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

ABSTRACT: Glucocorticoid receptor (GR) polymorphisms modulate glucocorticoid (GC) sensitivity and are associated with altered metabolic profiles.To evaluate the presence of GR polymorphisms (BclI (rs41423247), N363S (rs56149945), ER22/23EK (rs6189/rs6190), and 9? (rs6198) and investigate their associations with metabolic alterations in patients in long-term remission of Cushing's syndrome (CS).Cross-sectional case-control study.Sixty patients in long-term remission of CS were genotyped. Associations between GR polymorphisms and multiple vascular, body composition and metabolic parameters were investigated.Allelic frequencies of the polymorphisms and their associations with several cardiometabolic risk factors.This study shows that carriers of the 9? 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.The 9? 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.

SUBMITTER: Roerink SH

PROVIDER: S-EPMC4901092 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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

Roerink Sean H P P SH Wagenmakers M A E M MA Smit J W A JW van Rossum E F C EF Netea-Maier R T RT Plantinga T S TS Hermus A R M M AR

Endocrine 20160213 1

<h4>Context</h4>Glucocorticoid receptor (GR) polymorphisms modulate glucocorticoid (GC) sensitivity and are associated with altered metabolic profiles.<h4>Objective</h4>To 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).<h4>Design and setting</h4>Cross-sectional case-control study.<h4>Patients and ...[more]

PMID: 26873309

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Project description:Long-term remitted Cushing's disease (LTRCD) patients commonly continue to present persistent psychological and cognitive deficits, and alterations in brain function and structure. Although previous studies have conducted gray matter volume analyses, assessing cortical thickness and surface area of LTRCD patients may offer further insight into the neuroanatomical substrates of Cushing's disease. Structural 3T magnetic resonance images were obtained from 25 LTRCD patients, and 25 age-, gender-, and education-matched healthy controls (HCs). T1-weighted images were segmented using FreeSurfer software to extract mean cortical thickness and surface area values of 68 cortical gray matter regions and two whole hemispheres. Paired sample t tests explored differences between the anterior cingulate cortex (ACC; region of interest), and the whole brain. Validated scales assessed psychiatric symptomatology, self-reported cognitive functioning, and disease severity. After correction for multiple comparisons, ROI analyses indicated that LTRCD-patients showed reduced cortical thickness of the left caudal ACC and the right rostral ACC compared to HCs. Whole-brain analyses indicated thinner cortices of the left caudal ACC, left cuneus, left posterior cingulate cortex, right rostral ACC, and bilateral precuneus compared to HCs. No cortical surface area differences were identified. Cortical thickness of the left caudal ACC and left cuneus were inversely associated with anxiety symptoms, depressive symptoms, and disease duration, although certain associations did not persist after correction for multiple testing. In six of 68 regions examined, LTRCD patients had reduced cortical thickness in comparison to HCs. Cortical thickness of the left caudal ACC was inversely associated with disease duration. This suggests that prolonged and excessive exposure to glucocorticoids may be related to cortical thinning of brain structures involved in emotional and cognitive processing.

Project description:INTRODUCTION: The glucocorticoid receptor (GR) plays an important regulatory role in the immune system. Four polymorphisms in the GR gene are associated with differences in glucocorticoid (GC) sensitivity; the minor alleles of the polymorphisms N363 S and BclI are associated with relative hypersensitivity to GCs, while those of the polymorphisms ER22/23EK and 9? are associated with relative GC resistance. Because differences in GC sensitivity may influence immune effector functions, we examined whether these polymorphisms are associated with the susceptibility to develop Rheumatoid Arthritis (RA) and RA disease severity. METHODS: The presence of GR polymorphisms was assessed in healthy controls (n = 5033), and in RA patients (n = 368). A second control group (n = 532) was used for confirmation of results. In RA patients, the relationship between GR polymorphisms and disease severity was examined. RESULTS: Carriers of the N363 S and BclI minor alleles had a lower risk of developing RA: odds ratio (OR) = 0.55 (95% confidence interval (CI) 0.32-0.96, P = 0.032) and OR = 0.73 (95% CI 0.58-0.91, P = 0.006), respectively. In contrast, 9? minor allele carriers had a higher risk of developing RA: OR = 1.26 (95% CI 1.00-1.60, P = 0.050). For ER22/23EK minor allele carriers a trend to an increased risk OR = 1.42 (95% CI 0.95-2.13, P = 0.086) was found. All ER22/23EK carriers (32/32) had erosive disease, while only 77% (259/336) of the non-carriers did (P = 0.008). In addition, ER22/23EK carriers were treated more frequently with anti-tumor necrosis factor-alpha (TNF?) therapy (P < 0.05). CONCLUSIONS: The minor alleles of the 9? and ER22/23EK polymorphisms seem to be associated with increased predisposition to develop RA. Conversely, the minor alleles of the N363 S and BclI polymorphisms are associated with reduced susceptibility to develop RA. These opposite associations suggest that constitutionally determined GC resistance may predispose to development of auto-immunity, at least in RA, and vice versa.

Dataset Information

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

Publications

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

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