Genetic variants in the glucocorticoid receptor gene (NR3C1) and cardiovascular disease risk. The Leiden 85-plus Study

Maris Kuningas Æ Simon P. Mooijaart Æ P. Eline Slagboom Æ Rudi G. J. Westendorp Diana van Heemst

Received: 23 December 2005 /Accepted: 30 January 2006/Published online: 5 May 2006   Springer Science+Business Media, Inc. 2006

Abstract Recently, the ER22/23EK, N363S and BclI polymorphisms in the glucocorticoid receptor (GR) gene have been linked to altered cortisol sensitivity and to cortisol-associated disorders. The aim of this study was to investigate the effect of these genetic variants in the GR gene on cardio- vascular disease and mortality in elderly persons aged 85 years and over. In the population-based Leiden 85-plus Study, 552 participants were geno- typed for the ER22/23EK, N363S and BclI poly- morphisms, and the effects of the polymorphisms on metabolic profile, body composition, and on the prevalence of cardiovascular pathologies at baseline, were assessed. Allcause and cardiovascular disease mortality risks dependent on the SNPs were calcu- lated after a 4.2-year follow-up. The analyses of metabolic profile revealed that carriers of the ER22/

23EK polymorphism have higher HbA1C levels (P < 0.001) and carriers of the N363S SNP have higher LDL cholesterol (P < 0.001) and triglyceride concentrations (P=0.03), compared to the non-car- riers. The only significant association between genotype and body composition analyses was for height and the ER22/23EK polymorphism. Men carrying the ER22/23EK polymorphism were taller (P=0.02) compared to non-carriers. No associations with cardiovascular pathologies, allcause and car- diovascular mortality were observed for any of the polymorphisms. We conclude that, in spite the effect of the ER22/23EK and N363S SNPs on metabolism, these polymorphisms together with the BclI SNP, do not affect the risks of cardiovascular disease and survival at old age.

Keywords Ageing Æ Cardiovascular disease Æ Glucocorticoid receptor Æ Metabolism Æ Survival

M. Kuningas Æ S. P. Mooijaart Æ R. G. J. Westendorp Æ D. van Heemst (&) Department of Gerontology and Geriatrics C

-R, Leiden University Medical Center (LUMC), PO box

,

RC Leiden, The Netherlands e-mail: D.van_Heemst@lumc.nl

Introduction

In response to various stimuli, including stress, cortisol coordinates metabolic, endocrine, immune, and ner- vous system responses (Chrousos 1995, 1998; Munck et al. 1984; de Kloet et al. 1998; McEwen 1998). Cortisol exerts the majority of its functions through glucocorticoid receptors (GRs). Disturbances in cor- tisol signaling, resulting either from altered hormone availability or decreased/increased receptor-mediated

M. Kuningas

Department of Biotechnology, Institute of Molecular and Cell Biology, Tartu University, Tartu, Estonia

P. E. Slagboom

Leiden 85-plus Study, using cross-sectional and prospective study designs.

signal transduction have been associated with variety of phenotypes including cardiovascular ease, which is a major cause of death at old age.

It is known that sensitivity to cortisol varies con- siderably between individuals as demonstrated by the dexamethasone suppression test (Huizenga et al. 1998b). Therefore, the underlying susceptibility to cortisol-associated disorders may vary. A degree of inter-individual variation in responsiveness to corti- sol is attributable to three polymorphisms in the GR gene (NR3C1). Recently an ER22/23EK variation in the GR gene was associated with a resistance to cortisol, and shown to result in a better metabolic and cardiovascular health profile, leading to increased survival rate (van Rossum et al. 2002, 2004a, b). On the other hand, increased sensitivity to cortisol, re- lated to the N363S (Huizenga et al. 1998a) and BclI (van Rossum et al. 2003) polymorphisms, has been shown to cause opposite effects. In middle-aged subjects, the N363S and BclI polymorphisms were associated with increased body mass index (BMI) and with several risk factors for atherosclerosis and coronary artery disease (Lin et al. 2003; van Rossum et al. 2003; Di Blasio et al. 2003). Together these results suggest that the GR gene plays an important role in modulating the susceptibility to cardiovascular disease. However, there are disparities in the pub- lished literature. For instance in some studies asso- ciations between these three polymorphisms and metabolic parameters or body composition have been found (van Rossum et al. 2002, 2003, 2004b; Huiz- enga et al. 1998a; Lin et al. 1999, 2003; Di Blasio et al. 2003), whereas in other studies no association, or opposite effects have been observed (van Rossum et al. 2002, 2004a; Rosmond et al. 2001; Dobson et al. 2001; Echwald et al. 2001; Panarelli et al. 1998). However, the recent results with cardiovas- cular disease (Lin et al. 2003) and survival (van Rossum et al. 2004a) have never been replicated in elderly subjects. Therefore, the effect of the GR gene on cardiovascular disease and survival at old age remains to be elucidated.

Subjects and methods

Subjects