title: DNA methylation map of human atherosclerosis.
abstract: BACKGROUND
  Epigenetic alterations may contribute to the development of atherosclerosis. In particular, DNA methylation, a reversible and highly regulated DNA modification, could influence disease onset and progression because it functions as an effector for environmental influences, including diet and lifestyle, both of which are risk factors for cardiovascular diseases.
  
  
  RESULTS
  To address the role of DNA methylation changes in atherosclerosis, we compared a donor-matched healthy and atherosclerotic human aorta sample using whole-genome shotgun bisulfite sequencing. We observed that the atherosclerotic portion of the aorta was hypermethylated across many genomic loci in comparison with the matched healthy counterpart. Furthermore, we defined specific loci of differential DNA methylation using a set of donor-matched aortic samples and a high-density (>450 000 CpG sites) DNA methylation microarray. The functional importance in the disease was corroborated by crossing the DNA methylation signature with the corresponding expression data of the same samples. Among the differentially methylated CpGs associated with atherosclerosis onset, we identified genes participating in endothelial and smooth muscle functions. These findings provide new clues toward a better understanding of the molecular mechanisms of atherosclerosis.
  
  
  CONCLUSIONS
  Our data identify an atherosclerosis-specific DNA methylation profile that highlights the contribution of different genes and pathways to the disorder. Interestingly, the observed gain of DNA methylation in the atherosclerotic lesions justifies efforts to develop DNA demethylating agents for therapeutic benefit.
authors.affiliation: From the Division of Health Sciences, Department of Medical Sciences, University of Guanajuato, León, Guanajuato, Mexico (S.Z.); Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Catalonia, Spain (H.H., F.J.C., N.V., S.S., A.G., S.M., M.E.); Department of Pathology, Bellvitge University Hospital, Bellvitge Biomedical Research Institute (IDIBELL) (E.C.), Barcelona, Spain; Department of Pathology and Experimental Therapeutics (E.C.), Department of Anatomy and Pathology, Hospital Clinic (J.R.-R.), Department of Physiological Sciences II, School of Medicine (M.E.), University of Barcelona, Barcelona, Catalonia, Spain; Experimental Cardiovascular Research, Lund University, Malmö, Sweden (I.G.); and Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain (M.E.). mesteller@idibell.cat szaina@ugto.mx.
authors.forename: Silvio
authors.initials: S
authors.lastname: Zaina
authors.affiliation: From the Division of Health Sciences, Department of Medical Sciences, University of Guanajuato, León, Guanajuato, Mexico (S.Z.); Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Catalonia, Spain (H.H., F.J.C., N.V., S.S., A.G., S.M., M.E.); Department of Pathology, Bellvitge University Hospital, Bellvitge Biomedical Research Institute (IDIBELL) (E.C.), Barcelona, Spain; Department of Pathology and Experimental Therapeutics (E.C.), Department of Anatomy and Pathology, Hospital Clinic (J.R.-R.), Department of Physiological Sciences II, School of Medicine (M.E.), University of Barcelona, Barcelona, Catalonia, Spain; Experimental Cardiovascular Research, Lund University, Malmö, Sweden (I.G.); and Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain (M.E.).
authors.forename: Holger
authors.initials: H
authors.lastname: Heyn
authors.affiliation: From the Division of Health Sciences, Department of Medical Sciences, University of Guanajuato, León, Guanajuato, Mexico (S.Z.); Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Catalonia, Spain (H.H., F.J.C., N.V., S.S., A.G., S.M., M.E.); Department of Pathology, Bellvitge University Hospital, Bellvitge Biomedical Research Institute (IDIBELL) (E.C.), Barcelona, Spain; Department of Pathology and Experimental Therapeutics (E.C.), Department of Anatomy and Pathology, Hospital Clinic (J.R.-R.), Department of Physiological Sciences II, School of Medicine (M.E.), University of Barcelona, Barcelona, Catalonia, Spain; Experimental Cardiovascular Research, Lund University, Malmö, Sweden (I.G.); and Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain (M.E.).
authors.forename: F Javier
authors.initials: FJ
authors.lastname: Carmona
authors.affiliation: From the Division of Health Sciences, Department of Medical Sciences, University of Guanajuato, León, Guanajuato, Mexico (S.Z.); Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Catalonia, Spain (H.H., F.J.C., N.V., S.S., A.G., S.M., M.E.); Department of Pathology, Bellvitge University Hospital, Bellvitge Biomedical Research Institute (IDIBELL) (E.C.), Barcelona, Spain; Department of Pathology and Experimental Therapeutics (E.C.), Department of Anatomy and Pathology, Hospital Clinic (J.R.-R.), Department of Physiological Sciences II, School of Medicine (M.E.), University of Barcelona, Barcelona, Catalonia, Spain; Experimental Cardiovascular Research, Lund University, Malmö, Sweden (I.G.); and Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain (M.E.).
authors.forename: Nuray
authors.initials: N
authors.lastname: Varol
authors.affiliation: From the Division of Health Sciences, Department of Medical Sciences, University of Guanajuato, León, Guanajuato, Mexico (S.Z.); Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Catalonia, Spain (H.H., F.J.C., N.V., S.S., A.G., S.M., M.E.); Department of Pathology, Bellvitge University Hospital, Bellvitge Biomedical Research Institute (IDIBELL) (E.C.), Barcelona, Spain; Department of Pathology and Experimental Therapeutics (E.C.), Department of Anatomy and Pathology, Hospital Clinic (J.R.-R.), Department of Physiological Sciences II, School of Medicine (M.E.), University of Barcelona, Barcelona, Catalonia, Spain; Experimental Cardiovascular Research, Lund University, Malmö, Sweden (I.G.); and Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain (M.E.).
authors.forename: Sergi
authors.initials: S
authors.lastname: Sayols
authors.affiliation: From the Division of Health Sciences, Department of Medical Sciences, University of Guanajuato, León, Guanajuato, Mexico (S.Z.); Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Catalonia, Spain (H.H., F.J.C., N.V., S.S., A.G., S.M., M.E.); Department of Pathology, Bellvitge University Hospital, Bellvitge Biomedical Research Institute (IDIBELL) (E.C.), Barcelona, Spain; Department of Pathology and Experimental Therapeutics (E.C.), Department of Anatomy and Pathology, Hospital Clinic (J.R.-R.), Department of Physiological Sciences II, School of Medicine (M.E.), University of Barcelona, Barcelona, Catalonia, Spain; Experimental Cardiovascular Research, Lund University, Malmö, Sweden (I.G.); and Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain (M.E.).
authors.forename: Enric
authors.initials: E
authors.lastname: Condom
authors.affiliation: From the Division of Health Sciences, Department of Medical Sciences, University of Guanajuato, León, Guanajuato, Mexico (S.Z.); Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Catalonia, Spain (H.H., F.J.C., N.V., S.S., A.G., S.M., M.E.); Department of Pathology, Bellvitge University Hospital, Bellvitge Biomedical Research Institute (IDIBELL) (E.C.), Barcelona, Spain; Department of Pathology and Experimental Therapeutics (E.C.), Department of Anatomy and Pathology, Hospital Clinic (J.R.-R.), Department of Physiological Sciences II, School of Medicine (M.E.), University of Barcelona, Barcelona, Catalonia, Spain; Experimental Cardiovascular Research, Lund University, Malmö, Sweden (I.G.); and Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain (M.E.).
authors.forename: José
authors.initials: J
authors.lastname: Ramírez-Ruz
authors.affiliation: From the Division of Health Sciences, Department of Medical Sciences, University of Guanajuato, León, Guanajuato, Mexico (S.Z.); Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Catalonia, Spain (H.H., F.J.C., N.V., S.S., A.G., S.M., M.E.); Department of Pathology, Bellvitge University Hospital, Bellvitge Biomedical Research Institute (IDIBELL) (E.C.), Barcelona, Spain; Department of Pathology and Experimental Therapeutics (E.C.), Department of Anatomy and Pathology, Hospital Clinic (J.R.-R.), Department of Physiological Sciences II, School of Medicine (M.E.), University of Barcelona, Barcelona, Catalonia, Spain; Experimental Cardiovascular Research, Lund University, Malmö, Sweden (I.G.); and Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain (M.E.).
authors.forename: Antonio
authors.initials: A
authors.lastname: Gomez
authors.affiliation: From the Division of Health Sciences, Department of Medical Sciences, University of Guanajuato, León, Guanajuato, Mexico (S.Z.); Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Catalonia, Spain (H.H., F.J.C., N.V., S.S., A.G., S.M., M.E.); Department of Pathology, Bellvitge University Hospital, Bellvitge Biomedical Research Institute (IDIBELL) (E.C.), Barcelona, Spain; Department of Pathology and Experimental Therapeutics (E.C.), Department of Anatomy and Pathology, Hospital Clinic (J.R.-R.), Department of Physiological Sciences II, School of Medicine (M.E.), University of Barcelona, Barcelona, Catalonia, Spain; Experimental Cardiovascular Research, Lund University, Malmö, Sweden (I.G.); and Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain (M.E.).
authors.forename: Isabel
authors.initials: I
authors.lastname: Gonçalves
authors.affiliation: From the Division of Health Sciences, Department of Medical Sciences, University of Guanajuato, León, Guanajuato, Mexico (S.Z.); Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Catalonia, Spain (H.H., F.J.C., N.V., S.S., A.G., S.M., M.E.); Department of Pathology, Bellvitge University Hospital, Bellvitge Biomedical Research Institute (IDIBELL) (E.C.), Barcelona, Spain; Department of Pathology and Experimental Therapeutics (E.C.), Department of Anatomy and Pathology, Hospital Clinic (J.R.-R.), Department of Physiological Sciences II, School of Medicine (M.E.), University of Barcelona, Barcelona, Catalonia, Spain; Experimental Cardiovascular Research, Lund University, Malmö, Sweden (I.G.); and Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain (M.E.).
authors.forename: Sebastian
authors.initials: S
authors.lastname: Moran
authors.affiliation: From the Division of Health Sciences, Department of Medical Sciences, University of Guanajuato, León, Guanajuato, Mexico (S.Z.); Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Catalonia, Spain (H.H., F.J.C., N.V., S.S., A.G., S.M., M.E.); Department of Pathology, Bellvitge University Hospital, Bellvitge Biomedical Research Institute (IDIBELL) (E.C.), Barcelona, Spain; Department of Pathology and Experimental Therapeutics (E.C.), Department of Anatomy and Pathology, Hospital Clinic (J.R.-R.), Department of Physiological Sciences II, School of Medicine (M.E.), University of Barcelona, Barcelona, Catalonia, Spain; Experimental Cardiovascular Research, Lund University, Malmö, Sweden (I.G.); and Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain (M.E.). mesteller@idibell.cat szaina@ugto.mx.
authors.forename: Manel
authors.initials: M
authors.lastname: Esteller
mesh_terms: D001011:Aorta / Q000378:metabolism* / Q000473:pathology; D050197:Atherosclerosis / Q000235:genetics*; D002874:Chromosome Mapping / Q000379:methods*; D016000:Cluster Analysis; D018899:CpG Islands; D019175:DNA Methylation; D004032:Diet; D018450:Disease Progression; D044127:Epigenesis, Genetic; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D008019:Life Style; D012307:Risk Factors; D013447:Sulfites / Q000737:chemistry
chemical_list: D013447:Sulfites; C042345:hydrogen sulfite
keywords: DNA methylation; aorta; epigenomics; genome-wide association analysis