DataSheet1_SLC4A4, FRAS1, and SULT1A1 Genetic Variations Associated With Dabigatran Metabolism in a Healthy Chinese Population.docx

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.

研究背景：本研究旨在明确中国健康受试者体内达比加群（dabigatran）代谢相关的遗传变异，重点聚焦药代动力学（pharmacokinetics, PK）与药效动力学（pharmacodynamics, PD）指标。
研究方法：本研究纳入某生物等效性试验中年龄18~65岁、基因型未知的中国健康成年受试者，所有受试者均按照ClinicalTrial.org注册的试验方案（NCT03161496）入组。所有受试者单次口服达比加群酯（dabigatran etexilate）150 mg。评估了PK参数（主要结局指标：总达比加群与游离达比加群的血药浓度-时间曲线下面积AUC0-t）与PD参数（主要结局指标：抗凝血因子IIa（anti-FIIa）活性、活化部分凝血活酶时间（APTT）以及凝血酶原时间（PT））。本研究开展了全外显子组测序（whole-exome sequencing）与全基因组关联分析（genome-wide association analyses），同时针对达比加群相关的候选基因开展了关联分析。
研究结果：本研究共纳入118名中国健康受试者。根据提示性显著性阈值（1.0×10⁻⁴），共发现3个单核苷酸多态性（Single Nucleotide Polymorphisms, SNPs）与总达比加群的AUC0-t相关：SLC4A4基因rs138389345位点（p=5.99×10⁻⁵）、FRAS1基因rs6835769位点（p=6.88×10⁻⁵）以及SULT1A1基因rs9282862位点（p=7.44×10⁻⁵）。进一步分析显示，上述SNPs同样对游离达比加群的AUC0-t、血浆峰浓度以及抗FIIa活性存在显著影响（p<0.05）。此外，本研究在13个已报道的达比加群代谢相关候选基因（ABCB1、ABCC2、ABCG2、CYP2B6、CYP1A2、CYP2C19、CYP3A5、CES1、SLCO1B1、SLC22A1、UGT1A1、UGT1A9及UGT2B7）中，鉴定出30个全新的潜在药物代谢相关SNPs。
研究结论：本研究证实，中国健康受试者体内的遗传变异确实会影响达比加群的代谢过程。未来需开展进一步研究以明确上述SNPs的具体功能机制，同时需在更大样本量的队列以及其他种族人群中验证本研究结果。