Here we show that (i) GPR15 is upregulated in early-onset MI subjects; (ii) GPR15 mRNA expression mediates the effect of smoking on MI; (iii) GPR15 DNA methylation predicts risk for MI, independently of smoking; (iv) SNP rs2230344 is associated with early-onset MI; and v) Gpr15 knockout reduces survival after MI and affects response to hypoxia and GPCR pathways in an experimental mouse model of myocardial infarction. This evidence concerns the gene GPR15 and myocardial infarction.