A Cardiac-Specific Regulatory Genetic Variant for Protein Kinase C α is Significantly Associated with Mortality in Patients with Heart Failure

Abstract

Introduction Protein kinase C α (PRKCA) is a fundamental regulator of beta-adrenergic signaling and cardiac contractility. Previous studies suggested that increased cardiac expression of PRKCA is associated with adverse cardiac outcomes. Cardiac expression of PRKCA is partly genetically regulated, with the recently identified rs9909004 (T→C) as the most likely regulatory variant in failing human heart tissue, but the clinical impact of rs9909004 genotype remains unknown. Therefore the objectives of this study were to determine whether PRKCA rs9909004 genotype is associated with mortality in patients with heart failure and reduced ejection fraction (HFrEF), and if so, whether the genotype effects are modified by beta-blocker (BB) exposure. Hypothesis The T allele of rs9909004, associated with increased cardiac expression of PRKCA, will be associated with increased risk for all-cause mortality in HFrEF patients, and its effect will be less pronounced in HFrEF patients treated with higher BB exposure. Methods Insured HFrEF patients (n = 1,122) were enrolled from a single health care system into a prospective registry beginning in 2007, and they were genotyped with the Affymetrix Axiom® biobank array. BB exposure was quantified using pharmacy claims. Time-updating Cox models were used to test the independent association of rs9909004 genotype (additive genetic model for T allele) with all-cause mortality with adjustment for the following covariates: Meta-Analysis Global Group in Chronic Heart Failure (MAGGIC) risk score; BB exposure; N-terminal pro B-type natriuretic peptide (NT-proBNP) level; and the patients’ self-reported race. The interaction of rs9909004 genotype with BB exposure was tested in similarly adjusted models stratified by BB status (yes/no for any exposure) and then in the total cohort using a multiplicative interaction term. Results Patients were mean age 68 ± 12 years with left ventricular ejection fraction 35% ± 11; 51% were African-Americans, and 35% were women. Follow-up was median 3.0 years with 255 deaths (23%). The T allele frequency was 59% in African-Americans and 53% in whites. The T allele significantly associated with increased risk for all-cause mortality with an adjusted hazard ratio (HR) = 1.34 (95% CI = 1.06-1.71, p = 0.016). Interestingly, the association of this genotype with all-cause mortality was not modified BB exposure. The adjusted HRs were similar regardless of BB status (no BB, HR = 1.46, p = 0.146; yes BB, HR = 1.33, p = 0.041), and the formal test of interaction with BB was also not significant (p = 0.306, β=0.35). Conclusions The T allele of rs9909004 in PRKCA is a significant risk factor for mortality in patients with HFrEF, independent of other risk predictors, and its effect was not modified by BB exposure.