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A common variant in PIK3CG gene associated with the prognosis of heart failure

Dong Hu1,2, Lei Xiao3, Shiyang Li4

  • 1Division of Cardiology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Journal of Cellular and Molecular Medicine
|September 8, 2024
PubMed

Insights

Common variants in the Phosphoinositide 3-kinase γ (PI3Kγ) gene (PIK3CG) impact heart failure (HF) prognosis. A specific PIK3CG variant affects gene expression and may offer a therapeutic target for HF treatment.

Area of Science:

  • Cardiovascular Biology
  • Genetics
  • Molecular Medicine

Background:

  • Phosphoinositide 3-kinase γ (PI3Kγ) plays a role in myocardial remodeling and heart failure (HF).
  • PI3Kγ exhibits both kinase-dependent and kinase-independent activities, influenced by G-protein-coupled receptors.
  • Previous research indicates PI3Kγ involvement in conditions like transientאַקטיביטי (TAC) and ischemia/reperfusion (I/R) injury.

Purpose of the Study:

  • To investigate the association between common variants in the PI3Kγ gene (PIK3CG) and the prognosis of heart failure (HF).
  • To explore the functional mechanisms by which identified genetic variants influence PIK3CG expression and cellular response.
  • To assess the potential of PIK3CG as a therapeutic target for HF.

Main Methods:

  • Re-sequencing and genotyping of the PIK3CG gene in a Chinese Han population.
  • Two-stage population study design to validate genetic associations.
  • Functional assays including analysis of microRNA binding (has-miR-133a-3p), mRNA and protein expression, and cellular apoptosis under hypoxia/reoxygenation (H/R) conditions.

Main Results:

  • A common variant (rs10215499) in the 3'UTR of PIK3CG was significantly associated with HF prognosis in both study cohorts.
  • The rs10215499-A allele suppressed PIK3CG translation by enhancing has-miR-133a-3p binding, leading to lower mRNA and protein levels compared to the GG genotype.
  • Overexpression of PIK3CG protected against H/R-induced apoptosis in AC16 cells, while PIK3CG silencing exacerbated it.

Conclusions:

  • The common variant rs10215499 in the PIK3CG 3'-UTR may influence HF prognosis by modulating miR-133a-3p binding and subsequent PIK3CG expression.
  • PIK3CG demonstrates a protective role against hypoxia/reoxygenation-induced apoptosis in cardiomyocytes.
  • PIK3CG represents a potential therapeutic target for future heart failure treatments.

Keywords:
PIK3CGheart failureprognosisvariant

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