title: Genome-wide DNA methylation study identifies genes associated with the cardiovascular biomarker GDF-15.
abstract: Growth-differentiation factor 15 (GDF-15) is expressed in low to moderate levels in most healthy tissues and increases in response to inflammation. GDF-15 is associated with cardiovascular dysfunction and over-expressed in the myocardium of patients with myocardial infarction (MI). However, little is known about the function of GDF-15 in cardiovascular disease, and the underlying regulatory network of GDF-15 is not known. To investigate a possible association between GDF-15 levels and DNA methylation, we performed a genome-wide DNA methylation study of white blood cells in a population-based study (N = 717). Significant loci where replicated in an independent cohort (N = 963). We also performed a gene ontology (GO) enrichment analysis. We identified and replicated 16 CpG-sites (false discovery rate [FDR] < 0.05), at 11 independent loci including MIR21. MIR21 encodes a microRNA (miR-21) that has previously been shown to be associated with the development of heart disease. Interestingly, GDF15 mRNA contains a binding site for miR-21. Four sites were also differentially methylated in blood from participants previously diagnosed with MI and 14 enriched GO terms (FDR < 0.05, enrichment > 2) were identified, including 'cardiac muscle cell differentiation'. This study shows that GDF-15 levels are associated with differences in DNA methylation in blood cells, and a subset of the loci are also differentially methylated in participants with MI. However, there might be interactions between GDF-15 levels and methylation in other tissues not addressed in this study. These results provide novel links between GDF-15 and cardiovascular disease.
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, and weronica.ek@igp.uu.se.
authors.forename: Weronica E
authors.initials: WE
authors.lastname: Ek
authors.affiliation: Department of Medical Sciences, Molecular epidemiology and Science for Life Laboratory, Uppsala University, Uppsala 75108, Sweden.
authors.forename: Åsa K
authors.initials: ÅK
authors.lastname: Hedman
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, and.
authors.forename: Stefan
authors.initials: S
authors.lastname: Enroth
authors.affiliation: Department of Biostatistics, University of Liverpool, Liverpool L69 3BX, UK, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK and.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Morris
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK and.
authors.forename: Cecilia M
authors.initials: CM
authors.lastname: Lindgren
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK and.
authors.forename: Anubha
authors.initials: A
authors.lastname: Mahajan
authors.affiliation: Department of Medical Sciences, Molecular epidemiology and Science for Life Laboratory, Uppsala University, Uppsala 75108, Sweden.
authors.forename: Stefan
authors.initials: S
authors.lastname: Gustafsson
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, and.
authors.forename: Ulf
authors.initials: U
authors.lastname: Gyllensten
authors.affiliation: Department of Medical Sciences, Cardiovascular Epidemiology, Uppsala University Hospital, Uppsala 75185, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Lind
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, and.
authors.forename: Åsa
authors.initials: Å
authors.lastname: Johansson
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers / Q000097:blood; D002318:Cardiovascular Diseases / Q000097:blood / Q000235:genetics*; D018899:CpG Islands; D004247:DNA / Q000097:blood / Q000235:genetics; D019175:DNA Methylation; D005260:Female; D055106:Genome-Wide Association Study; D055436:Growth Differentiation Factor 15 / Q000097:blood / Q000235:genetics*; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000097:blood / Q000235:genetics; D008875:Middle Aged
chemical_list: D015415:Biomarkers; C526140:GDF15 protein, human; D055436:Growth Differentiation Factor 15; C524940:MIRN21 microRNA, human; D035683:MicroRNAs; D004247:DNA