Differentially hypomethylated cell-free DNA and coronary collateral circulation

Jongseong Ahn, Sunghoon Heo, Soo jin Ahn, Duhee Bang, Sang Hak Lee

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Background: The factors affecting cardioprotective collateral circulation are still incompletely understood. Recently, characteristics, such as CpG methylation of cell-free DNA (cfDNA), have been reported as markers with clinical utility. The aim of this study was to evaluate whether cfDNA methylation patterns are associated with the grade of coronary collateral circulation (CCC). Result: In this case–control study, clinical and angiographic data were obtained from 143 patients (mean age, 58 years, male 71%) with chronic total coronary occlusion. Enzymatic methyl-sequencing (EM-seq) libraries were prepared using the cfDNA extracted from the plasma. Data were processed to obtain the average methylation fraction (AMF) tables of genomic regions from which blacklisted regions were removed. Unsupervised analysis of the obtained AMF values showed that some of the changes in methylation were due to CCC. Through random forest preparation process, 256 differentially methylated region (DMR) candidates showing strong association with CCC were selected. A random forest classifier was then constructed, and the area under the curve of the receiver operating characteristic curve indicated an appropriate predictive function for CCC. Finally, 20 DMRs were identified to have significantly different AMF values between the good and poor CCC groups. Particularly, the good CCC group exhibited hypomethylated DMRs. Pathway analysis revealed five pathways, including TGF-beta signaling, to be associated with good CCC. Conclusion: These data have demonstrated that differential hypomethylation was identified in dozens of cfDNA regions in patients with good CCC. Our results support the clinical utility of noninvasively obtained epigenetic signatures for predicting collateral circulation in patients with vascular diseases.

Original languageEnglish
Article number140
JournalClinical Epigenetics
Issue number1
Publication statusPublished - 2022 Dec

Bibliographical note

Funding Information:
This work was supported by (i) the Midcareer Researcher Program (NRF-2021R1A2C2094264) through the National Research Foundation of Korea (NRF), funded by the Ministry of Science, ICT and Future Planning; (ii) Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health and Welfare, Republic of Korea [Grant Number: HI14C1277(HR14C0003)]; (iii) the National Research Foundation of Korea grant funded by the Korean government (2021R1I1A1A01046940); and (iv) the Severance Hospital Research Fund for Clinical excellence (SHRC) (C-2019-0022).

Publisher Copyright:
© 2022, The Author(s).

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Developmental Biology
  • Genetics(clinical)


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