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

Cavin K. Ward-Caviness*, Golareh Agha, Brian H. Chen, Liliane Pfeiffer, Rory Wilson, Petra Wolf, Christian Gieger, Joel Schwartz, Pantel S. Vokonas, Lifang Hou, Allan C. Just, Stefania Bandinelli, Dena G. Hernandez, Andrew B. Singleton, Holger Prokisch, Thomas Meitinger, Gabi Kastenmüller, Luigi Ferrucci, Andrea A. Baccarelli, Melanie WaldenbergerAnnette Peters

*Corresponding author for this work

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article number161
JournalClinical Epigenetics
Volume10
Issue number1
DOIs
StatePublished - Dec 27 2018

Fingerprint

DNA Methylation
Epigenomics
Leukocytes
Myocardial Infarction
Dermatoglyphics
Metabolomics
Gene Expression
Branched Chain Amino Acids
Research
Methylation
Area Under Curve
Survivors

Keywords

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

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Developmental Biology
  • Genetics(clinical)

Cite this

Ward-Caviness, Cavin K. ; Agha, Golareh ; Chen, Brian H. ; Pfeiffer, Liliane ; Wilson, Rory ; Wolf, Petra ; Gieger, Christian ; Schwartz, Joel ; Vokonas, Pantel S. ; Hou, Lifang ; Just, Allan C. ; Bandinelli, Stefania ; Hernandez, Dena G. ; Singleton, Andrew B. ; Prokisch, Holger ; Meitinger, Thomas ; Kastenmüller, Gabi ; Ferrucci, Luigi ; Baccarelli, Andrea A. ; Waldenberger, Melanie ; Peters, Annette. / Analysis of repeated leukocyte DNA methylation assessments reveals persistent epigenetic alterations after an incident myocardial infarction. In: Clinical Epigenetics. 2018 ; Vol. 10, No. 1.
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keywords = "Branched chain amino acid metabolism, DNA methylation, Epigenetic fingerprint, Epigenetics, Fingerprint, Metabolites, Myocardial infarction, Systems biology",
author = "Ward-Caviness, {Cavin K.} and Golareh Agha and Chen, {Brian H.} and Liliane Pfeiffer and Rory Wilson and Petra Wolf and Christian Gieger and Joel Schwartz and Vokonas, {Pantel S.} and Lifang Hou and Just, {Allan C.} and Stefania Bandinelli and Hernandez, {Dena G.} and Singleton, {Andrew B.} and Holger Prokisch and Thomas Meitinger and Gabi Kastenm{\"u}ller and Luigi Ferrucci and Baccarelli, {Andrea A.} and Melanie Waldenberger and Annette Peters",
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Ward-Caviness, CK, Agha, G, Chen, BH, Pfeiffer, L, Wilson, R, Wolf, P, Gieger, C, Schwartz, J, Vokonas, PS, Hou, L, Just, AC, Bandinelli, S, Hernandez, DG, Singleton, AB, Prokisch, H, Meitinger, T, Kastenmüller, G, Ferrucci, L, Baccarelli, AA, Waldenberger, M & Peters, A 2018, 'Analysis of repeated leukocyte DNA methylation assessments reveals persistent epigenetic alterations after an incident myocardial infarction', Clinical Epigenetics, vol. 10, no. 1, 161. https://doi.org/10.1186/s13148-018-0588-7

Analysis of repeated leukocyte DNA methylation assessments reveals persistent epigenetic alterations after an incident myocardial infarction. / Ward-Caviness, Cavin K.; Agha, Golareh; Chen, Brian H.; Pfeiffer, Liliane; Wilson, Rory; Wolf, Petra; Gieger, Christian; Schwartz, Joel; Vokonas, Pantel S.; Hou, Lifang; Just, Allan C.; Bandinelli, Stefania; Hernandez, Dena G.; Singleton, Andrew B.; Prokisch, Holger; Meitinger, Thomas; Kastenmüller, Gabi; Ferrucci, Luigi; Baccarelli, Andrea A.; Waldenberger, Melanie; Peters, Annette.

In: Clinical Epigenetics, Vol. 10, No. 1, 161, 27.12.2018.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Analysis of repeated leukocyte DNA methylation assessments reveals persistent epigenetic alterations after an incident myocardial infarction

AU - Ward-Caviness, Cavin K.

AU - Agha, Golareh

AU - Chen, Brian H.

AU - Pfeiffer, Liliane

AU - Wilson, Rory

AU - Wolf, Petra

AU - Gieger, Christian

AU - Schwartz, Joel

AU - Vokonas, Pantel S.

AU - Hou, Lifang

AU - Just, Allan C.

AU - Bandinelli, Stefania

AU - Hernandez, Dena G.

AU - Singleton, Andrew B.

AU - Prokisch, Holger

AU - Meitinger, Thomas

AU - Kastenmüller, Gabi

AU - Ferrucci, Luigi

AU - Baccarelli, Andrea A.

AU - Waldenberger, Melanie

AU - Peters, Annette

PY - 2018/12/27

Y1 - 2018/12/27

N2 - 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.

AB - 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.

KW - Branched chain amino acid metabolism

KW - DNA methylation

KW - Epigenetic fingerprint

KW - Epigenetics

KW - Fingerprint

KW - Metabolites

KW - Myocardial infarction

KW - Systems biology

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UR - http://www.scopus.com/inward/citedby.url?scp=85059244403&partnerID=8YFLogxK

U2 - 10.1186/s13148-018-0588-7

DO - 10.1186/s13148-018-0588-7

M3 - Article

C2 - 30587240

AN - SCOPUS:85059244403

VL - 10

JO - Clinical Epigenetics

JF - Clinical Epigenetics

SN - 1868-7075

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