SLC4A4, FRAS1, and SULT1A1 Genetic Variations Associated With Dabigatran Metabolism in a Healthy Chinese Population

Abstract

Background: The purpose of this study was to identify genetic variations associated with the metabolism of dabigatran in healthy Chinese subjects, with particular focus given to pharmacokinetics (PK) and pharmacodynamics (PD).Methods: Healthy Chinese adults aged 18–65 years with unknown genotypes from a bioequivalence trial were included according to the protocol registered at ClinicalTrial.org (NCT03161496). All subjects received a single dose (150 mg) of dabigatran etexilate. PK (main outcomes: area under the concentration-time, AUC0-t, of total and free dabigatran) and PD (main outcomes: anti-FIIa activity, APTT, and PT) parameters were evaluated. Whole-exome sequencing and genome-wide association analyses were performed. Additionally, candidate gene association analyses related to dabigatran were conducted.Results: A total of 118 healthy Chinese subjects were enrolled in this study. According to the p-value suggestive threshold (1.0 × 10−4), the following three SNPs were found to be associated with the AUC0–t of total dabigatran: SLC4A4 SNP rs138389345 (p = 5.99 × 10−5), FRAS1 SNP rs6835769 (p = 6.88 × 10−5), and SULT1A1 SNP rs9282862 (p = 7.44 × 10−5). Furthermore, these SNPs were also found to have significant influences on the AUC0–t of free dabigatran, maximum plasma concentration, and anti-FIIa activity (p < 0.05). Moreover, we identified 30 new potential SNPs of 13 reported candidate genes (ABCB1, ABCC2, ABCG2, CYP2B6, CYP1A2, CYP2C19, CYP3A5, CES1, SLCO1B1, SLC22A1, UGT1A1, UGT1A9, and UGT2B7) that were associated with drug metabolism.Conclusion: Genetic variations were indeed found to impact dabigatran metabolism in a population of healthy Chinese subjects. Further research is needed to explore the more detailed functions of these SNPs. Additionally, our results should be verified in studies that use larger sample sizes and investigate other ethnicities.

Genetic variations in relation to bleeding and pharmacodynamics of dabigatran in Chinese patients with nonvalvular atrial fibrillation: A nationwide multicentre prospective cohort study

“…22 We found ABCG2 rs2231156 had a significant impact on bleeding and PD; however, the prior study only discovered the positive result in time to peak concentration of healthy participants. 22 Some limitations in our study must be discussed. First, although the sample size of our study was larger than few other researches (Table S1), the number of patients included (n = 170) was still limited, and our results should be verified in other studies with more patients.…”

“…Through automated multiparameter haemostasis analyzer (Sysmex CS‐2100i), validated Coagulation or Chromogenic Method Kits were used to measure PT, APTT and anti‐FIIa activity. The detailed and validated methods of determining these parameters have been published in our previous studies 22,24 …”

“…From prior pharmacogenomic researches (Table S1) and reviews, 13,17 a total of 25 candidate genes were chosen, including ABCB1 , ABCC2 , ABCG2 , CES1 , CES1P2 , CYP1A2 , CYP2A6 , CYP2B6 , CYP2C19 , CYP2C8 , CYP2C9 , CYP2D6 , CYP2J2 , CYP3A4 , CYP3A5 , CYP4F2 , FRAS1 , SLC22A1 , SLC4A4 , SLCO1B1 , SULT1A1 , UGT1A1 , UGT1A9 , UGT2B7 and UGT2B15 . The detailed methods about genome‐wide and candidate gene association analyses were similar to those used in our GWA study on healthy participants with dabigatran 22 . Regional plots were created in LocusZoom, 28 and additional graphics were generated using R. Except otherwise specified, continuous variables were presented as mean ± standard deviation, and a two‐sided p ‐value of less than .05 was regarded as statistically significant.…”

“…After genomic DNA preparation and quality assessment, whole-exome sequencing was used for genotyping, which has also been published in our previous study. 22…”

Population pharmacokinetic analysis for dabigatran etexilate in Chinese patients with non-valvular atrial fibrillation

“…After transferring the plasma samples to cryovials, we stored them at −80 • C and transferred them to the Peking University First Hospital for PD analysis within 6 months. We determined the PD parameters, including prothrombin time (PT), APTT, and anti-FIIa activity using an automated multiparameter hemostasis analyzer (Sysmex R CS-2100i) as previously published (19,20).…”