title: Obesity and ischemic stroke modulate the methylation levels of KCNQ1 in white blood cells.
abstract: Obesity and stroke are multifactorial diseases in which genetic, epigenetic and lifestyle factors are involved. The research aims were, first, the description of genes with differential epigenetic regulation obtained by an 'omics' approach in patients with ischemic stroke and, second, to determine the importance of some regions of these selected genes in biological processes depending on the body mass index. A case-control study using two populations was designed. The first population consisted of 24 volunteers according to stroke/non-stroke and normal weight/obesity conditions. The second population included 60 stroke patients and 55 controls classified by adiposity. DNA from the first population was analyzed with a methylation microarray, showing 80 cytosine-guanine dinucleotides (CpG) sites differentially methylated in stroke and 96 CpGs in obesity, whereas 59 CpGs showed interaction. After validating these data by MassArray Epityper, the promoter region of peptidase M20 domain containing 1 (PM20D1) gene was significantly hypermethylated in stroke patients. One CpG site at Caldesmon 1 (CALD1) gene showed an interaction between stroke and obesity. Two CpGs located in the genes Wilms' tumor 1 (WT1) and potassium voltage-gated channel, KQT-like subfamily, member 1 (KCNQ1) were significantly hypermethylated in obese patients. In the second population, KCNQ1 was also hypermethylated in the obese subjects. Two CpGs of this gene were subsequently validated by methylation-sensitive high-resolution melting. Moreover, KCNQ1 methylation levels were associated with plasma KCNQ1 protein concentrations. In conclusion, obesity induced changes in the KCNQ1 methylation pattern which were also dependent on stroke. Furthermore, the epigenetic marks differentially methylated in the stroke patients were dependent on the previous obese state. These DNA methylation patterns could be used as future potential stroke biomarkers.
authors.affiliation: Department of Nutrition, Food Sciences and Physiology, Centre for Nutrition Research, University of Navarra, Pamplona, Spain.
authors.forename: Ana M
authors.initials: AM
authors.lastname: Gómez-Úriz
authors.affiliation: Department of Nutrition, Food Sciences and Physiology, Centre for Nutrition Research, University of Navarra, Pamplona, Spain, CIBER Fisiopatología Obesidad y Nutrición (CIBERObn), Ministry of Economy and Competitiveness, Instituto de Salud Carlos III, Madrid, Spain, fmilagro@unav.es.
authors.forename: Fermín I
authors.initials: FI
authors.lastname: Milagro
authors.affiliation: Department of Nutrition, Food Sciences and Physiology, Centre for Nutrition Research, University of Navarra, Pamplona, Spain, CIBER Fisiopatología Obesidad y Nutrición (CIBERObn), Ministry of Economy and Competitiveness, Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: María L
authors.initials: ML
authors.lastname: Mansego
authors.affiliation: Department of Nutrition, Food Sciences and Physiology, Centre for Nutrition Research, University of Navarra, Pamplona, Spain.
authors.forename: Paúl
authors.initials: P
authors.lastname: Cordero
authors.affiliation: Neuroscience Area, Institute Biodonostia, Donostia-San Sebastian, Spain.
authors.forename: Itziar
authors.initials: I
authors.lastname: Abete
authors.affiliation: Department of Neurology, Neurovascular Unit, Department of Neurology, Hospital Universitario Donostia, Donostia-San Sebastian, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: De Arce
authors.affiliation: Neuroscience Area, Institute Biodonostia, Donostia-San Sebastian, Spain.
authors.forename: Estíbaliz
authors.initials: E
authors.lastname: Goyenechea
authors.affiliation: Neuroscience Area, Institute Biodonostia, Donostia-San Sebastian, Spain.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Blázquez
authors.affiliation: Department of Neurology, Neurovascular Unit, Department of Neurology, Hospital Universitario Donostia, Donostia-San Sebastian, Spain, Department of Neurosciences, University of Basque Country UPV-EHU, San Sebastián, Spain.
authors.forename: Maite
authors.initials: M
authors.lastname: Martínez-Zabaleta
authors.affiliation: Department of Nutrition, Food Sciences and Physiology, Centre for Nutrition Research, University of Navarra, Pamplona, Spain, CIBER Fisiopatología Obesidad y Nutrición (CIBERObn), Ministry of Economy and Competitiveness, Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: José Alfredo
authors.initials: JA
authors.lastname: Martínez
authors.affiliation: Neuroscience Area, Institute Biodonostia, Donostia-San Sebastian, Spain, Department of Neurology, Department of Neurosciences, University of Basque Country UPV-EHU, San Sebastián, Spain CIBERNED (Ministry of Economy and Competitiveness, Institute Carlos III), Madrid, Spain.
authors.forename: Adolfo
authors.initials: A
authors.lastname: López De Munain
authors.affiliation: Department of Nutrition, Food Sciences and Physiology, Centre for Nutrition Research, University of Navarra, Pamplona, Spain, CIBER Fisiopatología Obesidad y Nutrición (CIBERObn), Ministry of Economy and Competitiveness, Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Campión
mesh_terms: D000368:Aged; D015992:Body Mass Index; D002147:Calmodulin / Q000235:genetics / Q000378:metabolism; D002148:Calmodulin-Binding Proteins / Q000235:genetics / Q000378:metabolism; D016022:Case-Control Studies; D018899:CpG Islands; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D005819:Genetic Markers; D006801:Humans; D051657:KCNQ1 Potassium Channel / Q000097:blood / Q000235:genetics*; D007962:Leukocytes / Q000378:metabolism*; D016014:Linear Models; D008297:Male; D045726:Metalloproteases / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D009765:Obesity / Q000235:genetics*; D011401:Promoter Regions, Genetic; D020521:Stroke / Q000235:genetics*; D025721:WT1 Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D002147:Calmodulin; D002148:Calmodulin-Binding Proteins; D005819:Genetic Markers; D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human; D025721:WT1 Proteins; C583751:WT1 protein, human; D045726:Metalloproteases