Genetic variations in relation to bleeding and pharmacodynamics of dabigatran in Chinese patients with nonvalvular atrial fibrillation: A nationwide multicentre prospective cohort study
作者全名："Xiang, Qian; Xie, Qiufen; Liu, Zhiyan; Mu, Guangyan; Zhang, Hanxu; Zhou, Shuang; Wang, Zhe; Wang, Zining; Zhang, Yatong; Zhao, Zinan; Yuan, Dongdong; Guo, Liping; Wang, Na; Xiang, Jing; Song, Hongtao; Sun, Jianjun; Jiang, Jie; Cui, Yimin"
作者地址："[Xiang, Qian; Xie, Qiufen; Liu, Zhiyan; Mu, Guangyan; Zhang, Hanxu; Zhou, Shuang; Wang, Zhe; Wang, Zining; Cui, Yimin] Peking Univ First Hosp, Dept Pharm, Beijing, Peoples R China; [Zhang, Hanxu; Wang, Zhe; Cui, Yimin] Peking Univ, Sch Pharmaceut Sci, Hlth Sci Ctr, Beijing, Peoples R China; [Zhang, Yatong; Zhao, Zinan] Beijing Hosp, Dept Pharm, Beijing, Peoples R China; [Yuan, Dongdong; Guo, Liping] Zhengzhou Seventh Peoples Hosp, Dept Pharm, Zhengzhou, Peoples R China; [Wang, Na; Xiang, Jing] Chongqing Med Univ, Dept Pharm, Affiliated Hosp 2, Chongqing, Peoples R China; [Song, Hongtao] 900 Hosp Joint Logist Team, Dept Pharm, Fuzhou, Peoples R China; [Sun, Jianjun] Inner Mongolia Med Univ, Dept Pharm, Affiliated Hosp, Hohhot, Peoples R China; [Jiang, Jie] Peking Univ First Hosp, Dept Cardiol, Beijing, Peoples R China; [Cui, Yimin] Peking Univ, Inst Clin Pharmacol, Beijing, Peoples R China; [Cui, Yimin] 8 Xishiku St, Beijing 100034, Peoples R China"
通信作者："Cui, YM (通讯作者)，8 Xishiku St, Beijing 100034, Peoples R China."
来源：CLINICAL AND TRANSLATIONAL MEDICINE
关键词：atrial fibrillation; bleeding; dabigatran; genome-wide association analysis; pharmacodynamics; whole-exome sequencing
摘要："IntroductionTo identify the potential factors responsible for the individual variability of dabigatran, we investigated the genetic variations associated with clinical outcomes and pharmacodynamics (PD) in Chinese patients with nonvalvular atrial fibrillation (NVAF). Materials and methodsChinese patients with NVAF taking dabigatran etexilate with therapeutic doses were enrolled. The primary (bleeding events) and secondary (thromboembolic and major adverse cardiac events) outcomes for a 2-year follow-up were evaluated. Peak and trough PD parameters (anti-FIIa activity, activated partial thromboplastin time and prothrombin time) were detected. Whole-exome sequencing, genome-wide sequencing and candidate gene association analyses were performed. ResultsThere were 170 patients with NVAF treated with dabigatran (110 mg twice daily) who were finally included. Two single-nucleotide polymorphisms (SNPs) were significantly related with bleeding, which include UBASH3B rs2276408 (odds ratio [OR] = 8.79, 95% confidence interval [CI]: 2.99-25.83, p = 7.77 x 10(-5) at sixth month visit) and FBN2 rs3805625 (OR = 8.29, 95% CI: 2.87-23.89, p = 9.08 x 10(-5) at 12th month visit), as well as with increased trends at other visits (p < .05). Furthermore, minor allele carriers of 16 new SNPs increased PD levels, and those of one new SNP decreased PD values (p < 1.0 x 10(-5)). Lastly, 33 new SNPs were found to be associated with bleeding and PD among 14 candidate genes. Unfortunately, the low number of secondary outcomes precluded further association analyses. ConclusionsGenetic variations indeed affected bleeding and PD in Chinese patients with NVAF treated with dabigatran. The functions of these suggestive genes and SNPs might further be explored and verified in more in vivo and in vitro investigations."