = 7.77). However, no significant associations were found between all the SNPs and the incidence of minor bleeding events. Discussion 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[ 13 ]. 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[ 7 ]. 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[ 5 ]. 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[ 6 ]. 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[ 23 ]. 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[ 6 ]. 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. Conclusions In our real-world study, our results indicated that the CES1 polymorphism rs8192935 was associated with trough plasma concentrations of dabigatran. Carriers of the G allele had increased trough plasma concentrations of dabigatran compared to noncarriers. The ABCB1 polymorphisms rs4148738 and rs1045642 were associated with an increased risk for major bleeding events. These genetic associations could be useful for predicting the effect of dabigatran along with the bleeding risk for individuals, and further studies with larger sample sizes are needed to verify the findings. Abbreviations NVAF Non-valvular atrial fibrillation NOAC non-vitamin K antagonist oral anticoagulant DE Dabigatran etexilate CES1 carboxylesterase 1 ABCB1 ATP binding cassette subfamily B member 1 SNP Single nucleotide polymorphism. Declarations Acknowledgements The authors express their gratitude to department of cardiology of the Second Affiliated Hospital of Soochow University for their cooperation and assistance. Authors’ contributions Zhu Zhu and Chenyue Qian contributed to the conception and design of the work. Cunjing Su and Hong Tao contributed to the analysis and interpretation of the study data. Jiaojiao Mao and Zhening Guo contributed to data collection and patients follow-up. Xinyi Zhu and Jie Pan contributed to the drafting of the manuscript. All authors read and approved the final manuscript. Funding This work was supported by Suzhou Bureau of Science and Technology (Basic Research in Medical and Health Sciences, SYS2019060), Jiangsu Pharmaceutical Association (No. A201814), Jiangsu Research Hospital Society (No. JY202009), Suzhou Pharmaceutical Association (No. syhky201803) and Lift Project for Discipline Construction of The Second Affiliated Hospital of Soochow University (XKTJ-XK202010). Availability of data and materials The datasets used and analyzed during the current study are available from the corresponding author on reasonable request. Ethics approval and consent to participate This study was approved by the Ethics Review Board of the Second Affiliated Hospital of Soochow University (approval number JD-LK-2018-069-01) and was performed in accordance with the Declaration of Helsinki. All patients signed informed consent prior to this study. Written informed consent was obtained from each participant at each examination phase. Consent for publication Not applicable. Competing interests The authors declare that they have no conflicts of interest. Author details 1 Department of Pharmacy, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, China; 2 Department of cardiology, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, China. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-1544590","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":99435960,"identity":"8ad18657-d5d9-4255-952f-ecbda00970b8","order_by":0,"name":"Zhu Zhu","email":"","orcid":"","institution":"The Second Affiliated Hospital of Soochow University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Zhu","middleName":"","lastName":"Zhu","suffix":""},{"id":99435962,"identity":"c8aa6be2-0245-4496-a35c-fd3285b287b6","order_by":1,"name":"Chenyue Qian","email":"","orcid":"","institution":"The Second Affiliated Hospital of Soochow University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Chenyue","middleName":"","lastName":"Qian","suffix":""},{"id":99435963,"identity":"748c6be8-30ba-4a2d-8116-32995d27d49e","order_by":2,"name":"Cunjing Su","email":"","orcid":"","institution":"The Second Affiliated Hospital of Soochow University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Cunjing","middleName":"","lastName":"Su","suffix":""},{"id":99435964,"identity":"95896f51-6d34-4f78-8914-58a13b3d6198","order_by":3,"name":"Hong Tao","email":"","orcid":"","institution":"The Second Affiliated Hospital of Soochow University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Hong","middleName":"","lastName":"Tao","suffix":""},{"id":99435965,"identity":"cb6509f1-24b3-4945-a7cb-15b685e6b19f","order_by":4,"name":"Jiaojiao Mao","email":"","orcid":"","institution":"The Second Affiliated Hospital of Soochow University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Jiaojiao","middleName":"","lastName":"Mao","suffix":""},{"id":99435968,"identity":"9eb5db23-8c85-4db6-ab85-159b18eb0066","order_by":5,"name":"Zhening Guo","email":"","orcid":"","institution":"The Second Affiliated Hospital of Soochow University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Zhening","middleName":"","lastName":"Guo","suffix":""},{"id":99435970,"identity":"822e6556-b745-46fb-81c9-896d3c9ade41","order_by":6,"name":"Xinyi Zhu","email":"","orcid":"","institution":"The Second Affiliated Hospital of Soochow University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Xinyi","middleName":"","lastName":"Zhu","suffix":""},{"id":99435971,"identity":"238053ed-6e2f-4e28-aaf6-2d8810a3f0d9","order_by":7,"name":"Jie Pan","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAwElEQVRIiWNgGAWjYHACZjDJz8x8+AFpWiTb2dIMSNNicJ5HQYIo9ebsZw8b8+6wyzM+zMNgwFBjE01Qi2VPXnIy75nkYrPDvAceMBxLy20gpMXgQI7xYd425sRth/kSDBgbDhOh5fwbkJb6xM3NPAYSxGm5kWOczNt2OHEDM7FaLGe8MTace+Z44ozDwEBOIMYv5vw5xhJvd1Qn9vcfPvzgQ40NEQ4DYiZemLIEQsphWhh/EjR5FIyCUTAKRjQAAIldPnrHrG9tAAAAAElFTkSuQmCC","orcid":"","institution":"The Second Affiliated Hospital of Soochow University","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Jie","middleName":"","lastName":"Pan","suffix":""}],"badges":[],"createdAt":"2022-04-11 05:59:19","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-1544590/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-1544590/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":20565700,"identity":"68aa4a28-cb3f-4ec7-8cae-0f8c1595d05e","added_by":"auto","created_at":"2022-04-20 16:51:40","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":931821,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-1544590/v1/bebe600a-beff-451d-bbd1-069bb529e716.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"The impact of ABCB1 and CES1 polymorphisms on the safety of dabigatran in patients with non-valvular atrial fibrillation","fulltext":[{"header":"Introduction","content":"\u003cp\u003eNon-valvular atrial fibrillation (NVAF) is the most common cardiac arrhythmia and is associated with an increased risk of ischemic stroke globally[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Dabigatran etexilate (DE) is a novel non-vitamin K antagonist oral anticoagulant (NOAC) that is widely used in NVAF patients to prevent the formation of thrombus[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. DE was given in fixed-dose treatments without coagulation monitoring, which was shown to be more effective and safer for patients than vitamin K antagonists[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe effect of genetic factors on the pharmacokinetics of active dabigatran metabolites has been investigated in several studies[\u003cspan additionalcitationids=\"CR6 CR7 CR8 CR9\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Furthermore, dabigatran was also observed to cause clinical bleeding, which is closely associated with genetic polymorphisms[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. The major genetic determinants involved in the metabolism of DE are the carboxylesterase 1 (CES1) and ATP binding cassette subfamily B member 1 (ABCB1) genes[\u003cspan additionalcitationids=\"CR12\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Single nucleotide polymorphisms (SNPs) of CES1 and ABCB1 have shown a significant effect on dabigatran dosing variations and their safety parameters.\u003c/p\u003e \u003cp\u003eHowever, few studies have examined Asian populations that differ in the risk of bleeding and genetic polymorphisms under anticoagulant therapy conditions, and the genetic impact on dabigatran PK/PD in Chinese or Asian populations remains unclear[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. The only study conducted at Zhongshan Hospital 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[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eTo date, very few pharmacogenetic studies on dabigatran in Asian patients have been published, and the evidence level of these associations is low. Therefore, the purpose of our study was to identify the impact of gene polymorphisms on the plasma concentration and clinical events of dabigatran in Chinese patients treated with DE for NVAF.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy population\u003c/h2\u003e \u003cp\u003eThis was a prospective study performed in the atrial fibrillation (AF) clinic of the Second Affiliated Hospital of Soochow University in China between January 2018 and June 2019. A total of 86 patients treated with 110 mg DE twice daily were recruited for this study. All patients included in our study had received dabigatran for at least 18 continuous months and visited the clinic at least once a month for long-term follow-up. This study was approved by the Ethics Review Board of the Second Affiliated Hospital of Soochow University (approval number JD-LK-2018-069-01) and was performed in accordance with the Declaration of Helsinki. All patients signed informed consent prior to this study.\u003c/p\u003e \u003cp\u003eThe inclusion criteria were[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]: (1) diagnosed with NVAF; (2) receiving anticoagulant therapy with oral DE for a minimum of eighteen months; and (3) provided at least one valid blood sample for SNP detection. We excluded patients who were pregnant, younger than 18 years of age, suffered severe vascular heart disease, severe liver damage or cancer, had prior kidney transplant or long-term dialysis, or were unable to fulfill the follow-up visits.\u003c/p\u003e \u003cp\u003eBaseline characteristics were collected for all enrolled patients (shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). All bleeding and thromboembolic complications were recorded during the 1.5 years of follow-up. Major bleeding was defined as a reduction in the hemoglobin level of at least 20 g/L, transfusion of at least 2 U blood, or symptomatic bleeding in a critical area or organ. All other bleeding was considered minor[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Any bleeding events were composed of major and minor bleeding events.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eDemographics and clinical characteristics of dabigatran-treated patients enrolled in this study\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariables\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCharacteristics of the study population (n\u0026thinsp;=\u0026thinsp;86)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale, n(%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e49(56.98)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge(years), mean(SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e72.15\u0026thinsp;\u0026plusmn;\u0026thinsp;9.17\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBMI(kg/m2), mean(SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e25.01\u0026thinsp;\u0026plusmn;\u0026thinsp;3.76\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCreatinine clearance, mL/min\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e70.44\u0026thinsp;\u0026plusmn;\u0026thinsp;26.81\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCHA2DS2-VASc, mean(SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3.41\u0026thinsp;\u0026plusmn;\u0026thinsp;1.69\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHAS-BLED, mean(SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.15\u0026thinsp;\u0026plusmn;\u0026thinsp;0.88\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAST(U/L), mean(SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e22.84\u0026thinsp;\u0026plusmn;\u0026thinsp;11.91\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eALT(U/L), mean(SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e23.14\u0026thinsp;\u0026plusmn;\u0026thinsp;16.55\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHistory of hypertension, n(%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e62(72.09)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHistory of stroke, n(%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14(16.28)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHistory of diabetes mellitus, n(%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e23(26.74)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAspirin use, n(%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3(3.49)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eClopidogrel use, n(%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3(3.49)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAmiodarone use, n(%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4(4.65)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTrough concentration(ng/mL), mean(SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e51.32\u0026thinsp;\u0026plusmn;\u0026thinsp;38.63 (n\u0026thinsp;=\u0026thinsp;83)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePeak concentration(ng/mL), mean(SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e101.12\u0026thinsp;\u0026plusmn;\u0026thinsp;56.3 (n\u0026thinsp;=\u0026thinsp;58)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAny ischemic event, n(%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9(10.47)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAny bleeding, n(%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e17(19.77)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMajor bleeding, n(%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4(4.65)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMinor bleeding, n(%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13(15.12)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e\n\u003ch2\u003eSelection Of Snps And Genotyping\u003c/h2\u003e\n\u003cp\u003eA total of 86 patients treated with 110 mg DE twice daily were recruited for this study. Peripheral blood samples (3 mL) were collected in EDTA anticoagulant tubes for each patient. Genomic DNA was extracted using a Genomic DNA Purification Kit according to standard protocols. Genotyping of each polymorphism in the ABCB1 and CES1 genes was carried out by the MassARRAY\u0026reg; MALDI-TOF System.\u003c/p\u003e \u003cp\u003eFour SNPs in 2 genes (ABCB1 and CES1) were selected from the National Center for Biotechnology Information (NCBI) database (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). All of the SNPs satisfied the following criteria: (1) SNPs that are associated with cardiac arrhythmia occurrence or development according to the results of existing research[\u003cspan additionalcitationids=\"CR17 CR18 CR19 CR20\" citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]; (2) SNPs that may influence the function or expression of ABCB1 and CES1 by NCBI; and (3) minor allele frequency (MAF)\u0026thinsp;\u0026ge;\u0026thinsp;5% in the Chinese Han population.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eAllele frequencies by loci for ABCB1 and CES1 in the subjects\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGene\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSNP\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGenotype\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eN(%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eMinor allele\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eMAF(%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eHWE,\u003c/p\u003e \u003cp\u003ep value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eABCB1\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003e\u003cb\u003ers4148738\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e18(16.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e39.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.9\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e53(47.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eTT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e41(36.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003e\u003cb\u003ers1045642\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e18(16.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e37.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.45\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e49(43.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e45(40.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCES1\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003e\u003cb\u003ers2244613\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e43(38.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e40.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.25\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e48(42.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eTT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e21(18.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003e\u003cb\u003ers8192935\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e65(58.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e22.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.33\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e43(38.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e4(3.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003eAbbreviations: SNP, single nucleotide polymorphism; MAF, minor allele frequency; HWE, Hardy-Weinberg equilibrium\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e\n\u003ch2\u003eMeasurement Of Dabigatran Plasma Concentration\u003c/h2\u003e\n\u003cp\u003eA total of 3 ml of peripheral blood was collected from each patient, and those collected 12 hours after the previous dose were considered at the trough plasma level of dabigatran, while those obtained 2 hours after the dose were considered at the peak level. Blood samples containing dabigatran were obtained from whole blood by centrifugation at 3000 rpm at 4\u0026deg;C for 5 min and stored at -80\u0026deg;C for further detection. The plasma concentration of DE was detected by UPLC\u0026ndash;MS/MS as described previously[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e].\u003c/p\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eThe chi-squared test was used to evaluate the Hardy-Weinberg equilibrium or allele frequencies of all SNPs. Unconditional logistic regression was conducted to calculate the adjusted odds ratio (OR) and 95% confidence intervals (95% CI). The association analysis was tested using logistic regression analysis with Plink under additive, dominant, and recessive models. The test of significance was set at two-tailed \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.05.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eA total of 86 patients treated with 110 mg DE twice daily were recruited for this study. All subjects were Chinese and had a mean (SD) age of 72.15\u0026thinsp;\u0026plusmn;\u0026thinsp;9.17 at the time of recruitment. Four SNPs were genotyped in these subjects, and all SNPs conformed to Hardy-Weinberg equilibrium (P\u0026thinsp;\u0026gt;\u0026thinsp;0 05) (shown in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Eighty-three patients provided samples at the trough plasma level of dabigatran, and 58 patients provided samples at the peak plasma level of dabigatran. Peak and trough plasma concentrations of different genotypes are shown in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eAssociation between single nucleotide polymorphisms and peak and trough plasma concentrations of dabigatran\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGene\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSNP\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGenotype\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003eTrough (ng/mL)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003ePeak (ng/mL)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eABCB1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003ers4148738\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e46.20\u0026thinsp;\u0026plusmn;\u0026thinsp;31.10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e82.30\u0026thinsp;\u0026plusmn;\u0026thinsp;58.66\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e48.80\u0026thinsp;\u0026plusmn;\u0026thinsp;42.93\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e97.33\u0026thinsp;\u0026plusmn;\u0026thinsp;60.65\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eTT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e58.52\u0026thinsp;\u0026plusmn;\u0026thinsp;34.93\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e114.16\u0026thinsp;\u0026plusmn;\u0026thinsp;50.35\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.535\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.310\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003ers2032582\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e43.12\u0026thinsp;\u0026plusmn;\u0026thinsp;34.16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e87.89\u0026thinsp;\u0026plusmn;\u0026thinsp;54.86\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e45.95\u0026thinsp;\u0026plusmn;\u0026thinsp;31.91\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e109.01\u0026thinsp;\u0026plusmn;\u0026thinsp;41.55\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e46.20\u0026thinsp;\u0026plusmn;\u0026thinsp;31.10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e82.30\u0026thinsp;\u0026plusmn;\u0026thinsp;58.66\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e52.26\u0026thinsp;\u0026plusmn;\u0026thinsp;47.74\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e100.16\u0026thinsp;\u0026plusmn;\u0026thinsp;63.34\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eTT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e65.23\u0026thinsp;\u0026plusmn;\u0026thinsp;34.14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e154.06\u0026thinsp;\u0026plusmn;\u0026thinsp;74.07\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e69.66\u0026thinsp;\u0026plusmn;\u0026thinsp;37.17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e106.83\u0026thinsp;\u0026plusmn;\u0026thinsp;50.45\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.568\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.520\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003ers1045642\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e43.01\u0026thinsp;\u0026plusmn;\u0026thinsp;32.90\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e75.55\u0026thinsp;\u0026plusmn;\u0026thinsp;59.19\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;41\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e51.24\u0026thinsp;\u0026plusmn;\u0026thinsp;44.78\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e99.44\u0026thinsp;\u0026plusmn;\u0026thinsp;51.85\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e55.17\u0026thinsp;\u0026plusmn;\u0026thinsp;32.39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e114.45\u0026thinsp;\u0026plusmn;\u0026thinsp;58.29\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.650\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.169\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCES1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003ers2244613\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e44.21\u0026thinsp;\u0026plusmn;\u0026thinsp;30.20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e89.16\u0026thinsp;\u0026plusmn;\u0026thinsp;57.00\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e58.03\u0026thinsp;\u0026plusmn;\u0026thinsp;45.72\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e113.09\u0026thinsp;\u0026plusmn;\u0026thinsp;58.86\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eTT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e49.86\u0026thinsp;\u0026plusmn;\u0026thinsp;36.21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e91.54\u0026thinsp;\u0026plusmn;\u0026thinsp;48.04\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.338\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.304\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003ers8192935\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e42.73\u0026thinsp;\u0026plusmn;\u0026thinsp;29.04\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e89.58\u0026thinsp;\u0026plusmn;\u0026thinsp;54.35\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;36\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e58.66\u0026thinsp;\u0026plusmn;\u0026thinsp;45.46\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e112.23\u0026thinsp;\u0026plusmn;\u0026thinsp;58.03\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e112.69\u0026thinsp;\u0026plusmn;\u0026thinsp;40.63\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e141.08\u0026thinsp;\u0026plusmn;\u0026thinsp;63.29\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.013\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.202\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003eData are expressed as the mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThere was a significant association between the CES1 SNP rs8192935 and trough plasma concentrations of dabigatran (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.013). For the trough levels, carriers of the G allele had increased trough plasma concentrations of dabigatran compared to the noncarriers. No significant association was observed between other SNPs and the plasma concentration of dabigatran (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn an exploratory analysis, ischemic and bleeding events related to patients treated with DE were compared among different genotypes of ABCB1 and CES1 (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). Clinical outcomes, including ischemic events and bleeding events, were recorded throughout the 1.5-year follow-up. All bleeding events were composed of major and minor bleeding events.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eAssociation between single nucleotide polymorphisms and ischemic events and bleeding in all subjects.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"11\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c11\" colnum=\"11\"\u003e\u003c/div\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eGene\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eSNP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eMod\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003eStroke/SEE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003eAny Bleeding\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c9\" namest=\"c8\"\u003e \u003cp\u003eMajor bleeding\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c11\" namest=\"c10\"\u003e \u003cp\u003eMinor bleeding\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eOR (95%CI)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eOR (95%CI)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eOR (95%CI)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eOR (95%CI)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eP\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"5\" rowspan=\"6\"\u003e \u003cp\u003eABCB1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003ers4148738\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAdd\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.52 (0.62\u0026thinsp;~\u0026thinsp;3.70)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.359\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2.29 (1.05\u0026thinsp;~\u0026thinsp;5.01)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.038\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e3.29 (1.02\u0026thinsp;~\u0026thinsp;10.59)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.046\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e1.59 (0.73\u0026thinsp;~\u0026thinsp;3.44)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0.240\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDom\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.50 (0.63\u0026thinsp;~\u0026thinsp;3.60)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.360\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2.30 (1.06\u0026thinsp;~\u0026thinsp;4.96)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.035\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e8.17 (1.10\u0026thinsp;~\u0026thinsp;60.88)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.040\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e1.61 (0.74\u0026thinsp;~\u0026thinsp;3.49)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0.225\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRec\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.65 (0.65\u0026thinsp;~\u0026thinsp;4.15)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.290\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2.19 (1.00\u0026thinsp;~\u0026thinsp;4.76)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.048\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e2.55 (0.93\u0026thinsp;~\u0026thinsp;7.03)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.070\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e1.56 (0.71\u0026thinsp;~\u0026thinsp;3.42)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0.266\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003ers1045642\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAdd\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.45 (0.60\u0026thinsp;~\u0026thinsp;3.49)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.404\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2.31 (1.06\u0026thinsp;~\u0026thinsp;5.03)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.034\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e3.34 (1.04\u0026thinsp;~\u0026thinsp;10.74)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.043\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e1.61 (0.74\u0026thinsp;~\u0026thinsp;3.50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0.230\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDom\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.47 (0.61\u0026thinsp;~\u0026thinsp;3.52)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.388\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2.27 (1.06\u0026thinsp;~\u0026thinsp;4.87)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.034\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e7.77 (1.03\u0026thinsp;~\u0026thinsp;58.39)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.046\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e1.62 (0.74\u0026thinsp;~\u0026thinsp;3.49)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0.225\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRec\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.52 (0.62\u0026thinsp;~\u0026thinsp;3.74)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.362\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2.20 (1.00\u0026thinsp;~\u0026thinsp;4.82)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.049\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e2.50 (0.89\u0026thinsp;~\u0026thinsp;7.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.083\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e1.57 (0.72\u0026thinsp;~\u0026thinsp;3.46)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0.260\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"5\" rowspan=\"6\"\u003e \u003cp\u003eCES1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003ers2244613\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAdd\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.55 (0.63\u0026thinsp;~\u0026thinsp;3.79)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.339\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2.30 (1.05\u0026thinsp;~\u0026thinsp;5.04)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.038\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e2.62 (0.95\u0026thinsp;~\u0026thinsp;7.21)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.062\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e1.61 (0.74\u0026thinsp;~\u0026thinsp;3.50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0.225\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDom\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.50 (0.63\u0026thinsp;~\u0026thinsp;3.60)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.360\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2.28 (1.04\u0026thinsp;~\u0026thinsp;5.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.038\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e2.61 (0.94\u0026thinsp;~\u0026thinsp;7.24)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.066\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e1.62 (0.74\u0026thinsp;~\u0026thinsp;3.51)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0.227\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRec\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.54 (0.63\u0026thinsp;~\u0026thinsp;3.77)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.342\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2.33 (1.06\u0026thinsp;~\u0026thinsp;5.14)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.035\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e2.67 (0.97\u0026thinsp;~\u0026thinsp;7.33)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.058\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e1.63 (0.75\u0026thinsp;~\u0026thinsp;3.55)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0.216\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003ers8192935\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAdd\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.67 (0.65\u0026thinsp;~\u0026thinsp;4.29)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.290\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2.26 (1.03\u0026thinsp;~\u0026thinsp;4.96)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.042\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e2.50 (0.88\u0026thinsp;~\u0026thinsp;7.05)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.084\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e1.61 (0.74\u0026thinsp;~\u0026thinsp;3.53)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0.232\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDom\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.67 (0.65\u0026thinsp;~\u0026thinsp;4.31)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.290\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2.31 (1.04\u0026thinsp;~\u0026thinsp;5.10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.039\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e2.39 (0.83\u0026thinsp;~\u0026thinsp;6.83)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.105\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e1.67 (0.75\u0026thinsp;~\u0026thinsp;3.74)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0.209\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRec\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.54 (0.63\u0026thinsp;~\u0026thinsp;3.75)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.348\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2.42 (1.08\u0026thinsp;~\u0026thinsp;5.42)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.031\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e2.65 (0.96\u0026thinsp;~\u0026thinsp;7.34)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.060\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e1.72 (0.77\u0026thinsp;~\u0026thinsp;3.79)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0.180\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"11\"\u003eSEE: systemic embolic events; ADD: additive model; DOM: dominant model; REC: recessive model; additive model: comparing the minor allele with major allele subjects; dominant model: comparing carriers of the minor allele with the major homozygous subjects; recessive model: comparing carriers of the major allele with the minor homozygous subjects.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eOverall, the incidence of ischemic events (stroke/SEE) in the included population was 10.47%. The incidence of ischemic events did not vary considerably among genotypes of ABCB1 or CES1. The incidence of any bleeding event in the included population was 19.77%. There was a significant association between all the SNPs and the incidence of any bleeding event (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). Further analysis showed that there was a significant association between the ABCB1 SNP c.2482-2236G\u0026thinsp;\u0026gt;\u0026thinsp;A (rs4148738) and major bleeding events in the addictive model (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.046, OR\u0026thinsp;=\u0026thinsp;3.29) and dominant model (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.040, OR\u0026thinsp;=\u0026thinsp;8.17). Additionally, the ABCB1 SNP c.3435C\u0026thinsp;\u0026gt;\u0026thinsp;T (rs1045642) was associated with the incidence of major bleeding events in the addictive model (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.043, OR\u0026thinsp;=\u0026thinsp;3.34) and dominant model (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.046, OR\u0026thinsp;=\u0026thinsp;7.77). However, no significant associations were found between all the SNPs and the incidence of minor bleeding events.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe polymorphisms of both ABCB1 and CES1 genes may lead to a significant association with pharmacokinetic variations and clinical outcomes of dabigatran [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. In this study, we found that the CES1 SNP rs8192935 was associated with the plasma concentrations of dabigatran (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;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.\u003c/p\u003e \u003cp\u003eCES1 is responsible for the biotransformation of dabigatran etexilate into the active metabolite[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. 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[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. 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[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Thus, more studies should be conducted in the Chinese population.\u003c/p\u003e \u003cp\u003eOur 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[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. 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[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. 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.\u003c/p\u003e \u003cp\u003eDabigatran 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[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Earlier studies have found associations between genetic variability and plasma levels of direct oral anticoagulants[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. 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[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIt can be found that the trough and peak concentrations of the ABCB1 rs4148738 TT genotype are significantly higher than those of other genotypes (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). 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.\u003c/p\u003e \u003cp\u003eIn 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.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eIn our real-world study, our results indicated that the CES1 polymorphism rs8192935 was associated with trough plasma concentrations of dabigatran. Carriers of the G allele had increased trough plasma concentrations of dabigatran compared to noncarriers. The ABCB1 polymorphisms rs4148738 and rs1045642 were associated with an increased risk for major bleeding events. These genetic associations could be useful for predicting the effect of dabigatran along with the bleeding risk for individuals, and further studies with larger sample sizes are needed to verify the findings.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eNVAF\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eNon-valvular atrial fibrillation\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eNOAC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003enon-vitamin K antagonist oral anticoagulant\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eDE\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eDabigatran etexilate\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCES1\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ecarboxylesterase 1\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eABCB1\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eATP binding cassette subfamily B member 1\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eSNP\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eSingle nucleotide polymorphism.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors express their gratitude to department of cardiology of the Second Affiliated Hospital of Soochow University for their cooperation and assistance.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eZhu Zhu and Chenyue Qian contributed to the conception and design of the work. Cunjing Su and Hong Tao contributed to the analysis and interpretation of the study data. Jiaojiao Mao and Zhening Guo contributed to data collection and patients follow-up. Xinyi Zhu and Jie Pan contributed to the drafting of the manuscript. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by Suzhou Bureau of Science and Technology (Basic Research in Medical and Health Sciences, SYS2019060), Jiangsu Pharmaceutical Association (No. A201814), Jiangsu Research Hospital Society (No. JY202009), Suzhou Pharmaceutical Association (No. syhky201803) and Lift Project for Discipline Construction of The Second Affiliated Hospital of Soochow University (XKTJ-XK202010).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was approved by the Ethics Review Board of the Second Affiliated Hospital of Soochow University (approval number JD-LK-2018-069-01) and was performed in accordance with the Declaration of Helsinki. All patients signed informed consent prior to this study. Written informed consent was obtained from each participant at each examination phase.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no\u0026nbsp;conflicts\u0026nbsp;of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor details\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e1\u003c/sup\u003eDepartment of Pharmacy, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, China; \u003csup\u003e2\u003c/sup\u003eDepartment of cardiology, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, China.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eToorop MMA, Chen Q, Tichelaar V, Cannegieter SC, Lijfering WM: \u003cb\u003ePredictors, time course, and outcomes of persistence patterns in oral anticoagulation for non-valvular atrial fibrillation: a Dutch Nationwide Cohort Study\u003c/b\u003e. 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Adv Ther 2020, \u003cb\u003e37\u003c/b\u003e(8):3537\u0026ndash;3550.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLiu Y, Yang C, Qi W, Pei Z, Xue W, Zhu H, Dong M, Guo Y, Cong D, Wang F: \u003cb\u003eThe Impact of ABCB1 and CES1 Polymorphisms on Dabigatran Pharmacokinetics in Healthy Chinese Subjects\u003c/b\u003e. Pharmgenomics Pers Med 2021, \u003cb\u003e14\u003c/b\u003e:477\u0026ndash;485.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDimatteo C, D'Andrea G, Vecchione G, Paoletti O, Cappucci F, Tiscia GL, Buono M, Grandone E, Testa S, Margaglione M: \u003cb\u003ePharmacogenetics of dabigatran etexilate interindividual variability\u003c/b\u003e. 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Ter Arkh 2019, \u003cb\u003e91\u003c/b\u003e(8):22\u0026ndash;27.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMirzaev KB, Osipova DV, Kitaeva EJ, Shprakh VV, Abdullaev SP, Andreev DA, Mumladze RB, Sychev DA: \u003cb\u003eEffects of the rs2244613 polymorphism of the CES1 gene on the antiplatelet effect of the receptor P2Y12 blocker clopidogrel\u003c/b\u003e. Drug Metab Pers Ther 2019, \u003cb\u003e34\u003c/b\u003e(3).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRaymond J, Imbert L, Cousin T, Duflot T, Varin R, Wils J, Lamoureux F: \u003cb\u003ePharmacogenetics of Direct Oral Anticoagulants: A Systematic Review\u003c/b\u003e. J Pers Med 2021, \u003cb\u003e11\u003c/b\u003e(1).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRosian AN, Iancu M, Trifa AP, Rosian SH, Mada C, Gocan CP, Nita T, Istratoaie S, Boarescu PM, Buzoianu AD: \u003cb\u003eAn Exploratory Association Analysis of ABCB1 rs1045642 and ABCB1 rs4148738 with Non-Major Bleeding Risk in Atrial Fibrillation Patients Treated with Dabigatran or Apixaban\u003c/b\u003e. J Pers Med 2020, \u003cb\u003e10\u003c/b\u003e(3).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSychev DA, Levanov AN, Shelekhova TV, Bochkov PO, Denisenko NP, Ryzhikova KA, Mirzaev KB, Grishina EA, Gavrilov MA, Ramenskaya GV \u003cem\u003eet al\u003c/em\u003e: \u003cb\u003eThe impact of ABCB1 (rs1045642 and rs4148738) and CES1 (rs2244613) gene polymorphisms on dabigatran equilibrium peak concentration in patients after total knee arthroplasty\u003c/b\u003e. Pharmgenomics Pers Med 2018, \u003cb\u003e11\u003c/b\u003e:127\u0026ndash;137.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-cardiovascular-disorders","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcar","sideBox":"Learn more about [BMC Cardiovascular Disorders](http://bmccardiovascdisord.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bcar/default.aspx","title":"BMC Cardiovascular Disorders","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Dabigatran, ABCB1, CES1, Single nucleotide polymorphisms.","lastPublishedDoi":"10.21203/rs.3.rs-1544590/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-1544590/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eAims: This study aimed to analyze associations between genetic variants and plasma concentrations along with clinical outcomes in dabigatran in patients with non-valvular atrial fibrillation (NVAF).\u003c/p\u003e\u003cp\u003eMethods: We conducted a prospective study and enrolled NVAF patients treated with dabigatran in the real world. A total of 86 patients treated with 110 mg DE twice daily were recruited for this study. Blood samples were obtained from each patient and used for genotyping and determination of plasma dabigatran concentration. All bleeding and thromboembolic complications were recorded during the 1.5 years of follow-up.\u003c/p\u003e\u003cp\u003eResults: Eighty-three patients provided samples at the trough plasma level of dabigatran, and 58 patients provided samples at the peak plasma level of dabigatran. There was a significant association between the CES1 SNP rs8192935 and trough plasma concentrations of dabigatran (\u003cem\u003eP\u003c/em\u003e=0.013). The ABCB1 SNP c.2482-2236G\u0026gt;A (rs4148738) was associated with major bleeding events in the addictive model (\u003cem\u003eP\u003c/em\u003e=0.046, OR=3.29) and dominant model (\u003cem\u003eP\u003c/em\u003e=0.040, OR=8.17). Additionally, the ABCB1 SNP c.3435C\u0026gt;T (rs1045642) was associated with the incidence of major bleeding events in the addictive model (\u003cem\u003eP\u003c/em\u003e=0.043, OR=3.34) and dominant model (\u003cem\u003eP\u003c/em\u003e=0.046, OR=7.77). However, no significant associations were found between all the SNPs and the incidence of minor bleeding events.\u003c/p\u003e\u003cp\u003eConclusions: Our results indicated that the CES1 polymorphism rs8192935 was associated with trough plasma concentrations of dabigatran. Carriers of the G allele had increased trough plasma concentrations of dabigatran compared to noncarriers. The ABCB1 polymorphisms rs4148738 and rs1045642 were associated with an increased risk for major bleeding events for the first time in a Chinese population.\u0026nbsp;\u003c/p\u003e","manuscriptTitle":"The impact of ABCB1 and CES1 polymorphisms on the safety of dabigatran in patients with non-valvular atrial fibrillation","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2022-04-20 16:51:36","doi":"10.21203/rs.3.rs-1544590/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major revision","date":"2022-09-20T07:08:13+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2022-09-19T15:14:13+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"9ee6409d-2385-45bd-93d3-1f5c47f5d471","date":"2022-09-19T13:23:04+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2022-07-26T19:53:39+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"f70990aa-ccff-4be5-ba17-71c4a88dd320","date":"2022-07-16T16:35:22+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"44196262-b6e2-47d0-9641-27d6a3606645","date":"2022-07-16T15:03:26+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2022-07-11T16:47:10+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2022-07-06T10:35:37+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2022-04-18T14:36:24+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2022-04-18T14:31:53+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Cardiovascular Disorders","date":"2022-04-11T05:58:28+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-cardiovascular-disorders","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcar","sideBox":"Learn more about [BMC Cardiovascular Disorders](http://bmccardiovascdisord.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bcar/default.aspx","title":"BMC Cardiovascular Disorders","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"ef99e52b-a573-43b2-9fe7-999a8177925d","owner":[],"postedDate":"April 20th, 2022","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2022-10-21T10:14:35+00:00","versionOfRecord":[],"versionCreatedAt":"2022-04-20 16:51:36","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-1544590","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-1544590","identity":"rs-1544590","version":["v1"]},"buildId":"WrCJVZZCHTDjtuVLN7oU0","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}