Glucocorticoid Receptor Gene, Low-Grade Inflammation, and Heart Failure: The Heart and Soul Study

Abstract

Abstract Context: A common haplotype of the glucocorticoid receptor (GR) gene has been associated with increased susceptibility to coronary heart disease (CHD). Whether this haplotype predisposes to heart failure (HF) is unknown. Objective: The objective of the study was to determine whether GR haplotype 3 is associated with HF and whether this association is explained by low-grade inflammation (C-reactive protein). Design: In a prospective cohort study, participants were genotyped for common GR gene polymorphisms (ER22/23EK, BclI C/G, N363S, 9β A/G). Haplotype analyses were conducted. Setting: The study was conducted at one university medical center, two Veterans Affairs medical centers, and nine public health clinics. Patients: Patients included 526 white outpatients with stable CHD. Main Outcome Measures: Echocardiographic evidence of ventricular dysfunction, self-reported heart failure, and subsequent hospitalization for heart failure were measured. Results: After adjusting for age, sex, smoking, and body mass index, participants with two copies of haplotype 3 were more likely than those with 0 or 1 copy to report heart failure [hazard ratio (HR) 4.15, 95% confidence interval (CI) 1.5–11.3, P < 0.01], have systolic dysfunction (left ventricular ejection fraction <50%) (HR 3.0, 95% CI 0.9–9.9, P = 0.07), and be hospitalized for HF during a mean follow-up of 6 yr (HR 3.0, 95% CI 1.3–7.0, P = 0.01). These associations were attenuated after adjustment for higher C-reactive protein levels in patients with two copies of haplotype 3. Conclusions: We found that the GR gene haplotype 3 was associated with prevalent HF, systolic dysfunction, and subsequent HF hospitalization in patients with CHD. This association was partly mediated by low-grade inflammation.