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Association of ABCB1 promoter methylation with aspirin exposure, platelet function, and clinical outcomes in Chinese intracranial artery stenosis patients

  • Pharmacogenetics
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

DNA methylation typically acts to repress gene transcription. ABCB1 is involved in the intestinal absorption of aspirin. We aimed to investigate the impact of methylation status of ABCB1 promoter on aspirin exposure, platelet function, and clinical outcomes in Chinese intracranial artery stenosis patients receiving antiplatelet treatment.

Methods

Symptomatic intracranial artery stenosis patients (without carrying CYP2C19 loss-of-function alleles) receiving antiplatelet therapy were enrolled in this study. The clinical outcome was the composite events, vascular death, recurrent ischemic stroke, myocardial infarction, or transit ischemic attack. Patients were divided into cases and controls based on the 1-year follow-up. Venous blood samples were collected for methylation level analysis, drug determination, and thromboelastographic assay. The Pearson correlation analysis was used to investigate the association of potential influencing factors and visualize them using three-dimensional plot. Receiver operator curves were applied to compare the diagnostic performance of potential factors and calculate the cut-off values.

Results

We assessed 438 patients, 30 (non-carrier of CYP2C19 loss-of-function alleles) experienced adverse clinical events, and 30 patients without clinical events were selected as controls. Total of 34 CpG methylation sites were investigated for ABCB1 methylation. Compared with controls, the cases had significant lower methylation levels (CpG21.22), lower salicylic acid concentration, and lower arachidonic acid inhibition (P value < 0.05). A cut-off point of CpG21.22 0.015 was identified with a specificity of 0.759.

Conclusion

ABCB1 hypomethylation is associated with lower drug absorption, higher platelet reactivity, and an increased risk of ischemic events in our patients. This may provide important insights into the research of aspirin resistance.

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Acknowledgements

This study was supported by a grant from the National Natural Science Foundation of China (81503157), Organization Department of Beijing Municipal Committee (2014000021469G258), and Capital Medical University (16JL72).

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Authors and Affiliations

  1. Department of Pharmacy, Beijing Tiantan Hospital, Capital Medical University, Beijing, China

    Xingang Li, Kun Zhao & Zhigang Zhao

  2. Precision Medicine Research Center for Neurological Disorders, Beijing Tiantan Hospital, Capital Medical University, Beijing, China

    Xingang Li & Zhigang Zhao

  3. Department of Interventional Neuroradiology, Beijing Tiantan Hospital, Capital Medical University, National Clinical Research Center for Neurological Diseases, Beijing, China

    Ning Ma & Zhongrong Miao

  4. College of Pharmacy, Western New England University, Springfield, MA, USA

    Shusen Sun

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  1. Xingang Li
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  2. Kun Zhao
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Contributions

Z. Zhao and Z. Miao conceived and designed the study. X. Li designed the statistical analysis and drafted the manuscript. X. Li and S. Sun performed the analysis and wrote the manuscript. K. Zhao and N. Ma performed the experiments and follow-up. N. Ma and Z. Miao supervised the quality of the study. All authors read and approved the final manuscript.

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Correspondence to Shusen Sun, Zhongrong Miao or Zhigang Zhao.

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Li, X., Zhao, K., Ma, N. et al. Association of ABCB1 promoter methylation with aspirin exposure, platelet function, and clinical outcomes in Chinese intracranial artery stenosis patients. Eur J Clin Pharmacol 73, 1261–1269 (2017). https://doi.org/10.1007/s00228-017-2298-z

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