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G Protein-Coupled Receptor 15 Expression Is Associated with Myocardial Infarction
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–contro...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9820726/ https://www.ncbi.nlm.nih.gov/pubmed/36613626 http://dx.doi.org/10.3390/ijms24010180 |
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author | Haase, Tina Müller, Christian Stoffers, Bastian Kirn, Philipp Waldenberger, Melanie Kaiser, Frank J. Karakas, Mahir Kim, Sangwon V. Voss, Svenja Wild, Philipp S. Lackner, Karl J. Andersson, Jonas Söderberg, Stefan Lindner, Diana Zeller, Tanja |
author_facet | Haase, Tina Müller, Christian Stoffers, Bastian Kirn, Philipp Waldenberger, Melanie Kaiser, Frank J. Karakas, Mahir Kim, Sangwon V. Voss, Svenja Wild, Philipp S. Lackner, Karl J. Andersson, Jonas Söderberg, Stefan Lindner, Diana Zeller, Tanja |
author_sort | Haase, Tina |
collection | PubMed |
description | 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, Gpr15(gfp/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. |
format | Online Article Text |
id | pubmed-9820726 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-98207262023-01-07 G Protein-Coupled Receptor 15 Expression Is Associated with Myocardial Infarction Haase, Tina Müller, Christian Stoffers, Bastian Kirn, Philipp Waldenberger, Melanie Kaiser, Frank J. Karakas, Mahir Kim, Sangwon V. Voss, Svenja Wild, Philipp S. Lackner, Karl J. Andersson, Jonas Söderberg, Stefan Lindner, Diana Zeller, Tanja Int J Mol Sci Article 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, Gpr15(gfp/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. MDPI 2022-12-22 /pmc/articles/PMC9820726/ /pubmed/36613626 http://dx.doi.org/10.3390/ijms24010180 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Haase, Tina Müller, Christian Stoffers, Bastian Kirn, Philipp Waldenberger, Melanie Kaiser, Frank J. Karakas, Mahir Kim, Sangwon V. Voss, Svenja Wild, Philipp S. Lackner, Karl J. Andersson, Jonas Söderberg, Stefan Lindner, Diana Zeller, Tanja G Protein-Coupled Receptor 15 Expression Is Associated with Myocardial Infarction |
title | G Protein-Coupled Receptor 15 Expression Is Associated with Myocardial Infarction |
title_full | G Protein-Coupled Receptor 15 Expression Is Associated with Myocardial Infarction |
title_fullStr | G Protein-Coupled Receptor 15 Expression Is Associated with Myocardial Infarction |
title_full_unstemmed | G Protein-Coupled Receptor 15 Expression Is Associated with Myocardial Infarction |
title_short | G Protein-Coupled Receptor 15 Expression Is Associated with Myocardial Infarction |
title_sort | g protein-coupled receptor 15 expression is associated with myocardial infarction |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9820726/ https://www.ncbi.nlm.nih.gov/pubmed/36613626 http://dx.doi.org/10.3390/ijms24010180 |
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