Dataset Information

Analysis of BCLI, N363S and ER22/23EK Polymorphisms of the Glucocorticoid Receptor Gene in Adrenal Incidentalomas.

ABSTRACT:

Context

Patients with adrenal incidentalomas (AI) may experience detrimental consequences due to a minimal cortisol excess sustained by adrenal adenoma. SNPs of the glucocorticoid receptor gene (NR3C1) modulate individual sensitivity to glucocorticoids and may interfere with the clinical presentation.

Objective

To compare the frequency of N363S, ER22/23EK and BclI SNPs in patients with AI with the general population and to evaluate whether these SNPs are linked to consequences of cortisol excess.

Setting

Multicentric, retrospective analysis of patients referred from 2010 to 2014 to 4 centers (Orbassano, Milano, Messina [Italy] and Zagreb [Croatia]).

Patients

411 patients with AI; 153 males and 258 females and 186 from blood donors.

Main outcomes measures

All patients and controls were genotyped for BclI, N363S and ER22/23EK and SNPs frequency was associated with clinical and hormonal features.

Results

SNP frequency was: SNP frequency was: N363S 5.4% (MAF 0.027), BclI 54.7% (MAF 0.328), ER22/23EK 4.4% (MAF 0.022), without any significant difference between patients and controls. N363S was more frequent in hypertensive patients (p = 0.03) and was associated with hypertension (p = 0.015) in patients with suppressed cortisol after the 1-mg DST.

Conclusions

Our results demonstrate that SNPs of the glucocorticoid receptor gene do not play a pathogenetic role for AI. The impact of any single SNP on the phenotypic expression of minimal cortisol excess is limited and their analysis does not provide additional data that may be exploited for patient management.

SUBMITTER: Reimondo G

PROVIDER: S-EPMC5029814 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Analysis of BCLI, N363S and ER22/23EK Polymorphisms of the Glucocorticoid Receptor Gene in Adrenal Incidentalomas.

Reimondo Giuseppe G Chiodini Iacopo I Puglisi Soraya S Pia Anna A Morelli Valentina V Kastelan Darko D Cannavo Salvatore S Berchialla Paola P Giachino Daniela D Perotti Paola P Cuccurullo Alessandra A Paccotti Piero P Beck-Peccoz Paolo P De Marchi Mario M Terzolo Massimo M

PloS one 20160920 9

<h4>Context</h4>Patients with adrenal incidentalomas (AI) may experience detrimental consequences due to a minimal cortisol excess sustained by adrenal adenoma. SNPs of the glucocorticoid receptor gene (NR3C1) modulate individual sensitivity to glucocorticoids and may interfere with the clinical presentation.<h4>Objective</h4>To compare the frequency of N363S, ER22/23EK and BclI SNPs in patients with AI with the general population and to evaluate whether these SNPs are linked to consequences of ...[more]

PMID: 27649075

Similar Datasets

Project description:BACKGROUND: Since both excess glucocorticoid secretion and central obesity are clinical features of some obese patients, it is worthwhile to study a possible association of glucocorticoid receptor gene (GRL) variants with obesity. Previous studies have linked the N363S variant of the GRL gene to increased glucocorticoid effects such as higher body fat, a lower lean-body mass and a larger insulin response to dexamethasone. However, contradictory findings have been also reported about the association between this variant and obesity phenotypes. Individual studies may lack statistical power which may result in disparate results. This limitation can be overcome using meta-analytic techniques. METHODS: We conducted a meta-analysis to assess the association between the N363S polymorphism of the GRL gene and obesity risk. In addition to published research, we included also our own unpublished data -three novel case-control studies- in the meta-analysis The new case-control studies were conducted in German and Spanish children, adolescents and adults (total number of subjects: 1,117). Genotype was assessed by PCR-RFLP (Tsp509I). The final formal meta-analysis included a total number of 5,909 individuals. RESULTS: The meta-analysis revealed a higher body mass index (BMI) with an overall estimation of +0.18 kg/m2 (95% CI: +0.004 to +0.35) for homo-/heterozygous carriers of the 363S allele of the GRL gene in comparison to non-carriers. Moreover, differences in pooled BMI were statistically significant and positive when considering one-group studies from the literature in which participants had a BMI below 27 kg/m2 (+ 0.41 kg/m2 [95% CI +0.17 to +0.66]), but the differences in BMI were negative when only our novel data from younger (aged under 45) and normal weight subjects were pooled together (-0.50 kg/m2 [95% CI -0.84 to -0.17]). The overall risk for obesity for homo-/heterozygous carriers of the 363S allele was not statistically significant in the meta-analysis (pooled OR = 1.02; 95% CI: 0.56-1.87). CONCLUSION: Although certain genotypic effects could be population-specific, we conclude that there is no compelling evidence that the N363S polymorphism of the GRL gene is associated with either average BMI or obesity risk.

Project description:Abstract OBJECTIVE: Several biomarkers for glucocorticoid (GC) sensitivity have been proposed relevant for the inter-individual variation seen in treatment response and side effects to GC treatment. Four single nucleotide polymorphisms (SNPs) of the GC receptor (GR) gene have been associated with increased (Bcl1 and N363S) or decreased (9β and ER23/23EK) GC sensitivity. We investigated the influence of these proposed biomarkers for GC sensitivity on GC-induced adrenal insufficiency. SUBJECTS AND METHODS: We included 239 patients receiving long-term prednisolone treatment for rheumatoid arthritis (RA), polymyalgia rheumatica (PMR) / giant cell arteritis (GCA), or after renal transplantation (RTx). Four GR gene SNPs (Bcl1 rs41423247; 9β rs6198; N363S rs56149945; ER22/23EK rs6189 + rs6190) were sequenced by Sanger sequencing. Adrenal function was evaluated by a 250 µg corticotropin stimulation test. To compare allele frequencies with background population, two control groups were generated from two regional whole-genome databases. We downscaled each genome dataset to 239 individuals/group to balance statistical analysis. RESULTS: In total 239 patients were genotyped and 178 of these (RA n=103, PMR/GCA n=47, RTx n=28) treated with a median current dose of 5 mg prednisolone/day (interquartile range 5-7 mg) and a median treatment duration of 48 months (interquartile range 22-111 months) completed the corticotropin test. Seventy-three (41%, CI95%: 34-48%) patients had an insufficient response to the corticotropin test. Neither the risk of adrenal insufficiency, unstimulated nor stimulated P-cortisol levels were directly associated with any of the GR SNPs. However, for both insensitive SNPs 9β and ER23/23EK the effect of current prednisolone dose on stimulated P-cortisol was smaller (higher dose did not suppress the cortisol level as much) in carriers vs. non-carriers (p=0.035 and p=0.0075). The same sensitivity-associated tendency was seen for the N363S, but not the Bcl1 SNP. The Bcl1 SNP occurred more frequently in our cohort compared with control groups (63% vs. 40%, p<0.0001). The same trend was seen for the other sensitive but less frequent SNP N363S. The 9β SNP also occurred more frequently in our cohort (18% vs. 13%, p=0.029), but depending on regional sub cohorts in one control group. CONCLUSION: The GR SNPs did not directly associate to the risk of adrenal insufficiency, unstimulated nor stimulated cortisol levels, respectively. However, the effect of prednisolone dose on stimulated cortisol depended on the GR SNPs: Cortisol was less suppressed with higher current prednisolone dose in patients carrying the insensitive SNPs. The substantially higher frequency of the Bcl1 SNP is remarkable even with modest n=239. It questions whether there is an association between carrying the sensitive GR SNPs and inability to taper GC treatment ending up in this cohort of long-term treated patients.

Project description:OBJECTIVE:To determine all-cause mortality risk in patients with and without adrenal incidentaloma. METHODS:Retrospective cohort study of patients with CT abdomen performed within 24 h of emergency room presentation at an academic medical center from January 1, 2005, to December 31, 2009, without history of adrenal disease, adrenal lab testing, or cancer. Incidentaloma cohort identified by database query of imaging reports followed by manual review and matched to no-nodule controls at 3:1 on age?±?1 year and exam date ±?3 months. Mortality ascertained by in-hospital deaths and National Death Index query. Survival analysis performed with Kaplan-Meier curves and Cox proportional hazards models. RESULTS:Among 42,575 adults with abdominal CT exams, 969 adrenal incidentaloma patients and 2907 no-nodule controls were identified. All 3876 individuals entered survival analysis with 31,182 person-years at risk (median follow-up 8.9 years [IQR, 6.9-10.7]). All-cause mortality was significantly higher among those with adrenal incidentalomas (353/969, 36.4%) compared with those without (919/2907, 31.6%; mortality difference 7.6 per 1000 person-years; multivariable-adjusted hazard ratio [aHR] 1.14; 95% CI, 1.003-1.29). Exploratory analyses, limited by missing covariates, found that adrenal incidentalomas were associated with significantly increased incidence of malignancy (aHR 1.61; 95% CI, 1.22-2.12), diabetes (aHR 1.43; 95% CI, 1.18-1.71), heart failure (aHR 1.32; 95% CI, 1.07-1.63), peripheral vascular disease (aHR 1.28; 95% CI, 1.95-1.56), renal disease (aHR 1.21; 95% CI, 1.01-1.44), and chronic pulmonary disease (aHR 1.22; 95% CI, 1.01-1.46) compared with controls. CONCLUSIONS:Adrenal incidentalomas are associated with increased mortality and may represent a clinically valuable biomarker. KEY POINTS:• Adrenal incidentalomas are associated with increased mortality. • Adrenal incidentaloma size is not predictive of mortality. • On exploratory analyses, adrenal incidentalomas are associated with chronic illnesses.

Project description:BackgroundAutonomous cortisol secretion (ACS), resulting from cortisol-producing adenomas (CPA), causes endogenous steroid-induced osteoporosis (SIOP). However, the risk of endogenous SIOP cannot be explained by cortisol excess alone, and how other steroid metabolites affect bone status is unclear.MethodsACS was diagnosed as serum cortisol ≥1.8 μg/dL after the 1-mg dexamethasone suppression test (DST-cortisol). Using liquid chromatography tandem mass spectrometry, 21 plasma steroid metabolites were measured in 73 patients with ACS and 85 patients with non-functioning adrenal tumors (NFAT). Expression of steroidogenic enzymes and relevant steroid metabolites were analyzed in some of CPA tissues.FindingsDiscriminant and principal component analyses distinguished steroid profiles between the ACS and NFAT groups in premenopausal women. Premenopausal women with ACS exhibited higher levels of a mineralocorticoid metabolite, 11-deoxycorticosterone (11-DOC), and lower levels of androgen metabolites, dehydroepiandrosterone-sulfate, and androsterone-glucuronide. In premenopausal women with ACS, DST-cortisol negatively correlated with trabecular bone score (TBS). Additionally, 11-DOC negatively correlated with lumbar spine-bone mineral density, whereas androsterone-glucuronide positively correlated with TBS. The CPA tissues showed increased 11-DOC levels with increased expression of CYP21A2, essential for 11-DOC synthesis. Adrenal non-tumor tissues were atrophied with reduced expression of CYB5A, required for androgen synthesis.InterpretationThis study demonstrates that unbalanced production of adrenal steroid metabolites, derived from both adrenal tumor and non-tumor tissues, contributes to the pathogenesis of endogenous SIOP in premenopausal women with ACS.FundingJSPS KAKENHI, Secom Science and Technology Foundation, Takeda Science Foundation, Japan Foundation for Applied Enzymology, AMED-CREST, JSTA-STEP, JST-Moonshot, and Ono Medical Research Foundation.

Dataset Information

Analysis of BCLI, N363S and ER22/23EK Polymorphisms of the Glucocorticoid Receptor Gene in Adrenal Incidentalomas.

Context

Objective

Setting

Patients

Main outcomes measures

Results

Conclusions

Publications

Analysis of BCLI, N363S and ER22/23EK Polymorphisms of the Glucocorticoid Receptor Gene in Adrenal Incidentalomas.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets