Glucocorticoid receptor polymorphisms modulate cardiometabolic risk factors in patients in long-term remission of Cushing’s syndrome

Sean H P P Roerink,A R M M Hermus,J W A Smit,E F C Van Rossum,M A E M Wagenmakers,T S Plantinga,R T Netea-Maier

doi:10.1007/s12020-016-0883-z

Abstract

ContextGlucocorticoid receptor (GR) polymorphisms modulate glucocorticoid (GC) sensitivity and are associated with altered metabolic profiles.ObjectiveTo evaluate the presence of GR polymorphisms (BclI (rs41423247), N363S (rs56149945), ER22/23EK (rs6189/rs6190), and 9β (rs6198) and investigate their associations with metabolic alterations in patients in long-term remission of Cushing’s syndrome (CS).Design and settingCross-sectional case–control study.Patients and methodsSixty patients in long-term remission of CS were genotyped. Associations between GR polymorphisms and multiple vascular, body composition and metabolic parameters were investigated.Main outcome measuresAllelic frequencies of the polymorphisms and their associations with several cardiometabolic risk factors.ResultsThis study shows that carriers of the 9β polymorphism have a higher systolic blood pressure and lower resistin levels. The GC sensitizing BclI polymorphism is associated with an adverse cardiometabolic risk factor profile: higher fat percentages of extremities and legs, higher serum leptin and E-selectin levels, and higher intima media thickness in carriers versus non-carriers.ConclusionsThe 9β and BclI polymorphisms of the GR adversely affect the cardiometabolic profile in patients who are in remission after the treatment of CS. This suggests that genetically altered GC sensitivity modulates the long-term adverse cardiometabolic effects resulting from (endogenous) hypercortisolism.

Highlights

Cushing’s syndrome (CS) is a disorder resulting from chronic exposure to increased levels of glucocorticoids (GC), frequently caused by an ACTH-producing pituitary adenoma [Cushing’s disease (CD)] or by primary adrenal overproduction of cortisol [adrenal CS (ACS)] [1]
This study shows that carriers of the 9b polymorphism have a higher systolic blood pressure and lower resistin levels
The GC sensitizing BclI polymorphism is associated with an adverse cardiometabolic risk factor profile: higher fat percentages of extremities and legs, higher serum leptin and E-selectin levels, and higher intima media thickness in carriers versus non-carriers

Summary

Introduction

Cushing’s syndrome (CS) is a disorder resulting from chronic exposure to increased levels of glucocorticoids (GC), frequently caused by an ACTH-producing pituitary adenoma [Cushing’s disease (CD)] or by primary adrenal overproduction of cortisol [adrenal CS (ACS)] [1]. We [3] and others [4, 5] have shown that many adverse metabolic and cardiovascular characteristics, and body compositional changes persist after treatment, even after long-term remission. These adverse metabolic and cardiovascular characteristics are common in these patients, their incidence and severity vary among patients. This variation seems not to be explained by differences in cortisol excess or disease duration alone. A variable sensitivity to GC possibly plays a role in modulating the effect of cortisol excess [6]

Methods

Results

Conclusion