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

ABSTRACT

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.