Epigenome-Wide Association Study Identifies Cardiac Gene Patterning and a Novel Class of Biomarkers for Heart Failure

Benjamin Meder; Jan Haas; Farbod Sedaghat-Hamedani; Elham Kayvanpour; Karen Frese; Alan Lai; Rouven Nietsch; Christina Scheiner; Stefan Mester; Diana Martins Bordalo; Ali Amr; Carsten Dietrich; Dietmar Pils; Dominik Siede; Hauke Hund; Andrea Bauer; Daniel Benjamin Holzer; Arjang Ruhparwar; Matthias Mueller-Hennessen; Dieter Weichenhan; Christoph Plass; Tanja Weis; Johannes Backs; Maximilian Wuerstle; Andreas Keller; Hugo A Katus; Andreas E Posch

doi:10.1161/CIRCULATIONAHA.117.027355

Epigenome-Wide Association Study Identifies Cardiac Gene Patterning and a Novel Class of Biomarkers for Heart Failure

Circulation. 2017 Oct 17;136(16):1528-1544. doi: 10.1161/CIRCULATIONAHA.117.027355. Epub 2017 Aug 24.

Authors

Benjamin Meder¹, Jan Haas¹, Farbod Sedaghat-Hamedani¹, Elham Kayvanpour¹, Karen Frese¹, Alan Lai¹, Rouven Nietsch¹, Christina Scheiner¹, Stefan Mester¹, Diana Martins Bordalo¹, Ali Amr¹, Carsten Dietrich¹, Dietmar Pils¹, Dominik Siede¹, Hauke Hund¹, Andrea Bauer¹, Daniel Benjamin Holzer¹, Arjang Ruhparwar¹, Matthias Mueller-Hennessen¹, Dieter Weichenhan¹, Christoph Plass¹, Tanja Weis¹, Johannes Backs¹, Maximilian Wuerstle¹, Andreas Keller¹, Hugo A Katus², Andreas E Posch¹

Affiliations

¹ From Department of Internal Medicine III, Institute for Cardiomyopathies, University of Heidelberg, Germany (B.M., J.H., F.S.-H., E.K., K.F., A.L., R.N., C.S., S.M., D.M.-B., A.A., H.H., D.B.H., M.M.-H., T.W., H.A.K.); Siemens Healthcare GmbH, Strategy and Innovation, Erlangen, Germany (C.D., M.W., A.E.P.); Department of Bioinformatics, University of Saarland, Saarbrücken, Germany (A.K.); German Centre for Cardiovascular Research, Berlin, Germany (B.M., J.H., F.S.-H., E.K., K.F., A.L., D.S., M.M.-H., T.W., J.B., H.A.K.); Institute for Molecular Cardiology and Epigenetics, University of Heidelberg, Germany (D.S., J.B.); Funktionelle Genomanalyse, Deutsches Krebsforschungszentrum, Heidelberg, Germany (A.B.); Department of Cardiac Surgery, University of Heidelberg, Germany (A.R.); Siemens AG, Corporate Technology, Vienna, Austria (D.P.); Section for Clinical Biometrics, Center for Medical Statistics, Informatics, and Intelligent Systems, Medical University of Vienna, Austria (D.P.); and Division of Epigenomics and Cancer Risk Factors, Deutsches Krebsforschungszentrum, Heidelberg, Germany (D.W., C.P.).
² From Department of Internal Medicine III, Institute for Cardiomyopathies, University of Heidelberg, Germany (B.M., J.H., F.S.-H., E.K., K.F., A.L., R.N., C.S., S.M., D.M.-B., A.A., H.H., D.B.H., M.M.-H., T.W., H.A.K.); Siemens Healthcare GmbH, Strategy and Innovation, Erlangen, Germany (C.D., M.W., A.E.P.); Department of Bioinformatics, University of Saarland, Saarbrücken, Germany (A.K.); German Centre for Cardiovascular Research, Berlin, Germany (B.M., J.H., F.S.-H., E.K., K.F., A.L., D.S., M.M.-H., T.W., J.B., H.A.K.); Institute for Molecular Cardiology and Epigenetics, University of Heidelberg, Germany (D.S., J.B.); Funktionelle Genomanalyse, Deutsches Krebsforschungszentrum, Heidelberg, Germany (A.B.); Department of Cardiac Surgery, University of Heidelberg, Germany (A.R.); Siemens AG, Corporate Technology, Vienna, Austria (D.P.); Section for Clinical Biometrics, Center for Medical Statistics, Informatics, and Intelligent Systems, Medical University of Vienna, Austria (D.P.); and Division of Epigenomics and Cancer Risk Factors, Deutsches Krebsforschungszentrum, Heidelberg, Germany (D.W., C.P.). sekretariat.katus@med.uni-heidelberg.de.

PMID: 28838933
DOI: 10.1161/CIRCULATIONAHA.117.027355

Abstract

Background: Biochemical DNA modification resembles a crucial regulatory layer among genetic information, environmental factors, and the transcriptome. To identify epigenetic susceptibility regions and novel biomarkers linked to myocardial dysfunction and heart failure, we performed the first multi-omics study in myocardial tissue and blood of patients with dilated cardiomyopathy and controls.

Methods: Infinium human methylation 450 was used for high-density epigenome-wide mapping of DNA methylation in left-ventricular biopsies and whole peripheral blood of living probands. RNA deep sequencing was performed on the same samples in parallel. Whole-genome sequencing of all patients allowed exclusion of promiscuous genotype-induced methylation calls.

Results: In the screening stage, we detected 59 epigenetic loci that are significantly associated with dilated cardiomyopathy (false discovery corrected P≤0.05), with 3 of them reaching epigenome-wide significance at P≤5×10^-8. Twenty-seven (46%) of these loci could be replicated in independent cohorts, underlining the role of epigenetic regulation of key cardiac transcription regulators. Using a staged multi-omics study design, we link a subset of 517 epigenetic loci with dilated cardiomyopathy and cardiac gene expression. Furthermore, we identified distinct epigenetic methylation patterns that are conserved across tissues, rendering these CpGs novel epigenetic biomarkers for heart failure.

Conclusions: The present study provides to our knowledge the first epigenome-wide association study in living patients with heart failure using a multi-omics approach.

Keywords: DNA methylation; biomarker; dilated cardiomyopathy; epigenetics; heart failure; natriuretic peptides.

MeSH terms

Cardiomyopathy, Dilated / blood
Cardiomyopathy, Dilated / diagnosis
Cardiomyopathy, Dilated / genetics*
Case-Control Studies
CpG Islands
DNA Methylation*
Epigenesis, Genetic*
Epigenomics / methods*
Gene Expression Profiling
Genetic Loci*
Genetic Markers
Genetic Predisposition to Disease
Genome-Wide Association Study
Heart Failure / blood
Heart Failure / diagnosis
Heart Failure / genetics*
Heart Ventricles / chemistry*
High-Throughput Nucleotide Sequencing
Humans
Phenotype
RNA, Messenger / genetics
Sequence Analysis, RNA

Substances

Genetic Markers
RNA, Messenger