Genetic variations in relation to bleeding and pharmacodynamics of dabigatran in Chinese patients with nonvalvular atrial fibrillation: A nationwide multicentre prospective cohort study.
Genetic variations in relation to bleeding and pharmacodynamics of dabigatran in Chinese patients with nonvalvular atrial fibrillation: A nationwide multicentre prospective cohort study.
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中国非瓣膜性心房颤动患者与出血和达比加群药效学相关的遗传变异：一项全国性多中心前瞻性队列研究
DOI：
10.1002/ctm2.1104
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发表时间：
2022-12
影响因子：
10.6
通讯作者：
中科院分区：
文献类型：
--
作者：
摘要：为了确定导致达比加群个体差异的潜在因素，我们研究了与中国非瓣膜性心房颤动（NVAF）患者临床结局和药效学（PD）相关的遗传变异。材料与方法采用达比加群酯治疗剂量的中国非瓣膜性房颤患者为研究对象。对2年随访的主要（出血事件）和次要（血栓栓塞和主要心脏不良事件）结局进行评估。检测PD峰谷参数（抗FIIa活性、活化部分凝血活素时间和凝血酶原时间）。进行全外显子组测序、全基因组测序和候选基因关联分析。结果170例非瓣膜性房颤患者接受达比加群治疗（110 mg，每日2次）。两个单核苷酸多态性（snp）与出血显著相关，包括UBASH3B rs2276408（优势比[OR] = 8.79, 95%可信区间[CI]: 2.99-25.83，第6个月就诊时p = 7.77 × 10−5）和FBN2 rs3805625 (OR = 8.29, 95% CI: 2.87-23.89，第12个月就诊时p = 9.08 × 10−5)，其他就诊时也有增加趋势（p < 0.05）。此外，16个新SNP的小等位基因携带者增加PD水平，而1个新SNP的等位基因携带者降低PD值（p < 1.0 × 10−5）。最后，在14个候选基因中发现33个新的snp与出血和PD相关。不幸的是，次要结局的数量较少妨碍了进一步的关联分析。结论遗传变异确实影响了达比加群治疗的非瓣瓣性房颤患者的出血和PD。这些暗示基因和snp的功能可能会在更多的体内和体外研究中进一步探索和验证。
Abstract Introduction To 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 methods Chinese 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. Results There 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 × 10−5 at sixth month visit) and FBN2 rs3805625 (OR = 8.29, 95% CI: 2.87–23.89, p = 9.08 × 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 × 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. Conclusions Genetic 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.
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影响因子：
3.4
作者：
Ji, Qiuyi;Zhang, Chunyu;Lv, Qianzhou
通讯作者：
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