Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2024 Nov 22;16(1):167.
doi: 10.1186/s13148-024-01777-w.

Exploratory DNA methylation analysis in post-mortem heart tissue of sudden unexplained death

Charlotte Sutter  1 , Cordula Haas  2 , Peter K Bode  3 , Jacqueline Neubauer #  1 , Jeppe Dyrberg Andersen #  4
Affiliations

Exploratory DNA methylation analysis in post-mortem heart tissue of sudden unexplained death

Charlotte Sutter et al. Clin Epigenetics. .

Abstract

Background: Sudden unexplained death (SUD) is a devastating event in the young. Despite efforts to identify causal genetic variants, many cases remain unexplained after genetic screening. This study aimed to investigate an alternative potential contributor to SUD by studying the human methylome using the MethylationEPIC v2.0 BeadChip kit in heart tissue from SUD cases. The genome-wide methylation results of the SUD cases were compared to the results of a control cohort. The SUD cases were divided into three main groups based on their autopsy reports, heart morphology and histopathology (primaryN: macroscopically and histologically normal heart; primaryCM: macroscopically or histologically abnormal heart, suspected cardiomyopathies; and secondary: myocardial damage due to other underlying conditions). The main focus of this study was to identify differentially methylated regions (DMRs) between the case groups and the control cohort.

Results: We identified DMRs for both the primaryN and primaryCM groups, whereas the secondary group yielded no such results. In the primaryN cases, the corresponding genes for each DMR led to the identification of genes with common biological pathways. Some were associated with heart morphology (e.g. heart outflow tract morphogenesis or trabecular morphogenesis), but the majority belonged to more general cellular regulatory pathways (e.g. transcription coactivator activity, long non-coding RNAs, etc.). Although no common pathways were found for the primaryCM group, some common regulatory molecular functions were identified, such as p53 binding and transcription coactivator activity.

Conclusions: Our study is the first to investigate the whole human methylome in heart tissue of SUD cases. We propose that there are observable differences in the methylation patterns of the case groups that may have contributed to SUD. Still, further studies are required to improve our understanding of the impact of methylation levels on SUD risk and to pinpoint methylation-based screening opportunities for SUD relatives.

Keywords: Cardiac diseases; Differentially methylated regions; EPICv2 array; Human methylome; Sudden unexplained death.

PubMed Disclaimer

Conflict of interest statement

Declarations. Ethics approval and consent to participate: Ethical approval for this study was provided by the local ethics committee in Zurich (KEK-No. 2013-0086), and the study was conducted in full conformance with Swiss laws and regulations. The requirements of the local ethics committee included written informed consent of family members. If no family members were available, the cases were anonymized. Consent for publication: All authors of the manuscript have read and agreed to its content and consent to publish it. Competing interests: The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Gene ontology (GO) term analysis of biological pathways for the genes associated with the differentially methylated regions (DMRs) of the primaryN group. FDR, False discovery rate
Fig. 2
Fig. 2
Gene ontology (GO) term analysis of molecular functions for the genes associated with the differentially methylated regions (DMRs) of the primaryCM group
See this image and copyright information in PMC

References

    1. Isbister J, Semsarian C. Sudden cardiac death: an update. Intern Med J. 2019;49(7):826–33. 10.1111/imj.14359. - PubMed
    1. Zeppenfeld K, Tfelt-Hansen J, de Riva M, Winkel BG, Behr ER, Blom NA, et al. 2022 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death. Eur Heart J. 2022;43(40):3997–4126. 10.1093/eurheartj/ehac262. - PubMed
    1. Lynge TH, Nielsen JL, Risgaard B, van der Werf C, Winkel BG, Tfelt-Hansen J. Causes of sudden cardiac death according to age and sex in persons aged 1–49 years. Heart Rhythm. 2023;20(1):61–8. 10.1016/j.hrthm.2022.08.036. - PubMed
    1. Winkel BG, Holst AG, Theilade J, Kristensen IB, Thomsen JL, Ottesen GL, et al. Nationwide study of sudden cardiac death in persons aged 1–35 years. Eur Heart J. 2011;32(8):983–90. 10.1093/eurheartj/ehq428. - PubMed
    1. Wong CX, Brown A, Lau DH, Chugh SS, Albert CM, Kalman JM, et al. Epidemiology of sudden cardiac death: global and regional perspectives. Heart Lung Circul. 2019;28(1):6–14. 10.1016/j.hlc.2018.08.026. - PubMed

LinkOut - more resources