Glucocorticoid receptor gene, low-grade inflammation, and heart failure: the Heart and Soul study

J Clin Endocrinol Metab. 2010 Jun;95(6):2885-91. doi: 10.1210/jc.2009-2251. Epub 2010 Apr 6.


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, 9beta 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.

Publication types

  • Multicenter Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Aged
  • Biomarkers / blood
  • C-Reactive Protein / metabolism
  • Coronary Disease / genetics
  • Coronary Disease / physiopathology
  • Electrocardiography
  • Female
  • Follow-Up Studies
  • Genotype
  • Haplotypes
  • Heart Failure / genetics*
  • Hospitalization / statistics & numerical data
  • Humans
  • Hydrocortisone / urine
  • Inflammation / genetics*
  • Interleukin-6 / metabolism
  • Male
  • Middle Aged
  • Polymorphism, Genetic / genetics
  • Receptors, Glucocorticoid / genetics*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Stroke Volume / physiology
  • Ventricular Dysfunction / genetics
  • Ventricular Dysfunction / physiopathology


  • Biomarkers
  • Interleukin-6
  • Receptors, Glucocorticoid
  • C-Reactive Protein
  • Hydrocortisone