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Analysis of repeated leukocyte DNA methylation assessments reveals persistent epigenetic alterations after an incident myocardial infarction
Citation:
Ward-Caviness, C., G. Agha, B. Chen, L. Pfeiffer, R. Wilson, P. Wolf, C. Gieger, J. Schwartz, P. Vokonas, L. Hou, A. Just, S. Bandinelli, D. Hernandez, H. Prokisch, T. Meitinger, G. Kastenmuller, L. Ferrucci, A. Baccarelli, M. Waldenberger, AND A. Peters. Analysis of repeated leukocyte DNA methylation assessments reveals persistent epigenetic alterations after an incident myocardial infarction. Clinical Epigenetics. BioMed Central Ltd, London, Uk, 10(1):161, (2018). https://doi.org/10.1186/s13148-018-0588-7
Impact/Purpose:
This article examines longitudinal associations between DNA methylation and incident myocardial infarction to determine if there are persistent alterations in DNA methylation as a result of an incident MI. We discover a set of epigenetic loci whose change in methylation over time is strongly associated with the occurrence of an incident MI between examinations. These loci are linked to gene expression and metabolomic alterations which when combined suggest the involvement of branched chain amino acid and energy metabolism pathways and possibly inform on the development of diabetes secondary to an incident MI. This article is expected to provide useful information on how major life events which may be influenced by a number of environmental factors affect DNA methylation.
Description:
Background Most research into myocardial infarctions (MIs) have focused on preventative efforts. For survivors, the occurrence of an MI represents a major clinical event that can have long-lasting consequences. There has been little to no research into the molecular changes that can occur as a result of an incident MI. Here, we use three cohorts to identify epigenetic changes that are indicative of an incident MI and their association with gene expression and metabolomics. Results Using paired samples from the KORA cohort, we screened for DNA methylation loci (CpGs) whose change in methylation is potentially indicative of the occurrence of an incident MI between the baseline and follow-up exams. We used paired samples from the NAS cohort to identify 11 CpGs which were predictive in an independent cohort. After removing two CpGs associated with medication usage, we were left with an “epigenetic fingerprint” of MI composed of nine CpGs. We tested this fingerprint in the InCHIANTI cohort where it moderately discriminated incident MI occurrence (AUC = 0.61, P = 6.5 × 10−3). Returning to KORA, we associated the epigenetic fingerprint loci with cis-gene expression and integrated it into a gene expression-metabolomic network, which revealed links between the epigenetic fingerprint CpGs and branched chain amino acid (BCAA) metabolism. Conclusions There are significant changes in DNA methylation after an incident MI. Nine of these CpGs show consistent changes in multiple cohorts, significantly discriminate MI in independent cohorts, and were independent of medication usage. Integration with gene expression and metabolomics data indicates a link between MI-associated epigenetic changes and BCAA metabolism.
URLs/Downloads:
DOI: Analysis of repeated leukocyte DNA methylation assessments reveals persistent epigenetic alterations after an incident myocardial infarction