Article Text

Download PDFPDF
Global DNA hypermethylation in peripheral blood mononuclear cells and cardiovascular disease risk: a population-based propensity score-matched cohort study
  1. Yoshiki Tsuboi1,
  2. Hiroya Yamada2,
  3. Eiji Munetsuna3,
  4. Ryosuke Fujii1,
  5. Mirai Yamazaki4,
  6. Yoshitaka Ando5,
  7. Genki Mizuno5,
  8. Hiroaki Ishikawa5,
  9. Koji Ohashi5,
  10. Shuji Hashimoto2,
  11. Nobuyuki Hamajima6,
  12. Koji Suzuki1
  1. 1Department of Preventive Medical Sciences, Fujita Health University School of Medical Sciences, Toyoake, Aichi, Japan
  2. 2Department of Hygiene, Fujita Health University School of Medicine, Toyoake, Aichi, Japan
  3. 3Department of Biochemistry, Fujita Health University School of Medicine, Toyoake, Aichi, Japan
  4. 4Department of Medical Technology, Kagawa Prefectural University of Health Sciences, Takamatsu, Kagawa, Japan
  5. 5Department of Clinical Biochemistry, Fujita Health University School of Medical Sciences, Toyoake, Aichi, Japan
  6. 6Department of Healthcare Administration, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan
  1. Correspondence to Professor Koji Suzuki, Department of Preventive Medical Sciences, Fujita Health University School of Medical Sciences, Toyoake, Aichi, Japan; ksuzuki{at}


Background DNA methylation plays an important role in the pathogenesis and progression of cardiovascular disease (CVD) but the prospective association of DNA methylation with CVD has not been evaluated. Here, we conducted a prospective study to examine whether long interspersed nuclear element-1 (LINE-1) DNA methylation is associated with CVD mortality in a Japanese population.

Methods We targeted 822 Japanese who participated in a health check-up in 1990 and had no clinical history of cancer, stroke or ischaemic heart disease. DNA was extracted from peripheral blood mononuclear cells and LINE-1 DNA methylation at three CpG sites was measured using a pyrosequencing method. We used propensity score (PS) matching to reduce the effect of potential confounding.

Results During 18 118.7 persons-years of follow-up, there were 329 deaths from all-causes and 85 deaths from CVD. In PS-matched analysis, a significantly higher HR for CVD mortality was observed in the hypermethylation group than in the hypomethylation group for elderly participants (HR 2.77; 95% CI 1.55 to 4.93). No significant association between LINE-1 DNA methylation and CVD was observed for middle-aged participants.

Conclusions Based on this prospective study, we suggest that LINE-1 DNA hypermethylation is associated with increased CVD mortality risk in an elderly population.

  • epidemiology
  • cohort studies
  • mortality
  • genetics
  • cardiovascular disease

Statistics from


  • Contributors YT, RF and KS discussed interpretation of data and wrote the manuscript. KS designed the study and directed its implementation. YT and SH performed the statistical analysis. HY, EM, HI and KO collected the study data and helped supervise the project. NH collected and provided DNA samples. YT, MY, YA and GM measured DNA methylation. All authors discussed the results, commented on the manuscript and contributed to all take responsibility for it.

  • Funding This study was supported by the Japan Society for the Promotion of Science (JSPS) under Grants-in-Aid for Scientific Research (Numbers 26293144, 17K09139, 16H06277 and 20K10515).

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Ethics approval The protocol for this study was approved by the Ethics Committee of Fujita Health University (Approval No. HG19-069).

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement Data are available upon reasonable request. No data are available. The data sets used in this study include personal information.Thus, datasets are available from the corresponding author, Prof.Koji Suzuki, on your reasonable requests.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.