Identificación de modificaciones epigenéticas como posibles biomarcadores de la obesidad y el ictus.

Abstract

DNA methylation is an epigenetic mechanism that regulates gene expression. These epigenetic marks are modified by some pathology such as obesity, and it could be change by stroke. The main objective of this work was to determine the influence of ischemic stroke in the epigenetic pattern of genes involved in cerebrovascular disease and obesity, and their interaction with body mass index and the study of the effect of a hypocaloric diet in these epigenetic changes. In order to realize this objective this work was consisted in a case-control design with four populations. In all populations cases were selected from the Neurology Service of Hospital Donostia, with a first episode of ischemic stroke, evaluated in the first 24 hours for a neurologist of the onset of symptoms. The control groups were constituted by non-vascular neurological disorder patients that were matched by sex and age with the cases. Cases and controls were divided in bothgroups using the BMI classification criteria proposed by the WHO. In the first place it was studied the changes in epigenetic profile of human tumor necrosis factor (TNFα) and paraoxonase (PON) promoters and the relationship with the susceptibility to stroke when considering body composition and dietary intake. In the other hand, it was raised to describe candidate genes with differential epigenetic regulation in patients with ischemic stroke and, to determine the importance of some regions of these candidate genes in different biological processes mediated by BMI. Fist an array was realized and the results were validated with this population and the methylation from regions of four genes was measured in other 115 individuals (PM20D1, CALD1, WT1 and KCNQ1). Modifications in KCNQ1 region was observed and translated in changes of the protein levels. Finally 40 obese patients with and without previous ischemic stroke was included in a 20 week nutritional intervention. Methylation levels of WT1 and KCNQ1 regions were measured, at the beginning and at the end of the treatment. It was observed changes in methylation levels and inflammatory response biomarkers produced by the hypocaloric diet. It can be concluded in general that an ischemic stroke modifies the epigenetic pattern of genes involved in cerebrovascular and metabolic diseases. These changes are depended of previous BMI. In particular, KCNQ1, methylation and secretion levels are revealed as a promising biomarker for stroke and obesity.