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GLCCI1 rs37973 is associated with the response of adrenal hormone to inhaled corticosteroids in asthma.

ABSTRACT: Background:Previous studies have demonstrated that glucocorticoid-induced transcript 1 gene (GLCCI1) rs37973 mutant genotype is associated with poor inhaled corticosteroid (ICS) response in asthmatics. As human airway relaxation is regulated by circulation epinephrine, which can be enhanced by corticosteroid. It is unknown whether or not GLCCI1 rs37973 is associated with circulation epinephrine and cortisol concentrations in asthma. The aim of this study is to evaluate these relationships. Methods:A total of 182 asthmatics and 180 healthy controls were recruited for the study. 30 mild-to-moderate asthmatics received fluticasone propionate (125 ?g, bid) treatment for 12 weeks. GLCCI1 rs37973 genotyping was performed with the iPlex MassARRAY genotyping platform. The plasma concentrations of cortisol and epinephrine of each participant were detected by enzyme linked immunosorbent assay (ELISA) kits. Results:GLCCI1 rs37973 homozygotes mutant genotype GG had a higher plasma epinephrine concentration (median concentration 27.032 pg/ml, nGG = 36; median concentration 23.149 pg/ml, nAA+AG = 146; P = 0.015) and cortisol concentration (median concentration 1.141 ng/ml, nGG = 36; median concentration 0.921 ng/ml, nAA+AG = 146; P = 0.013). Both epinephrine concentration and cortisol concentration in plasma were positively correlated with FEV1 (r = 0.889 and r = 0.821, respectively. nasthma = 182). For asthmatics treated with ICS, rs37973 was associated with change in plasma epinephrine and cortisol concentration in a recessive model (AA + AG vs GG), with GG had less improvement in epinephrine concentration [?EPIAA+AG = 6.843 (9.26) pg/ml, nAA+AG = 26; ?EPIGG = -1.666 (6.52) pg/ml, nGG = 4; P = 0.018] and cortisol concentration [?CORAA+AG = 0.3040 (0.21) ng/ml, nAA+AG = 26; ?CORGG = -0.066 (0.24) ng/ml, nGG = 4; P = 0.009]. Conclusions:Our study suggested that the poor ICS response in GLCCI1 rs37973 mutant genotype might be related to the less increased amplitudes of plasma epinephrine and cortisol in asthmatic patients. Trial registration:ChiCTR-RCC-13003634 www.chictr.org.cn. Active since September 27, 2013.

SUBMITTER: Xun Q

PROVIDER: S-EPMC6439416 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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GLCCI1 rs37973 is associated with the response of adrenal hormone to inhaled corticosteroids in asthma.

Xun Qiufen Q Hu Chengping C Li Xiaozhao X Hu Xinyue X Qin Ling L He Ruoxi R Lu Rongli R Feng Juntao J

The World Allergy Organization journal 20190314 3

<h4>Background</h4>Previous studies have demonstrated that glucocorticoid-induced transcript 1 gene (<i>GLCCI1)</i> rs37973 mutant genotype is associated with poor inhaled corticosteroid (ICS) response in asthmatics. As human airway relaxation is regulated by circulation epinephrine, which can be enhanced by corticosteroid. It is unknown whether or not <i>GLCCI1</i> rs37973 is associated with circulation epinephrine and cortisol concentrations in asthma. The aim of this study is to evaluate thes ...[more]

PMID: 30937140

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Project description:To describe recovery of adrenal insufficiency in asthmatic children treated with inhaled corticosteroids (ICS) and cortisol replacement therapy.Retrospective, observational study.A total of 113 patients, 74 male; age 10.4 (3.3-16.5) years; beclomethasone-equivalent ICS dose, 800 ?g, (100-1,000), tested by low dose short Synacthen (tetracosactide) test (LDSST), were studied. Test results were classified by basal and peak cortisol concentration: "normal" (basal >100 nmol/L, peak >500 nmol/L), "suboptimal" (basal >100 nmol/L, peak 350-499 nmol/L), "abnormal" (basal <100 nmol/L and/or peak <350 nmol/L). Patients with suboptimal results received hydrocortisone during periods of stress only, and those with abnormal responses received daily hydrocortisone, increased during periods of stress. A total of 73 patients (68%) had ?2 LDSSTs over 2.2 years (0.2-7.7).Change in cortisol response to repeat LDSST (movement between diagnostic groups, difference in basal and peak cortisol >15% [2× the inter-assay coefficient of variation]), change in BMI and height standard deviation score (SDS).Baseline test results were abnormal in 17 patients (15%) and all of them had repeat tests. In 13 patients (76%), test results improved (normal in six, suboptimal in seven) and four (24%) remained abnormal. Baseline tests results were suboptimal in 54 patients (48%), of whom 50 (93%) were retested. Repeat tests were normal in 36 patients (72%), remained suboptimal in 11 (22%), and were abnormal in three (6%). Baseline tests results were normal in 42 patients, of whom six patients (14%) were retested. Results remained normal in three (50%), were suboptimal in two (33%), and abnormal in one (17%). Basal and peak cortisol levels increased by >15% in 33/73 (45%) and 42/73 (57%) patients, respectively, and decreased by >15% in 14/73 (19%) and 7/73 (10%), respectively. There was no significant change in height or BMI SDS.Recovery of adrenal function is common and occurs during continued ICS and cortisol replacement therapy.

Project description:Inhaled corticosteroids (ICS) are the most effective controller medications for asthma, and variability in ICS response is associated with genetic variation. Despite ICS treatment, some patients with poor asthma control experience severe asthma exacerbations, defined as a hospitalization or emergency room visit. We hypothesized that some individuals may be at increased risk of asthma exacerbations, despite ICS use, due to genetic factors. A GWAS of 237,726 common, independent markers was conducted in 806 Caucasian asthmatic patients from two population-based biobanks: BioVU, at Vanderbilt University Medical Center (VUMC) in Tennessee (369 patients), and Personalized Medicine Research Project (PMRP) at the Marshfield Clinic in Wisconsin (437 patients). Using a case-control study design, the association of each SNP locus with the outcome of asthma exacerbations (defined as asthma-related emergency department visits or hospitalizations concurrent with oral corticosteroid use), was evaluated for each population by logistic regression analysis, adjusting for age, gender and the first four principal components. A meta-analysis of the results was conducted. Validation of expression of selected candidate genes was determined by evaluating an independent microarray expression data set. Our study identified six novel SNPs associated with differential risk of asthma exacerbations (P?<?10(-05)). The top GWAS result, rs2395672 in CMTR1, was associated with an increased risk of exacerbations in both populations (OR?=?1.07, 95% CI 1.03-1.11; joint P?=?2.3?×?10(-06)). Two SNPs (rs2395672 and rs279728) were associated with increased risk of exacerbations, while the remaining four SNPs (rs4271056, rs6467778, rs2691529, and rs9303988) were associated with decreased risk. Three SNPs (rs2395672, rs6467778, and rs2691529) were present in three genes: CMTR1, TRIM24 and MAGI2. The CMTR1 mRNA transcript was significantly differentially expressed in nasal lavage samples from asthmatics during acute exacerbations, suggesting potential involvement of this gene in the development of this phenotype. We show that genetic variability may contribute to asthma exacerbations in patients taking ICS. Furthermore, our studies implicate CMTR1 as a novel candidate gene with potential roles in the pathogenesis of asthma exacerbations.

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GLCCI1 rs37973 is associated with the response of adrenal hormone to inhaled corticosteroids in asthma.

Publications

GLCCI1 rs37973 is associated with the response of adrenal hormone to inhaled corticosteroids in asthma.

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