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

Qian Xiang; Qiufen Xie; Zhiyan Liu; Guangyan Mu; Hanxu Zhang; Shuang Zhou; Zhe Wang; Zining Wang; Yatong Zhang; Zinan Zhao; Dongdong Yuan; Liping Guo; Na Wang; Jing Xiang; Hongtao Song; Jianjun Sun; Jie Jiang; Yimin Cui

doi:10.1002/ctm2.1104

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

Clin Transl Med. 2022 Dec;12(12):e1104. doi: 10.1002/ctm2.1104.

Authors

Qian Xiang¹, Qiufen Xie¹, Zhiyan Liu¹, Guangyan Mu¹, Hanxu Zhang^{1

2}, Shuang Zhou¹, Zhe Wang^{1

2}, Zining Wang¹, Yatong Zhang³, Zinan Zhao³, Dongdong Yuan⁴, Liping Guo⁴, Na Wang⁵, Jing Xiang⁵, Hongtao Song⁶, Jianjun Sun⁷, Jie Jiang⁸, Yimin Cui^{1

2

9}

Affiliations

¹ Department of Pharmacy, Peking University First Hospital, Beijing, China.
² School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing, China.
³ Department of Pharmacy, Beijing Hospital, Beijing, China.
⁴ Department of Pharmacy, Zhengzhou Seventh People's Hospital, Zhengzhou, China.
⁵ Department of Pharmacy, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
⁶ Department of Pharmacy, 900 Hospital of the Joint Logistics Team, Fuzhou, China.
⁷ Department of Pharmacy, The Affiliated Hospital of Inner Mongolia Medical University, Huhehaote, China.
⁸ Department of Cardiology, Peking University First Hospital, Beijing, China.
⁹ Institute of Clinical Pharmacology, Peking University, Beijing, China.

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.

Keywords: atrial fibrillation; bleeding; dabigatran; genome-wide association analysis; pharmacodynamics; whole-exome sequencing.

Publication types

Multicenter Study

MeSH terms

Atrial Fibrillation* / drug therapy
Atrial Fibrillation* / genetics
China
Dabigatran* / therapeutic use
Hemorrhage / chemically induced
Hemorrhage / genetics
Humans
Polymorphism, Single Nucleotide / genetics
Prospective Studies

Substances

Dabigatran