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. 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.
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.
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.
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