G Protein-Coupled Receptor 15 Expression Is Associated with Myocardial Infarction
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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.
in: INT J MOL SCI, Jahrgang 24, Nr. 1, 180, 22.12.2022.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - G Protein-Coupled Receptor 15 Expression Is Associated with Myocardial Infarction
AU - Haase, Tina
AU - Müller, Christian
AU - Stoffers, Bastian
AU - Kirn, Philipp
AU - Waldenberger, Melanie
AU - Kaiser, Frank J
AU - Karakas, Mahir
AU - Kim, Sangwon V
AU - Voss, Svenja
AU - Wild, Philipp S
AU - Lackner, Karl J
AU - Andersson, Jonas
AU - Söderberg, Stefan
AU - Lindner, Diana
AU - Zeller, Tanja
PY - 2022/12/22
Y1 - 2022/12/22
N2 - 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.
AB - 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.
KW - Animals
KW - Mice
KW - Carotid Intima-Media Thickness
KW - Case-Control Studies
KW - Leukocytes, Mononuclear/metabolism
KW - Myocardial Infarction/genetics
KW - Receptors, G-Protein-Coupled/genetics
KW - Smoking/adverse effects
U2 - 10.3390/ijms24010180
DO - 10.3390/ijms24010180
M3 - SCORING: Journal article
C2 - 36613626
VL - 24
JO - INT J MOL SCI
JF - INT J MOL SCI
SN - 1661-6596
IS - 1
M1 - 180
ER -