title: B-vitamins intake, DNA-methylation of One Carbon Metabolism and homocysteine pathway genes and myocardial infarction risk: the EPICOR study.
abstract: OBJECTIVE
  Several epidemiological studies highlighted the association between folate and B-vitamins low intake and cardiovascular diseases (CVD) risk. Contrasting results were reported on the relationship between folate intake and DNA-methylation. Folate and B-vitamins may modulate DNA-methylation of specific enzymes which are included in the One-Carbon Metabolism (OCM) and in the homocysteine (Hcy) pathways. The aim of the study was to evaluate whether DNA-methylation profiles of OCM and Hcy genes could modulate the myocardial infarction (MI) risk conferred by a low B-vitamins intake.
  
  
  RESULTS
  Study sample (206 MI cases and 206 matched controls) is a case-control study nested in the prospective EPIC cohort. Methylation levels of 33 candidate genes where extracted by the whole epigenome analysis (Illumina-HumanMethylation450K-BeadChip). We identified three differentially methylated regions in males (TCN2 promoter, CBS 5'UTR, AMT gene-body) and two in females (PON1 gene-body, CBS 5'UTR), each of them characterized by an increased methylation in cases. Functional in silico analysis suggested a decreased expression in cases. A Recursively Partitioned Mixture Model cluster algorithm identified distinct methylation profiles associated to different MI risk: high-risk vs. low-risk methylation profile groups, OR = 3.49, p = 1.87 × 10(-)(4) and OR = 3.94, p = 0.0317 in males and females respectively (multivariate logistic regression adjusted for classical CVD risk factors). Moreover, a general inverse relationship between B-vitamins intake and DNA-methylation of the candidate genes was observed.
  
  
  CONCLUSIONS
  Our findings support the hypothesis that DNA-methylation patterns in specific regions of OCM and Hcy pathways genes may modulate the CVD risk conferred by folate and B-vitamins low intake.
authors.affiliation: Human Genetics Foundation, Torino, Italy; Department of Medical Sciences, University of Torino, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Fiorito
authors.affiliation: Human Genetics Foundation, Torino, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Guarrera
authors.affiliation: Human Genetics Foundation, Torino, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Valle
authors.affiliation: Human Genetics Foundation, Torino, Italy; Department of Medical Sciences, University of Torino, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Ricceri
authors.affiliation: Human Genetics Foundation, Torino, Italy; Department of Medical Sciences, University of Torino, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Russo
authors.affiliation: Department of Preventive and Predictive Medicine, Epidemiology and Prevention Unit, Fondazione IRCSS Istituto Nazionale dei Tumori, Milano, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Grioni
authors.affiliation: Department of Clinical and Experimental Medicine, Federico II University, Napoli, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Mattiello
authors.affiliation: Human Genetics Foundation, Torino, Italy; Department of Medical Sciences, University of Torino, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Di Gaetano
authors.affiliation: Human Genetics Foundation, Torino, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Rosa
authors.affiliation: Human Genetics Foundation, Torino, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Modica
authors.affiliation: Department of Epidemiology and Prevention, IRCCS Istituto Neurologico Mediterraneo Neuromed, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Iacoviello
authors.affiliation: Cancer Registry and Histopathology Unit, "Civile-M.P. Arezzo" Hospital, Ragusa, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Frasca
authors.affiliation: Cancer Registry and Histopathology Unit, "Civile-M.P. Arezzo" Hospital, Ragusa, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Tumino
authors.affiliation: Department of Preventive and Predictive Medicine, Epidemiology and Prevention Unit, Fondazione IRCSS Istituto Nazionale dei Tumori, Milano, Italy.
authors.forename: V
authors.initials: V
authors.lastname: Krogh
authors.affiliation: Department of Clinical and Experimental Medicine, Federico II University, Napoli, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Panico
authors.affiliation: Human Genetics Foundation, Torino, Italy; Epidemiology and Public Health, Imperial College London, UK.
authors.forename: P
authors.initials: P
authors.lastname: Vineis
authors.affiliation: Human Genetics Foundation, Torino, Italy; Cancer Epidemiology, CPO-Piemonte, Torino, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Sacerdote
authors.affiliation: Human Genetics Foundation, Torino, Italy; Department of Medical Sciences, University of Torino, Italy. Electronic address: giuseppe.matullo@unito.it.
authors.forename: G
authors.initials: G
authors.lastname: Matullo
mesh_terms: D000328:Adult; D050960:Aminomethyltransferase / Q000235:genetics; D043303:Aryldialkylphosphatase / Q000235:genetics; D016022:Case-Control Studies; D019175:DNA Methylation / Q000187:drug effects*; D005260:Female; D005500:Follow-Up Studies; D006710:Homocysteine / Q000096:biosynthesis; D006801:Humans; D016015:Logistic Models; D008297:Male; D053858:Metabolic Networks and Pathways / Q000235:genetics*; D008875:Middle Aged; D015999:Multivariate Analysis; D009203:Myocardial Infarction / Q000453:epidemiology* / Q000517:prevention & control; D011401:Promoter Regions, Genetic; D011446:Prospective Studies; D012307:Risk Factors; D014155:Transcobalamins / Q000235:genetics; D014803:Vitamin B Complex / Q000008:administration & dosage*
chemical_list: D014155:Transcobalamins; D006710:Homocysteine; D014803:Vitamin B Complex; D050960:Aminomethyltransferase; D043303:Aryldialkylphosphatase; C468406:PON1 protein, human
keywords: B-vitamins; DNA-methylation; Homocysteine; Myocardial infarction; One Carbon Metabolism