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Biomolecules 2018, 8(3), 74; https://doi.org/10.3390/biom8030074

Novel DNA Methylation Sites Influence GPR15 Expression in Relation to Smoking

1
Clinic for General and Interventional Cardiology, University Heart Center Hamburg, 20246 Hamburg, Germany
2
German Centre for Cardiovascular Research (DZHK), 13316 Berlin, Germany
3
Institute of Experimental Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf (UKE), 20246 Hamburg, Germany
4
Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany
5
Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany
6
Center for Cardiology, Cardiology I, University Medical Center Mainz, Johannes Gutenberg University-Mainz, 55131 Mainz, Germany
7
Center for Thrombosis and Hemostasis, University Medical Center Mainz, Johannes Gutenberg-University Mainz, 55131 Mainz, Germany
8
Center for Translational Vascular Biology (CTVB), University Medical Center Mainz, Johannes Gutenberg-University Mainz, 55131 Mainz, Germany
9
Department of Ophthalmology, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany
10
Preventive Cardiology and Preventive Medicine, Center for Cardiology, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany
11
Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany
12
Department of Psychosomatic Medicine and Psychotherapy, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany
13
University Medical Center, Institute of Medical Biostatistics, Epidemiology and Informatics (IMBEI), 55131 Mainz, Germany
14
Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center, Johannes Gutenberg University Mainz, 55131 Mainz, Germany
*
Author to whom correspondence should be addressed.
Received: 16 July 2018 / Revised: 6 August 2018 / Accepted: 9 August 2018 / Published: 20 August 2018
(This article belongs to the Special Issue Biomolecules for Translational Approaches in Cardiology)
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Abstract

Smoking is a major risk factor for cardiovascular diseases and has been implicated in the regulation of the G protein-coupled receptor 15 (GPR15) by affecting CpG methylation. The G protein-coupled receptor 15 is involved in angiogenesis and inflammation. An effect on GPR15 gene regulation has been shown for the CpG site CpG3.98251294. We aimed to analyze the effect of smoking on GPR15 expression and methylation sites spanning the GPR15 locus. DNA methylation of nine GPR15 CpG sites was measured in leukocytes from 1291 population-based individuals using the EpiTYPER. Monocytic GPR15 expression was measured by qPCR at baseline and five-years follow up. GPR15 gene expression was upregulated in smokers (beta (ß) = −2.699, p-value (p) = 1.02 × 10−77) and strongly correlated with smoking exposure (ß = −0.063, p = 2.95 × 10−34). Smoking cessation within five years reduced GPR15 expression about 19% (p = 9.65 × 10−5) with decreasing GPR15 expression over time (ß = 0.031, p = 3.81 × 10−6). Additionally, three novel CpG sites within GPR15 affected by smoking were identified. For CpG3.98251047, DNA methylation increased steadily after smoking cessation (ß = 0.123, p = 1.67 × 10−3) and strongly correlated with changes in GPR15 expression (ß = 0.036, p = 4.86 × 10−5). Three novel GPR15 CpG sites were identified in relation to smoking and GPR15 expression. Our results provide novel insights in the regulation of GPR15, which possibly linked smoking to inflammation and disease progression. View Full-Text
Keywords: GPR15; smoking; biomarker; DNA methylation GPR15; smoking; biomarker; DNA methylation
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Haase, T.; Müller, C.; Krause, J.; Röthemeier, C.; Stenzig, J.; Kunze, S.; Waldenberger, M.; Münzel, T.; Pfeiffer, N.; Wild, P.S.; Michal, M.; Marini, F.; Karakas, M.; Lackner, K.J.; Blankenberg, S.; Zeller, T. Novel DNA Methylation Sites Influence GPR15 Expression in Relation to Smoking. Biomolecules 2018, 8, 74.

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