Pediatric

Zagazig University Medical Journal

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ORIGINAL ARTICLE
Association between Glucocorticosteroid Receptors (NR3C1) Gene
Polymorphism and Bronchial Asthma in Children
Khalid Mohamed Salah 1, Mona Mohamed Al Shafie 1, Osama Abdelaziz Gaber2, Mahmoud
Tharwat Awad 1 *
1
Pediatric Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt
2
Medical Biochemistry Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt

* Corresponding author: ABSTRACT

Mahmoud Tharwat Awad Background: There is a large variation in the magnitude of the response
Pediatric Department, to asthma medications. Pharmacogenetics is responsible for a significant
Faculty of Medicine, Zagazig part of this variation. We aimed at studying the effect of the
University, Zagazig, Egypt Glucocoricoid receptors NR3C1 BCLI single nucleotide polymorphism
(SNP) on the susceptibility to bronchial asthma in children and to
[email protected] evaluate its effect on the response to inhaled corticosteroids (ICS).
Method: Seventy five asthmatic children and a control group of 66 non
asthmatic children were included in the study. The level of asthma
symptom control and pulmonary function tests were measured initially
Submit date: and 3 months after treatment with inhaled corticosteroids. The genotypes
Revise date: were studied using PCR-RFLP method. Results: No statistically
Accept date significant difference was found between asthmatic group and the control
group as regard the studied genotype. Among asthmatic children, The CC
genotype was statistically associated with controlled asthma symptoms 3
months after treatment and the GG genotype was associated with poor
asthma symptom control. Also, FEV1% after 3 months of treatment was
statistically lower in children with the GG genotype as compared to
children with the CG and CC genotypes. Conclusion: glucocorticoid
receptor NR3C1 SNP was not associated with asthma susceptibility in the
studied group. However, the presence of the GG genotype was associated
with decreased response to ICSs among asthmatic children as regards
asthma symptom control and FEV1% response.
Key words: Asthma, Pharmacogenetics, Inhaled corticosteroids

INTRODUCTION asthmatic children fail to respond to ICS and

B ronchial asthma is an important global

health problem which affects all age
groups and its prevalence is increasing in
they are often treated with high doses of ICS,
which then has the potential to cause
significant side-effects [3]. While part of this
many countries especially among children [1]. heterogeneity of response is due to adherence
It is estimated to affect around 300 million and environmental effects, genetic variations
people worldwide and is believed to be the also influence the response to treatment and
most common chronic disease in children [2]. genetic markers may help to guide treatment
Inhaled corticosteroids (ICS) are the [5].
favored first-line treatment for persistent The NR3C1 gene which encodes the
asthma. By binding to glucocorticoid glucocorticosteroid receptor (GCR) is
receptors, they suppress the activation of localized on chromosome 5q31-q32 and
inflammatory genes and modulate activity of consists of nine exons. Single nucleotide
genes involved in airway epithelial barrier polymorphisms; SNPs; within this gene may
and airway remodeling [3]. There is a large have a regulatory effect on expression and
variation in the magnitude of the response to lead to changes in the RNA splicing process,
asthma medication, and around 5–15% of thus affects the Gluccorticoid sensitivity [6].
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 Zagazig University Medical Journal
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We conducted a pharmacogenetic study evaluating the effect of BCLI single

nucleotide polymorphism of the NR3C1 gene careful clinical examination. A blood sample
on the response to inhaled corticosteroid in for genotyping was collected
asthmatic children as evaluated by both Children with bronchial asthma had their
symptoms control level and improvement of level of asthma symptom control assessed and
Pulmonary functions. Treatment was prescribed according to the
METHODS step up approach as determined by GINA
The study was carried out at the Pulmonology guidelines [1]. Serum total IgE and
Unit, Pediatric Department, and Zagazig eosinophilic count were obtained.
University Children Hospital in co-operation Regular follow up at the outpatient clinic was
with the Scientific and Medical Research done at least monthly where adherence to
Center of the Faculty of Medicine, Zagazig medications was emphasized, control level
University. The study was held over an 18 was assessed and adjustment of the treatment
month period between March 2017 and was done accordingly.
September 2018. Three months after treatment we assessed the
The research protocol was approved by the level of symptoms control and the composite
Institutional review Board (IRB) of the asthma severity index score was calculated as
faculty of medicine Zagazig University. All described by Wildfire Et al [7]. The online
children's parents gave their informed consent forum is available at
before being included in our study WWW.asthmaseverity.org.
The Work has been carried out in accordance Pulmonary function test was done for all
with the code of Ethics of the World Medical asthmatic children initially and repeated 3
Asssociation (Declaration of Helsinki) for months after treatment using the Jaeger
studies involving humans. Master Screen™ IOS, version 5.2
Type of the study: manufactured by VIASYS Healthcare GmbH,
Our study was designed as a case-control Hochberg, Germany. FEV1, FVC and
study. FEV1/FVC were expressed as percentage of
Subjects: predicted for weight and age according to
Subjects included in the study were 2 groups: standardized criteria described by Miller et al
The asthmatic group included 75 children [8].
aged 5 to 16 years (mean age 8.21± 2.14) Genotyping:
diagnosed as bronchial asthma according to Sample: 2ml of venous blood sample was
The Global Initiative For Asthma (GINA) collected in sterile EDTA containing tubes for
guidelines, 2016 [1]. They were 37 males and DNA extraction
38 females. DNA extraction was performed using G-
The control group included 66 children, 34 spin™ Total DNA Extraction Mini Kit (Intron
males and 32 females with a mean age of Biotechnology, Korea) according to
8.6±2.41, who had no evidence of bronchial instruction manual.
asthma, allergy or atopy and also had no first For analysis of the NR3C1 BclI Single
degree relatives with bronchial asthma, Nucleotide Polymorphism polymerase chain
allergy or atopy. reaction followed by restriction fragment
Patients with chronic lung disease other than length polymorphism as described by Pietras
bronchial asthma like cystic fibrosis or et al [9]. was implemented with some
interstitial lung disease were excluded from modifications.
the study. PCR amplification was done using the
Methodology: following primers, designed by (Intron
All children included in the study were Biotechnology, Korea); the forward primer
subjected to complete history taking and was5’-GAGAAATTCACCCCTACCAAC-3’,
the reverse primer was 5’-

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 Khalid M, et al. Zagazig University Medical Journals

AGAGCCCTATTCTTCAAACTG-3’.A mass index the demographic data of the

reaction volume of 25 μl was prepared using studied group is summarized in (table 1).
2.5 μl 10 × buffer, 2.5μl MgCl2, 2.0 μl dNTP, The Bcl I single nucleotide polymorphism of
1 μl from each of the forward and reverse the Glucocorticoid receptors (GR) NR3C1
primers, 0.25 μl of the Taq enzyme, 3 μl of gene CC, CG and GG among asthma group
the extracted DNA and 12.75 μl double were 45.5%, 33.3% and 21.3% respectively.
distilled water. While, among control group the frequencies
The following thermal profile was followed: were 46.9%, 36.3% and 16.6% respectively.
Initial denaturation 95 ˚c for 2 minutes, No statistically significant difference was
followed by 40 cycles which consists of : 94 found between asthmatic group and the
˚c for 30 seconds, 60 ˚c for 30 seconds, 72 ˚c control group as regard genotype. Also the G
for 30 seconds, and a final step at 72 ˚c for 7 allele and the C allele frequency distribution
minutes to finish the reaction. were not different between children with
Restriction digestion reaction was done by bronchial asthma and the children of the
mixing10 μl of PCR products with 1.2 μl of control group. The data are summarized in
bcl-I restriction endonucleases, 2 μl of 10 × (table 2).
loading buffer and7 μL of distilled water and We also found no significant association
incubation at 37°C for 10 hours. between different genotypes and different
The digested product samples were prepared asthma characteristics including age of onset
and electrophoresed on agarose. The electric of asthma, family history of asthma, exercise
current was set at 100 mA & 70 volts for induced asthma, atopic status including total
about one hour, and then the gel was IgE level and Eosinophilic count these data
visualized under UV transilluminator with are summarized in (table 3).
100 base pair ladder and photographed. At the beginning of the study, 23 children
Interpretation: The presence of one restriction (30.7%) had controlled asthma symptoms, 28
site hallmarks the wild-type allele while its children (37.3%) had partially controlled and
absence indicates the mutated allele, 24 (32.0%) had uncontrolled symptoms.
homozygous typical - wild- allele CC There was no statistically significant
genotype resulted in two digestion fragments difference between different genotypes as
of267 and 151 bp length, the homozygous regards asthma control or pulmonary function
mutant allele GG genotype resulted in one tests at the beginning of the study. The data
fragment of 418 bp length, while the presence are summarized in (table 4)
of heterozygote CG genotype resulted in 3 After 3 months of treatment with ICS 35
base pair lengths of 418- 267 and 151 bp children (46.7%) had controlled asthma
length. (Figure 1) symptoms, while 32 children 42.7% had
Statistical analysis: partially controlled and 8 children 10.7% had
Statistical Package for the Social Sciences uncontrolled symptoms.
((SPSS version 20.0) IBM Corp., Armonk, Among Children with the CC genotype 58.8
NY, USA) was used to analyze the Data. % had controlled asthma symptoms 3 months
P value of < 0.05 was considered statistically after treatment as compared to 48% and
significant and value < 0.001 was considered 18.8of children with the CG and the GG
highly significant. Independent t test, Chi genotypes respectively. Meanwhile, among
square test(X2), ANOVA test and Kruskal children with the GG genotype 25 % of
Wallis test were used when appropriate. children with the GG genotype had
RESULTS uncontrolled asthma symptoms as compared
The mean age for the asthma group was to 4% and 8.8% of children with the CG and
8.21±2.14 and that of the control group was the CC genotypes respectively. The difference
8.6±2.41with no statistically significant was statistically significant P value of 0.04.
difference. Also, there was no statistically There was also statistically significant
significant difference as regard sex or body difference among the 3 genotypes as regards

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 Khalid M, et al. Zagazig University Medical Journals

the FEV1% measured 3 months after the GG genotype as compared to children

treatment. Data are summarized in (table 5) with the CG and CC genotypes. (Figure 2)
The mean Composite asthma severity index
score was significantly higher in children with

Table1. Demographic characteristics of the studied groups

Asthmatic Control group t/X² P
group (N=75) (N=66)

Age (mean±SD) 8.21± 2.14 8.6 ±2.41 -0.89 0.37

Sex Male N (%) 37(49.3%) 34(51.5%) 0.067 0.79
Female N (%) 38(50.7%) 32(48.5%)
BMI (mean±SD) 22.55± 3.32 22.71± 3.65 0.974 0.331
Total 75 66

Table2.Genotype and allele distribution among studied groups

Asthmatic Group N Control Group X² P
(%) N (%)
Genotype CC 34 (45.5%) 31 (46.9%) 0.512 0.77
CG 25 (33.3%) 24 (36.4%)

GG 16 (21.3%) 11 (16.6%)

Total 75 66

Allele C 93 (62.0%) 86 (65.1%) 0.300 0.58

frequency

G 57 (38.0% 46 (34.8%)

Table 3. Relation between Genotype distribution and different Asthma characteristics

Genotype F/X² P
CC CG GG
Age Of onset of 3.05±1.7 3.1±1.9 2.8±1.9 0.28 0.88
Asthma

Family -ve 19(55.9%) 9 (36.0%) 8 (50%)

history 0.72 0.69
+ve 15 (44.1%) 16(64.0%) 8 (50%)

Exercise no 14(41.2%) 8 (32.0%) 5(31.2%) 2.31 0.31

induced
asthma yes 20(58.8%) 17(68.0%) 11 (68.8%)

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Total IgE 113.9 124 248 3.42 1.98

level(IU/ml) (57-267) (63.2-312) (117-352)
(Median, IQR)
Eosinophilic 400 500 500 0.42 0.81
count/UL (260-700) (200-700) (300-600)
(Median,IQR)

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Table 4. Level of asthma symptom Control and pulmonary function test at the beginning of the
study:
Genotype X² P
CC CG GG
Level of asthma N (%) N (%) N (%)
control:
Children with 10 (29.4%) 9 (36.0%) 4 (25.0%)
controlled asthma 0.36 0.54
With partially 14 (41.1%) 10(40.0%) 4 (25.0%)
controlled asthma
With uncontrolled 10 (29.4%) 6(24.0%) 8 (50.0%)
asthma
Pulmonary function
tests:

FEV1% 77.25±9.14 77.23±10.3 73.23±10.0 1.06 0.35

(mean±SD)
FEV1/FVC% 76.53±7.06 76.36±8.25 73.05±10.6 1.02 0.39
(mean±SD)

Table 5. Level of asthma symptom Control and pulmonary function test 3 months after treatment:

Genotype X² P
CC CG GG
Level of asthma N (%) N (%) N (%)
control:
Children with 20 (58.8%) 12 (48.0%) 3 (18.8%)
controlled asthma 9.65 0.046*
With partially 11 (32.4%) 12 (48.0%) 9 (56.3%)
controlled asthma
With uncontrolled 3 (8.8%) 1 (4.0%) 4 (25.0%)
asthma
Pulmonary function
tests:

FEV1% 84.7±6.41 82.01±8.46 78.65±8.84 3.46 0.037*

(mean±SD)
FEV1/FVC% 80.82±5.6 78.82±6.2 76.5±6.7 5.01 0.08
(mean±SD)

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Figure 1. Photographing Gel Electrophoresis results of PCR amplification and restriction Products .

Figure 2. comparison of the asthma severity index score among different genotypes

DISCUSSION Our study was a case control study which

Precision or personalized medicine is included 75 asthmatic children who were
based on adjusting the treatment approach of indicated for Inhaled corticosteroids therapy
diseases based on the personal genetic profile, as a controller and 66 healthy control
disease mechanism, and the patient’s life style children. Both asthma group and control
[10]. An important aspect of precision groups were closely matched regarding their
medicine is the pharmacogenetics. age and gender distribution with no
Pharmacogenetics is a new field of research significant gender between both groups.
which links genetic variation with drug We investigated the NR3C1 BClI SNP by
effects to determine impact on pharmacology using PCR-RFLP technique. In contrary to
and clinical application [11]. our research hypothesis, our results showed
Our study aimed at studying the no significant association between different
pharmacogenetics of the Inhaled genotypes and bronchial asthma in the studied
corticosteroids in treatment of asthma on population. Moreover, we did not find any
children by studying the Glucocorticoid correlation between allele frequency and the
receptor NR3C1 single nucleotide occurrence of bronchial asthma among our
polymorphism which was linked in previous children.
studies to the sensitivity to glucocorticoids.
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Several researchers have studied the associated with good asthma symptom control
effects of Glucocoticoid receptors NR3C1 after 3 months of treatment as compared to
gene polymorphism on the development of patients with the GG genotype. 58% of
bronchial asthma. Similar to our results, a patients with CC and 48% of patients with
large study by Vink et al, including 2 CG genotypes achieved good control while
independent cohorts, found no significant only 18% of patients with the GG genotype
association with bronchial asthma did. Similarly patients with the GG genotype
susceptibility in adolescents [12]. Similar had lower FEV1% when evaluated 3 months
results were also reported by after treatment as compared to the CC and CG
Szczepankiewicz et al, [13]. and Cheng et al, genotypes.
[14]. Panek and colleagues [6]. also reported In agreement with our results, Kmyta et al,
no statistically significant differences in the [20]. showed that patients with the GG
frequencies of the GRNR3C1 gene polymorphism had poor asthma control. The
polymorphism between asthma patients and association between the GG genotype and
healthy controls, although the same group had poor lung function was even reported in
previously reported increased risk of asthma patients with cystic fibrosis in an earlier study
among the GG homozygote genotype in their [21]. Also In agreement with our results,
preliminary study [9]. Moreover, a study that Mohamed et al, [18]. reported higher
evaluated the allele frequency among children frequency of the C allele among
with high versus low asthma predictive index glucocorticoid sensitive asthmatic patients as
also found no significant difference [15]. determined by improving FEV1% of more
Contradictory to our results, significant than 30% after a course of oral
association of the GG homozygous genotype corticosteroids. And similar results were
with bronchial asthma was found in 2 studies reported by Yun et al, [17].
by Kmyta et al, [16]. and Yun et al, [17]. On Contradicting our study is the study by
the other hand, a preliminary Egyptian study Keskin et al, [22]. who reported better
found higher frequency of the C allele among response to inhaled corticosteroids among
adults with asthma [18]. A similar result was children with the GG genotype. Unlike our
also reported by Murzina et al, [19]. study their primary outcome was the
Asthma is a multi-factorial disease and the improvement in the FEV1% 4 hours after ICS
fact that different genetic associations are not during asthma exacerbation. This could be
replicated in different studies, reflects the explained by different mechanisms of action
complex interactions between different underlying the rapid effect of ICS being non-
genetic and environmental factors that genomic effect as opposed to the delayed
underlie such a complex disease. As with genomic mechanism behind the anti-
other diseases with Multi-factorial inflammatory effect [23]. Interestingly,
inheritance, individual genes do not account researchers have found that while Skin
for a large amount of the heritability of sensitivity to budesonide was enhanced in
asthma [20]. Possibly our relatively small patients with the GG genotype, white blood
sample size could not identify statistically cells of the GG subjects were less sensitive to
significant association. dexamethasone in vitro [21].
We investigated the distribution of the In our study we evaluated the association
NR3C1 gene polymorphism in atopic and non between Glucocorticoid receptors NR3C1
atopic asthmatic children. We found no gene polymorphism and the composite asthma
association between different genotypes and severity index score (CASI). Our results
either the serum total IgE, or the eosinophilic showed that the CASI score was statistically
count. Similar to our results Mohammed et al, higher in children with the GG genotype. The
[18]
reported no association with the atopic CASI is a subjective measure that evaluates
status in asthmatics. several aspects of asthma severity on multiple
Our results showed that patients with the aspects, which include symptom control,
CC and CG genotypes were significantly medication use, lung function tests and
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 Khalid M, et al. Zagazig University Medical Journals

exacerbations. This score was advised by corticosteroids and leukotriene modifiers: a

GINA guidelines [1]. as a tool to assess systematic review. Clin Exp Allergy. 2017;
asthma severity in children and adolescents. 47(2):271–293.
The CASI enables to determine the difference 4- Duong-Thi-Ly H, Nguyen-Thi-Thu H,
in severity between patients who may appear Nguyen-Hoang L, Nguyen-Thi-Bich H,
similar only on the basis of symptom control, Craig TJ, Duong-Quy S. Effects of genetic
thus we believe that it is a useful tool for factors to inhaled corticosteroid response
clinical research especially in the area of in children with asthma: a literature
pharmacogenetics [24]. review. J Int Med Res. 2017; 45(6):1818-
Our study has some limitations including 1830.
the small number of children included in the 5- Keskin O, Uluca Ü, Birben E, Coşkun Y,
study and also being a cross sectional rather Ozkars MY, Keskin M, et al. Genetic
than a prospective randomized study. associations of the response to inhaled
We recommend that larger multicenter corticosteroids in children during an
studies evaluating the pharmacogenetic asthma exacerbation. Pediatric Allergy and
markers for inhaled corticosteroids, preferably Immunology. 2016; 27(5):507-13.
designed as genotyped stratified prospective 6- Panek M, Pietras T, Fabijan A,
trials, are needed to assess the application of Milanowski M, Wieteska L, Gorski P, et
such studies in clinical practice. al. Effect of glucocorticoid receptor gene
In conclusion: our study showed no polymorphisms on asthma phenotypes.
significant difference in the frequency of BclI Experimental and therapeutic medicine.
polymorphisms of the NR3C1 gene 2013; 5(2):572-80.
distribution between asthmatic and non 7- Wildfire JJ, Gergen PJ, Sorkness CA,
asthmatic children. Among asthmatic Mitchell HE, Calatroni A, Kattan M, et al.
children, however, the presence of the GG Development and validation of the
genotype was associated with decreased Composite Asthma Severity Index—an
response to inhaled corticosteroids and worse outcome measure for use in children and
composite asthma severity index score. adolescents. Journal of Allergy and
Acknowledgement: We would like to Clinical Immunology. 2012;129(3):694-
express our gratitude to the Scientific and 701.
Medical Research Center of the Faculty of 8- Miller MR, Hankinson J, Brusasco V,
Medicine, Zagazig University for their Burgos F, Casaburi R, Coates A, et al.
support. Standardisation of spirometry. European
Declaration of interest respiratory journal. 2005;26(2):319-38.
The authors report no conflicts of interest. The 9- Pietras T, Panek M, Tworek D, Oszajca
authors alone are responsible for the content and K, Wujcik R, Gorski P, et al. The Bcl I
writing of the paper. single nucleotide polymorphism of the
Funding information: None declared human glucocorticoid receptor gene h-
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To Cite This Article: Khalid MS,Mona MA, Osama AG, Mahmoud TA *.Association between
Glucocorticosteroid Receptors (NR3C1) Gene Polymorphism and Bronchial Asthma in Children.ZUMJ
2020;26(1);123-131.DOi: 10.21608/zumj.2019.11975.1204

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