Abstract
Phosphoinositide 3-kinase γ (PI3Kγ) is G-protein-coupled receptor-activated lipid kinase with both kinase-dependent and kinase-independent activity. Plenty of evidence have demonstrated that PI3Kγ participated in TAC and I/R-induced myocardial remodelling and heart failure (HF). In this study, we tested the hypothesis that common variants in the PI3Kγ gene (PIK3CG) were associated with the prognosis of HF in the Chinese Han population. Through re-sequencing and genotyping, we finally identified a common variant in the 3'UTR of PIK3CG strongly associated with the prognosis of HF in two-stage population: adjusted p = 0.007, hazard ratio = 0.56 (0.36-0.85) in the first cohort and adjusted p = 0.024, hazard ratio = 0.39 (0.17-0.88) in the replicated cohort. A series of functional assays revealed that rs10215499-A allele suppressed PIK3CG translation by facilitating has-miR-133a-3p binding, but not the G allele. Subjects carrying the GG genotype showed higher mRNA and protein level than those with AA and AG genotype. Furthermore, overexpression of PIK3CG could protect AC16 from hypoxia/reoxygenation (H/R)-induced apoptosis, while the case was opposite for PIK3CG silencing. In conclusion, common variant rs10215499 in the 3'-UTR of PIK3CG might affect the prognosis of HF by interfering with miR-133a-3p binding and PIK3CG is a promising target for HF treatment in the future.