DNA Methylation Mediates the Genetic Variants on Ticagrelor Major Metabolite Elimination and Platelet Function Recovery after Ticagrelor Discontinuation

Abstract

Aim: To investigate the influence of DNA methylation on ticagrelor major metabolite M8 elimination and platelet function recovery after ticagrelor discontinuation. Materials&methods: Among healthy Chinese subjects, a causal inference test was conducted to identify CpG sites located on absorption, distribution, metabolism and excretion genes that mediate genetic variants on M8 elimination. Colocalization analysis was used to identify the CpG sites that shared causal variants with platelet function recovery. Results: cg05300248 (CHST9), cg05640674 (SLC22A5) and cg00846580 (DHRS7) mediated genetic variants on the M8 elimination. cg06338150 (NOTCH1) and cg17456097 (RPS6KA1) were demonstrated to have strong evidence of colocalization with platelet function recovery. Conclusion: The results provide new biological insights into the impact of DNA methylation on M8 elimination and platelet function recovery after ticagrelor discontinuation.

Clinical trial registration: clinicaltrials.gov, identifier: NCT03092076

Keywords::

• causal inference test
• colocalization analysis
• DNA methylation
• methylation quantitative trait loci
• platelet function recovery
• ticagrelor

Supplementary data

To view the supplementary data that accompany this paper please visit the journal website at: www.tandfonline.com/doi/suppl/10.2217/epi-2021-0461

Author contributions

G Xu and JE Liu performed the experiment, performed data analysis and wrote the manuscript. W Zhong and JE Liu participated in patient recruitment and performed the experiment. Z Wang, X Liu and X Xiao revised the manuscript. H Li and J Chen participated in patient recruitment. S Zhong and W Lai designed the study and revised the manuscript. All authors reviewed and approved the final manuscript.

Financial&competing interests disclosure

This study was funded by Science and Technology Development Projects of Guangzhou, Guangdong, China (no. 202002030415, principle investigator: W Lai), National Natural Science Foundation of China (no. 81872934, principle investigator: S Zhong), the Key-Area Research and Development Program of Guangdong Province, China (no. 2019B020229003, principle investigator: S Zhong), Science and Technology Development Projects of Guangdong, China (no. 2017B030314041, principle investigator: S Zhong) and Excellent Young Talent Program of GDPH, China (no. KY012021187, principle investigator: X Xiao). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Writing assistance from EssayStar Company was utilized in the production of this manuscript to improve the article for language and style, and this service was funded by the author team.

Ethical conduct of research

This study was approved by the Medical Ethical Review Committee of Guangdong Provincial People’s Hospital and conducted according to the Declaration of Helsinki (ethical approval number: no. GDREC2015143H(R1)).

Data sharing statement

Data used were taken from published randomized controlled trials (NCT03092076), which were conducted according to the principles of the Declaration of Helsinki and with informed consent from participants.

Additional information

Funding

This study was funded by Science and Technology Development Projects of Guangzhou, Guangdong, China (no. 202002030415, principle investigator: W Lai), National Natural Science Foundation of China (no. 81872934, principle investigator: S Zhong), the Key-Area Research and Development Program of Guangdong Province, China (no. 2019B020229003, principle investigator: S Zhong), Science and Technology Development Projects of Guangdong, China (no. 2017B030314041, principle investigator: S Zhong) and Excellent Young Talent Program of GDPH, China (no. KY012021187, principle investigator: X Xiao). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.