Alexander Glahna*, Mathias Rheina, Rafael Riera Knorrenschildb,d, Mani Haschemi Nassaba, Michael Gröschlc, Annemarie Heberlein a, Marc Muschlera, Helge Frielinga, Stefan Bleicha, Thomas Hillemachera
a Center for Addiction Research (CARe), Department of Psychiatry, Socialpsychiatry and Psychotherapy, Hannover Medical School, Germany
b Clinic for Psychiatry, Psychotherapy and Psychosomatic Medicine (RR), Kutzenberg, Germany
c Celerion Switzerland AG, Bioanalytical Laboratory, Switzerland.
d Bezirksklinik Hochstadt. Division of Substance Use Disorders, Hochstadt am Main, Germany
Background: Natriuretic peptides participate in the complex collection of metabolic effects in reaction to chronic ethanol drinking. Brain Natriuretic Peptide (BNP) is a specific member of this family known to be expressed in heart and brain, thereby being a potential target for the individualization of diagnosis and therapy. Having witnessed effects on other natriuretic peptides in a longitudinal cohort of patients undergoing detoxification treatment collective, we were interested in the effects of detoxification treatment on BNP methylation in correlation to protein expression and major clinical markers for anxiety and craving. The epigenetic regulation of BNP, especially in the context of alcoholism, is unknown to this date.
GATA4 is part of a complex regulatory network, inducing DNA transcription upon binding to conserved recognition sites and leading to gene expression. With BNP expression being GATA4-dependent, we observed a tight correlation of GATA4 binding site methylation and protein expression, pointing towards a mechanism of activation and potential possibility to correlate epigenetic imprinting on this site with BNP expression levels and psychological traits such as anxiety and craving.
Method: 72 male patients were subjected to a longitudinal investigation (days 1, 7 and 14 of detoxification treatment) and are compared with 101 age-matched controls concerning epigenetic regulation and protein expression of BNP.
Results/Discussion: Surprisingly the global methylation analysis of the core regulative promoter region of BNP reveals counterintuitive data until the scope of analysis is narrowed to CpG sites in immediate proximity to predicted GATA sites. Function-driven site selection reveals a tendency of epigenetic regulation contributing to BNP regulation that otherwise would not have been recognized. Focusing on GATA-related CpG positions presents exactly inverse regulation compared to CpG 38-44. CpG 45/46 correlate with intuitive expectation and serum levels /OCDS scale output. Taken together, the findings point towards a potential core area in the BNP promoter that can be utilized to predict GATA4-dependent BNP expression during withdrawal.