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

Abstract

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. 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). In a prospective cohort study, participants were genotyped for common GR gene polymorphisms (ER22/23EK, BclI C/G, N363S, 9beta A/G). Haplotype analyses were conducted. The study was conducted at one university medical center, two Veterans Affairs medical centers, and nine public health clinics. Patients included 526 white outpatients with stable CHD. Echocardiographic evidence of ventricular dysfunction, self-reported heart failure, and subsequent hospitalization for heart failure were measured. 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. 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.