1. Epidemiology and Global Health
  2. Genetics and Genomics
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Epigenome-wide analysis of DNA methylation and coronary heart disease: a nested case-control study

  1. Jiahui Si
  2. Songchun Yang
  3. Dianjianyi Sun
  4. Canqing Yu
  5. Yu Guo
  6. Yifen Lin
  7. Iona Millwood
  8. Robin Walters
  9. Ling Yang
  10. Yiping Chen
  11. Huaidong Du
  12. Yujie Hua
  13. Jingchao Liu
  14. Junshi Chen
  15. Zhengming Chen
  16. Wei Chen
  17. Liming Li  Is a corresponding author
  18. Liming Liang  Is a corresponding author
  19. Jun Lv  Is a corresponding author
  20. on behalf of the China Kadoorie Biobank Collaborative Group
  1. Peking University, China
  2. Chinese Academy of Medical Sciences, China
  3. West China Hospital, Sichuan University, China
  4. Oxford University, United Kingdom
  5. Suzhou CDC, China
  6. Wuzhong CDC, China
  7. China National Center for Food Safety Risk Assessment, China
  8. Tulane University, United States
  9. Harvard TH Chan School of Public Health, United States
Research Article
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Cite this article as: eLife 2021;10:e68671 doi: 10.7554/eLife.68671

Abstract

Background: Identifying environmentally responsive genetic loci where DNA methylation is associated with coronary heart disease (CHD) may reveal novel pathways or therapeutic targets for CHD. We conducted the first prospective epigenome-wide analysis of DNA methylation in relation to incident CHD in the Asian population.

Methods: We did a nested case-control study comprising incident CHD cases and 1:1 matched controls who were identified from the 10-year follow-up of the China Kadoorie Biobank. Methylation level of baseline blood leukocyte DNA was measured by Infinium Methylation EPIC BeadChip. We performed the single cytosine-phosphate-guanine (CpG) site association analysis and network approach to identify CHD-associated CpG sites and co-methylation gene module.

Results: After quality control, 982 participants (mean age 50.1 years) were retained. Methylation level at 25 CpG sites across the genome was associated with incident CHD (genome-wide false discovery rate [FDR] < 0.05 or module-specific FDR <0.01). One SD increase in methylation level of identified CpGs was associated with differences in CHD risk, ranging from a 47% decrease to a 118% increase. Mediation analyses revealed 28.5% of the excessed CHD risk associated with smoking was mediated by methylation level at the promoter region of ANKS1A gene (P for mediation effect = 0.036). Methylation level at the promoter region of SNX30 was associated with blood pressure and subsequent risk of CHD, with the mediating proportion to be 7.7% (P = 0.003) via systolic blood pressure and 6.4% (P = 0.006) via diastolic blood pressure. Network analysis revealed a co-methylation module associated with CHD.

Conclusions: We identified novel blood methylation alterations associated with incident CHD in the Asian population and provided evidence of the possible role of epigenetic regulations in the smoking- and BP-related pathways to CHD risk.

Funding: This work was supported by National Natural Science Foundation of China (81390544 and 91846303). The CKB baseline survey and the first re-survey were supported by a grant from the Kadoorie Charitable Foundation in Hong Kong. The long-term follow-up is supported by grants from the UK Wellcome Trust (202922/Z/16/Z, 088158/Z/09/Z, 104085/Z/14/Z), grant (2016YFC0900500, 2016YFC0900501, 2016YFC0900504, 2016YFC1303904) from the National Key and Program of China, and Chinese Ministry of Science and Technology (2011BAI09B01).

Data availability

According to the Regulation of the People's Republic of China on the Administration of Human Genetic Resources, we are not allowed to provide Chinese human clinical and genetic data abroad without an official approval.According to our previous experience, the Administration of Human Genetic Resources of China suggests obtaining official approval after the acceptance of paper. We can make the raw data of part data (significant CpGs that were found in our study) not all data available. The process of obtaining official approval usually takes 2-3 months.For researchers who are interested to access the original data, the access policy and procedures are available at www.ckbiobank.org. In brief, the China Kadoorie Biobank (CKB) is being conducted jointly by the Clinical Trial Service Unit (CTSU), Nuffield Department of Population Health, University of Oxford, and Chinese Academy of Medical Sciences (CAMS) in Beijing. Requesters should be employees of a recognised academic institution, health service organisation or charitable research organisation with experience in medical research. Requestors should be able to demonstrate, through their peer reviewed publications in the area of interest, their ability to carry out the proposed study. After registration, details of the required information are provided on the CKB Data Access System. The CKB Access Team will review and respond to data requests within 6-8 weeks.We are providing our syntax of statistical analysis and the source data for Table 3 and Table 4. We can also upload summary statistics for all 747,726 CpG sites as source data for Table 2 if needed. Figure 2 is the direct output from R software. We can provide the output file if needed.

Article and author information

Author details

  1. Jiahui Si

    Epidemiology and Biostatistics, Peking University, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  2. Songchun Yang

    Epidemiology and Biostatistics, Peking University, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  3. Dianjianyi Sun

    Epidemiology and Biostatistics, Peking University, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  4. Canqing Yu

    Epidemiology and Biostatistics, Peking University, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0019-0014
  5. Yu Guo

    N/A, Chinese Academy of Medical Sciences, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  6. Yifen Lin

    Department of Urology, West China Hospital, Sichuan University, Chengdu, China
    Competing interests
    The authors declare that no competing interests exist.
  7. Iona Millwood

    Oxford University, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  8. Robin Walters

    Oxford University, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  9. Ling Yang

    Oxford University, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  10. Yiping Chen

    Oxford University, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  11. Huaidong Du

    Oxford University, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  12. Yujie Hua

    NCDs Prevention and Control Department, Suzhou CDC, Suzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  13. Jingchao Liu

    NCDs Prevention and Control Department, Wuzhong CDC, Suzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  14. Junshi Chen

    N/A, China National Center for Food Safety Risk Assessment, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  15. Zhengming Chen

    Oxford University, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  16. Wei Chen

    Department of Epidemiology, School of Public Health and Tropical Medicine, Tulane University, New Orleans, United States
    Competing interests
    The authors declare that no competing interests exist.
  17. Liming Li

    Epidemiology and Biostatistics, Peking University, Beijing, China
    For correspondence
    lmlee@vip.163.com
    Competing interests
    The authors declare that no competing interests exist.
  18. Liming Liang

    epartments of Epidemiology and Biostatistics, Harvard TH Chan School of Public Health, Boston, United States
    For correspondence
    lliang@hsph.harvard.edu
    Competing interests
    The authors declare that no competing interests exist.
  19. Jun Lv

    Epidemiology and Biostatistics, Peking University, Beijing, China
    For correspondence
    lvjun@bjmu.edu.cn
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7916-3870

Funding

National Natural Science Foundation of China (81390544)

  • Jun Lv

National Natural Science Foundation of China (91846303)

  • Jun Lv

Wellcome Trust (202922/Z/16/Z)

  • Zhengming Chen

National Key Research and Development Program of China (2016YFC0900500)

  • Yu Guo

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Human subjects: The study protocol was approved by the Ethics Review Committee of the Chinese Center for Disease Control and Prevention (Beijing, China), the Oxford Tropical Research Ethics Committee, University of Oxford (UK), and Peking University Institutional Review Board (Beijing, China). All participants provided written informed consent.

Reviewing Editor

  1. Edward D Janus, University of Melbourne, Australia

Publication history

  1. Received: March 23, 2021
  2. Accepted: September 12, 2021
  3. Accepted Manuscript published: September 13, 2021 (version 1)

Copyright

© 2021, Si et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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