title: Gene-specific DNA methylation profiles and LINE-1 hypomethylation are associated with myocardial infarction risk.
abstract: BACKGROUND
  DNA methylation profiles are responsive to environmental stimuli and metabolic shifts. This makes DNA methylation a potential biomarker of environmental-related and lifestyle-driven diseases of adulthood. Therefore, we investigated if white blood cells' (WBCs) DNA methylation profiles are associated with myocardial infarction (MI) occurrence. Whole-genome DNA methylation was investigated by microarray analysis in 292 MI cases and 292 matched controls from the large prospective Italian European Prospective Investigation into Cancer and Nutrition (EPIC) cohort (EPICOR study). Significant signals (false discovery rate (FDR) adjusted P < 0.05) were replicated by mass spectrometry in 317 MI cases and 262 controls from the Dutch EPIC cohort (EPIC-NL). Long interspersed nuclear element-1 (LINE-1) methylation profiles were also evaluated in both groups.
  
  
  RESULTS
  A differentially methylated region (DMR) within the zinc finger and BTB domain-containing protein 12 (ZBTB12) gene body and LINE-1 hypomethylation were identified in EPICOR MI cases and replicated in the EPIC-NL sample (ZBTB12-DMR meta-analysis: effect size ± se = -0.016 ± 0.003, 95 % CI = -0.021;-0.011, P = 7.54 × 10(-10); LINE-1 methylation meta-analysis: effect size ± se = -0.161 ± 0.040, 95 % CI = -0.239;-0.082, P = 6.01 × 10(-5)). Moreover, cases with shorter time to disease had more pronounced ZBTB12-DMR hypomethylation (meta-analysis, men: effect size ± se = -0.0059 ± 0.0017, P TREND = 5.0 × 10(-4); women: effect size ± se = -0.0053 ± 0.0019, P TREND = 6.5 × 10(-3)) and LINE-1 hypomethylation (meta-analysis, men: effect size ± se = -0.0010 ± 0.0003, P TREND = 1.6 × 10(-3); women: effect size ± se = -0.0008 ± 0.0004, P TREND = 0.026) than MI cases with longer time to disease. In the EPIC-NL replication panel, DNA methylation profiles improved case-control discrimination and reclassification when compared with traditional MI risk factors only (net reclassification improvement (95 % CI) between 0.23 (0.02-0.43), P = 0.034, and 0.89 (0.64-1.14), P < 1 × 10(-5)).
  
  
  CONCLUSIONS
  Our data suggest that specific methylation profiles can be detected in WBCs, in a preclinical condition, several years before the occurrence of MI, providing an independent signature of cardiovascular risk. We showed that prediction accuracy can be improved when DNA methylation is taken into account together with traditional MI risk factors, although further confirmation on a larger sample is warranted. Our findings support the potential use of DNA methylation patterns in peripheral blood white cells as promising early biomarkers of MI.
authors.affiliation: Human Genetics Foundation (HuGeF), Via Nizza 52, Turin, I-10126 Torino Italy.|Medical Sciences Department, University of Turin, Turin, Italy.
authors.forename: Simonetta
authors.initials: S
authors.lastname: Guarrera
authors.affiliation: Human Genetics Foundation (HuGeF), Via Nizza 52, Turin, I-10126 Torino Italy.|Medical Sciences Department, University of Turin, Turin, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Fiorito
authors.affiliation: Julius Center for Health Sciences and Primary Care, UMC Utrecht, Utrecht, The Netherlands.
authors.forename: N Charlotte
authors.initials: NC
authors.lastname: Onland-Moret
authors.affiliation: Human Genetics Foundation (HuGeF), Via Nizza 52, Turin, I-10126 Torino Italy.|Medical Sciences Department, University of Turin, Turin, Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Russo
authors.affiliation: Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Agnoli
authors.affiliation: Human Genetics Foundation (HuGeF), Via Nizza 52, Turin, I-10126 Torino Italy.|Medical Sciences Department, University of Turin, Turin, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Allione
authors.affiliation: Human Genetics Foundation (HuGeF), Via Nizza 52, Turin, I-10126 Torino Italy.|Medical Sciences Department, University of Turin, Turin, Italy.
authors.forename: Cornelia
authors.initials: C
authors.lastname: Di Gaetano
authors.affiliation: Department of Clinical and Experimental Medicine, Federico II University, Naples, Italy.
authors.forename: Amalia
authors.initials: A
authors.lastname: Mattiello
authors.affiliation: Cancer Epidemiology, CPO Piemonte, Turin, Italy.
authors.forename: Fulvio
authors.initials: F
authors.lastname: Ricceri
authors.affiliation: Department of Public Health, Second University of Naples, Naples, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Chiodini
authors.affiliation: Human Genetics Foundation (HuGeF), Via Nizza 52, Turin, I-10126 Torino Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Polidoro
authors.affiliation: Cancer Registry and Histopathology Unit, "Civile-M.P. Arezzo" Hospital, ASP 7, Ragusa, Italy.
authors.forename: Graziella
authors.initials: G
authors.lastname: Frasca
authors.affiliation: Julius Center for Health Sciences and Primary Care, UMC Utrecht, Utrecht, The Netherlands.|Centre for Nutrition, Prevention and Health Services, National Institute for Public Health and the Environment, Bilthoven, The Netherlands.
authors.forename: Monique W M
authors.initials: MWM
authors.lastname: Verschuren
authors.affiliation: Centre for Nutrition, Prevention and Health Services, National Institute for Public Health and the Environment, Bilthoven, The Netherlands.
authors.forename: Jolanda M A
authors.initials: JMA
authors.lastname: Boer
authors.affiliation: Department of Epidemiology and Prevention, IRCCS Istituto Neurologico Mediterraneo Neuromed, Pozzilli, IS Italy.
authors.forename: Licia
authors.initials: L
authors.lastname: Iacoviello
authors.affiliation: Julius Center for Health Sciences and Primary Care, UMC Utrecht, Utrecht, The Netherlands.
authors.forename: Yvonne T
authors.initials: YT
authors.lastname: van der Schouw
authors.affiliation: Cancer Registry and Histopathology Unit, "Civile-M.P. Arezzo" Hospital, ASP 7, Ragusa, Italy.
authors.forename: Rosario
authors.initials: R
authors.lastname: Tumino
authors.affiliation: Human Genetics Foundation (HuGeF), Via Nizza 52, Turin, I-10126 Torino Italy.|Epidemiology and Public Health, Imperial College London, London, UK.
authors.forename: Paolo
authors.initials: P
authors.lastname: Vineis
authors.affiliation: Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
authors.forename: Vittorio
authors.initials: V
authors.lastname: Krogh
authors.affiliation: Department of Clinical and Experimental Medicine, Federico II University, Naples, Italy.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Panico
authors.affiliation: Cancer Epidemiology, CPO Piemonte, Turin, Italy.
authors.forename: Carlotta
authors.initials: C
authors.lastname: Sacerdote
authors.affiliation: Human Genetics Foundation (HuGeF), Via Nizza 52, Turin, I-10126 Torino Italy.|Medical Sciences Department, University of Turin, Turin, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Matullo
keywords: Association study; DNA methylation; Early biomarkers; Myocardial infarction; Risk prediction; Risk stratification