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-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.