Association of Regulatory Genetic Variants for Protein Kinase Cα with Mortality and Drug Efficacy in Patients with Heart Failure

Cardiovasc Drugs Ther. 2019 Dec;33(6):693-700. doi: 10.1007/s10557-019-06909-6.


Purpose: Protein kinase C alpha (gene: PRKCA) is a key regulator of cardiac contractility. Two genetic variants have recently been discovered to regulate PRKCA expression in failing human heart tissue (rs9909004 [T → C] and rs9303504 [C → G]). The association of those variants with clinical outcomes in patients with heart failure (HF), and their interaction with HF drug efficacy, is unknown.

Methods: Patients with HF in a prospective registry starting in 2007 were genotyped by whole genome array (n = 951). The primary outcome was all-cause mortality. Cox proportional hazards models adjusted for established clinical risk factors and genomic ancestry tested the independent association of rs9909004 or rs9303504 and the variant interactions with cornerstone HF pharmacotherapies (beta-blockers or angiotensin-converting enzyme inhibitors/angiotensin receptor blockers) in additive genetic models.

Results: The minor allele of rs9909004, but not of rs9303504, was independently associated with a decreased risk for all-cause mortality: adjusted HR = 0.81 (95% CI = 0.67-0.98), p = 0.032. The variants did not significantly interact with mortality benefit associated with cornerstone HF pharmacotherapies (p > 0.1 for all).

Conclusions: A recently discovered cardiac-specific regulatory variant for PRKCA (rs9909004) was independently associated with a decreased risk for all-cause mortality in patients with HF. The variant did not interact with mortality benefit associated with cornerstone HF pharmacotherapies.

Keywords: Heart failure; Mortality; Protein kinase Cα (PRKCA); Regulatory variants.

MeSH terms

  • Adrenergic beta-Antagonists / therapeutic use
  • Aged
  • Aged, 80 and over
  • Angiotensin Receptor Antagonists / therapeutic use
  • Angiotensin-Converting Enzyme Inhibitors / therapeutic use
  • Cardiovascular Agents / adverse effects
  • Cardiovascular Agents / therapeutic use*
  • Female
  • Genetic Association Studies
  • Genetic Predisposition to Disease
  • Heart Failure / diagnosis
  • Heart Failure / drug therapy*
  • Heart Failure / genetics*
  • Heart Failure / mortality
  • Humans
  • Male
  • Middle Aged
  • Phenotype
  • Polymorphism, Single Nucleotide*
  • Prospective Studies
  • Protein Kinase C-alpha / genetics*
  • Registries
  • Risk Assessment
  • Risk Factors
  • Time Factors
  • Treatment Outcome


  • Adrenergic beta-Antagonists
  • Angiotensin Receptor Antagonists
  • Angiotensin-Converting Enzyme Inhibitors
  • Cardiovascular Agents
  • PRKCA protein, human
  • Protein Kinase C-alpha