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Haase, T.* ; Müller, C.* ; Stoffers, B.* ; Kirn, P.* ; Waldenberger, M. ; Kaiser, F.J.* ; Karakas, M.* ; Kim, S.V.* ; Voss, S.* ; Wild, P.S.* ; Lackner, K.J.* ; Andersson, J.* ; Söderberg, S.* ; Lindner, D.* ; Zeller, T.*

G Protein-coupled receptor 15 expression is associated with myocardial infarction.

Int. J. Mol. Sci. 24:180 (2023)
Publ. Version/Full Text Research data DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
Beyond the influence of lifestyle-related risk factors for myocardial infarction (MI), the mechanisms of genetic predispositions for MI remain unclear. We sought to identify and characterize differentially expressed genes in early-onset MI in a translational approach. In an observational case-control study, transcriptomes from 112 early-onset MI individuals showed upregulated G protein-coupled receptor 15 (GPR15) expression in peripheral blood mononuclear cells compared to controls (fold change = 1.4, p = 1.87 × 10-7). GPR15 expression correlated with intima-media thickness (β = 0.8498, p = 0.111), C-reactive protein (β = 0.2238, p = 0.0052), ejection fraction (β = -0.9991, p = 0.0281) and smoking (β = 0.7259, p = 2.79 × 10-10). The relation between smoking and MI was diminished after the inclusion of GPR15 expression as mediator in mediation analysis (from 1.27 (p = 1.9 × 10-5) to 0.46 (p = 0.21)). The DNA methylation of two GPR15 sites was 1%/5% lower in early-onset MI individuals versus controls (p = 2.37 × 10-6/p = 0.0123), with site CpG3.98251219 significantly predicting risk for incident MI (hazard ratio = 0.992, p = 0.0177). The nucleotide polymorphism rs2230344 (C/T) within GPR15 was associated with early-onset MI (odds ratio = 3.61, p = 0.044). Experimental validation showed 6.3-fold increased Gpr15 expression in an ischemic mouse model (p < 0.05) and 4-fold increased Gpr15 expression in cardiomyocytes under ischemic stress (p < 0.001). After the induction of MI, Gpr15gfp/gfp mice showed lower survival (p = 0.042) and deregulated gene expression for response to hypoxia and signaling pathways. Using a translational approach, our data provide evidence that GPR15 is linked to cardiovascular diseases, mediating the adverse effects of smoking.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords G Protein-coupled Receptor ; Biomarkers ; Cardiovascular Disease ; Epigenetics ; Gene Expression ; Inflammation ; Novel Molecular Target ; Pathogenesis ; Signal Pathway ; Translational Research; Herz-Kreislauf, Epigenetik, DZHK
ISSN (print) / ISBN 1422-0067
e-ISSN 1661-6596
Journal International Journal of Molecular Sciences
Quellenangaben Volume: 24, Issue: 1, Pages: , Article Number: 180 Supplement: ,
Publisher MDPI
Publishing Place Basel
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Epidemiology II (EPI2)
Grants University Medical Center Hamburg Eppendorf (UKE)
grant Research Promotion Fund of the Faculty of Medicine (FFM)
Else Kroener-Fresenius-Stiftung
Ernst und Berta Grimmke-Stiftung
German Research Foundation (DFG)
German Centre for Cardiovascular Research (DZHK e.V.)
Government of Rhineland-Palatinate ("Stiftung Rheinland-Pfalz fuer Innovation")
"Wissen schafft Zukunft" (Gutenberg Health Study)
Johannes Gutenberg-University of Mainz "Center for Translational Vascular Biology" (Gutenberg Health Study)
Boehringer Ingelheimer
PHILIPS Medical Systems (Gutenberg Health Study)
Swedish Heart and Lung Foundation
Gustaf Sjoelund Foundation
Country councils of Northern Sweden
Faculty of Medicine of Umea University
National Institute of Health (NIH)