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Clin Epigenetics. 2018 Dec 27;10(1):161. doi: 10.1186/s13148-018-0588-7.

Analysis of repeated leukocyte DNA methylation assessments reveals persistent epigenetic alterations after an incident myocardial infarction.

Author information

1
Institute of Epidemiology II, Helmholtz Zentrum München, Ingolstädter Landstraβe 1, 85764, Neuherberg, Germany. ward-caviness.cavin@epa.gov.
2
Mailman School of Public Health, Columbia University, 722 W 168th St, New York, NY, 10032, USA.
3
Longitudinal Studies Section, Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD, 21224, USA.
4
Research Unit Molecular Epidemiology, Helmholtz Zentrum München, Ingolstädter Landstraβe 1, 85764, Neuherberg, Germany.
5
Institute of Human Genetics, Helmholtz Zentrum München, Ingolstädter Landstraβe 1, 85764, Neuherberg, Germany.
6
Department of Epidemiology, Harvard T.H. Chan School of Public Health, 677 Huntington Ave, Boston, MA, 02115, USA.
7
VA Normative Aging Study, Veterans Affairs Boston Healthcare System and the Department of Medicine, Boston University School of Medicine, Boston, MA, USA.
8
Department of Medicine, Boston University School of Medicine, 72 E Concord St, Boston, MA, 02118, USA.
9
Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University, 680 N Lake Shore Dr, Chicago, IL, 60611, USA.
10
Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, 675 N. St. Clair, Chicago, IL, 60611, USA.
11
Department of Preventive Medicine, Icahn School of Medicine at Mount Sinai, 1468 Madison Ave, New York, NY, 10029, USA.
12
Geriatric Rehabilitation Unit, Azienda Sanitaria Firenze, Via del Cassero 19, San Casciano in Val di pesa, 50026, Florence, Italy.
13
Laboratory of Neurogenetics, Intramural Research Program, National Institute on Aging, National Institutes of Health, Bethesda, MD, 20814, USA.
14
Institut für Humangenetik, Technische Universität München, Arcistrasse 12, 80333, Munich, Germany.
15
DZHK (German Center for Cardiovascular Disease), partner site Munich Heart Alliance, Munich, Germany.
16
Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum München, Ingolstädter Landstraβe 1, 85764, Neuherberg, Germany.
17
Institute of Epidemiology II, Helmholtz Zentrum München, Ingolstädter Landstraβe 1, 85764, Neuherberg, Germany.

Abstract

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.

KEYWORDS:

Branched chain amino acid metabolism; DNA methylation; Epigenetic fingerprint; Epigenetics; Fingerprint; Metabolites; Myocardial infarction; Systems biology

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