==== Front Med Sci MonitMed. Sci. MonitMedical Science MonitorMedical Science Monitor : International Medical Journal of Experimental and Clinical Research1234-10101643-3750International Scientific Literature, Inc. 2998123610.12659/MSM.908814908814Clinical ResearchGlucocorticoid-Induced Transcription Factor 1 (GLCCI1) Variant Impacts the Short-Term Response to Intranasal Corticosteroids in Chinese Han Patients with Seasonal Allergic Rhinitis Dai Yuyang 12ABCDEFNi Siyang 1ABCEWu Feng 1ACDEZhao Xiuli 1AG 1 National Institute for Drug Clinical Trial, Beijing Tongren Hospital, Capital Medical University, Beijing, P.R. China 2 College of Chemical Biology and Pharmaceutical Sciences, Capital Medical University, Beijing, P.R. ChinaCorresponding Author: Xiuli Zhao; e-mail: lilyzhao1028@outlook.comA Study Design B Data Collection C Statistical Analysis D Data Interpretation E Manuscript Preparation F Literature Search G Funds Collection 2018 07 7 2018 24 4691 4697 04 1 2017 04 2 2018 © Med Sci Monit, 20182018This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)Background Genetic correlations with the response to intranasal corticosteroids (INCS) in seasonal allergic rhinitis (SAR) treatment are unknown. This study aimed to evaluate the role of gene polymorphisms in the response to INCS in Chinese Han patients with moderate to severe SAR. Material/Methods In this study, 286 Chinese Han patients with SAR were genotyped for 4 candidate genes: the glucocorticosteroid receptor (NR3C1) gene, glucocorticoid-induced transcription factor 1 (GLCCI1) gene, T-box 21 gene (TBX21), and ATP binding cassette subfamily B member 1 (ABCB1) gene. Patients were treated with INCS for 4 weeks. The total nasal symptom score (TNSS), total ocular symptom score (TOSS), and visual analogue scale (VAS) score were assessed at baseline and on week 4. The primary endpoint was the effective rate after 4 weeks of INCS therapy. Results In addition to the known contributing factors, one genotype of GLCCI1, namely, rs37973, was significantly associated with the INCS response (OR=0.598, 95% confidence interval: 0.41 to 0.87, P=0.007). The effective rate of the GG group was lower than those of the AA and AG groups (AA vs. GG: 73.7% vs. 51.6%, P=0.007; AG vs. GG: 78.8% vs. 51.6%, P=0.000). In addition, the TNSS, TOSS, and VAS were higher for the patients in the GG group than for those in the AA and AG groups on week 4. Conclusions The GLCCI1 rs37973 variant is a risk factor for glucocorticoid resistance in Chinese patients with SAR who receive short-term INCS treatment. MeSH Keywords GlucocorticoidsPharmacogeneticsPolymorphism, Single NucleotideRhinitis, Allergic, Seasonal ==== Body Background Seasonal allergic rhinitis (SAR) is an IgE-mediated inflammatory disease characterized by obstruction, rhinorrhea, sneezing, and itching and is often accompanied by ocular symptoms [1]. The incidence rate of SAR shows an increasing tendency, and SAR severely affects the quality of life and medical expenditures of patients [2,3]. Intranasal corticosteroids (INCS) are the primary medications in the control and management of SAR because INCS can reduce the production of inflammatory cytokines and induce the apoptosis of inflammatory cells, especially eosinophils [4]. Although INCS appears to provide effective treatment, the response to corticosteroids is characterized by high individual variance in the clinic [5]. Following INCS therapy, some patients show no significant improvements in their symptoms, an outcome known as steroid insensitivity. Steroid resistance occurs in asthma, nephrotic syndrome, and other diseases, thereby making clinical treatment challenging. Early diagnosis can prevent the use of unnecessary hormones and enable the use of other alternative and effective treatments in a timely manner. The factors that affect hormone response are varied, and several mechanisms, including allergen exposure, neutrocytosis, and drug gene polymorphisms, have been extensively studied [6]. Several single nucleotide polymorphisms (SNPs) in candidate genes are reportedly relevant to the glucocorticoid response. The T-box 21 (TBX21) gene, glucocorticosteroid receptor (NR3C1) gene, and ATP binding cassette subfamily B member 1 (ABCB1) gene may be associated with improvements in pulmonary function after treatment with inhaled corticosteroids (ICS) [7–9]. The glucocorticoid-induced transcription factor 1 (GLCCI1) gene, which maps to 7p21.3, is expressed in both lung and immune cells and may be an early marker of hormone-induced apoptosis. rs37973 has been identified as a functional SNP and is reported to be associated with the response of white patients with asthma to ICS [10]. The effects of genetic factors on the treatment of asthma with ICS has been extensively studied, but the effects of genetic factors on the INCS treatment of SAR remain unknown. Both asthma and SAR are type I allergic reactions, and they are very similar in terms of etiology, immunology, pathogenesis, and other aspects [11]. Based on the concept of combined allergic rhinitis and asthma syndrome (CARAS), researchers have assumed that genes affecting ICS therapy might also affect the efficacy of INCS. In the present study, 4 genes, namely, GLCCI1 (rs37973), TBX21 (rs9910408), ABCB1 (rs1045642), and NR3C1 (rs41423247), were assessed in Chinese Han patients with moderate to severe SAR for correlations between gene polymorphisms and the response to INCS. Material and Methods Patients and study design Patients aged 10 to 60 years with a history of moderate to severe SAR for at least 1 year from the Nasal Department of Tongren Hospital (Beijing, China) were enrolled for this non-interventional, prospective cohort study. The patients were of Han ethnicity and planned to be treated with INCS monotherapy. In addition, the patients had no significant medical conditions or nasal abnormalities that were known to interfere with the study (e.g., severe asthma, nasal septal deviation, nasal polyps, or nasosinusitis). The diagnosis was established according to the Clinical Practice Guideline: Allergic Rhinitis recommendations [3], based on clinical symptoms, nasal endoscopy examination, and serum IgE allergen detection. This study was conducted from April to September during the weed, grass, and tree pollen seasons in northern China. Approximately 2 mL of residual peripheral blood that had been used for serum IgE allergen detection was collected for genotyping. Eligible patients received an INCS treatment for 4 weeks before evaluation. Medications known to affect allergy symptoms, to be associated with poor compliance, or to be associated with adverse reactions during the observation period were excluded. This study was in compliance with the Helsinki declaration and was approved by the Ethics Committee of Beijing Tongren Hospital (TREC2015-KY03). The informed consent process was performed, and an informed consent form was signed by each patient. Data collection At the baseline visit, a well-designed self-administered questionnaire was used to collect the following information: demographic information, medical history, allergy history, smoking history, and family history of SAR. Before and after treatment, the total nasal symptom score (TNSS), total ocular symptom score (TOSS), and visual analogue scale (VAS) score were assessed to reflect the real symptom load. The TNSS was the sum of the scores for obstruction, sneezing, rhinorrhea, and nasal itching; the TOSS was the sum of scores for itchy eyes, tearing, and eye redness on a 4-point rating scale (0=none, 1=mild, 2=moderate, and 3=severe) [12]. The VAS score has been employed in multiple kinds of diseases and is sufficiently sensitive for the detection of changes in severity [13]. Briefly, to assess the severity from no symptoms (0 cm) to intolerable symptoms (10 cm), a 10-cm line was utilized. Patients graded their symptoms for the previous 24 hours by making marks on the line. Children were helped by their parents. Taking “change of TNSS=0.55” as the boundary, the patients were divided into 2 categories: good response and poor response [14]. The primary endpoint was the response rate after one 4-week INCS therapy course, and the secondary endpoints included changes in the TNSS, TOSS, and VAS and the nasal symptoms from before and after treatment. Genotyping Genomic DNA was extracted from peripheral blood. GLCCI1 (rs37973), TBX21 (rs9910408), ABCB1 (rs1045642), and NR3C1 (rs41423247) polymorphisms were genotyped with the improved Multiple Ligase Detection Reaction (iMLDR), with technical support from the Center for Human Genetics Research, Shanghai Genesky Biotechnology Company [15]. In addition, 15% of the DNA samples were genotyped again with different methods for quality control purposes. Statistical analysis The Hardy-Weinberg equilibrium of the allele and the genotype frequencies were analyzed. The Kruskal-Wallis or chi-Square tests were used to assess the differences in age, gender, body mass index, and disease characteristics at baseline between different genotype groups. One-way ANOVA was adopted to assess whether the changes in the TNSS, TOSS, and VAS score and the nasal symptom scores from before and after treatment differed according to genotype. Univariate and multivariate logistic regression models were performed to explore the association between SNPs and treatment outcomes. The odds ratio (OR), 95% confidence interval (CI), and P value for each analysis were calculated. Statistical analysis was carried out using SPSS 23.0 for Windows (SPSS, Inc., IBM). In all tests, P≤0.05 was considered statistically significant. Results Patient profiles and GLCCI1 rs37973 frequency From July 2015 to June 2017, 316 patients with SAR were enrolled, and 286 people were included in the statistical analysis (Figure 1). Among the studied SNPs, only rs37973 of GLCCI1 was associated with the INCS treatment response. No statistically significant differences in terms of demographic and disease characteristics (TNSS, TOSS, VAS and nasal symptom scores before and after treatment) were evident among the rs37973 groups at baseline (Table 1). The rs37973 frequency in the Han Chinese population was as follows: AA (n=76, 26.6%), AG (n=146, 51.0%), and GG (n=64, 22.4%). The distributions of all SNPs were in the Hardy-Weinberg equilibrium. Changes in the TNSS, TOSS and VAS before and after treatment according to rs37973 The mean values for the TNSS, TOSS, and VAS assessed by the clinician at baseline and week 4 for the rs37973 groups are shown in Figure 2. The nasal and ocular symptoms of the SAR patients improved significantly after INCS treatment. The AA and AG groups had significantly greater decreases in their scores than the GG group as assessed with the TNSS (AA vs. GG: −68.4% vs. −58.1%, P=0.004; AG vs. GG: −69.5% vs. −58.1%, P=0.001), but the decrease between the AA and AG groups was not significant. By comparison, the TOSS was significantly reduced in the AA group compared with the AG and GG groups (AA vs. AG: −93.8% vs. −84.6%, P=0.043; AA vs. GG: −93.8% vs. −81.3%, P=0.002). The VAS showed improvements that were similar to those of the TNSS in the AG and GG groups (−67.1% vs. −57.8%, P=0.008). Briefly, the GG group had higher scores than the AA or AG groups on week 4 in terms of the TNSS, TOSS, and VAS. The actual scores, improvement percentages, and P values are shown in Table 2. Changes in the nasal symptoms before and after treatment in terms of rs37973 The clinician-based assessments of the mean scores for the individual nasal symptoms, namely, obstruction, rhinorrhea, itching, and sneezing at baseline and on week 4, are presented in Figure 3. A decrease in mean scores was evident from baseline to week 4. Although no statistically significant difference between groups was observed for nasal itch (P=0.811), significant differences were demonstrated for obstruction (AA vs. GG: −66.2% vs. −55.1%, P=0.021; AG vs. GG: −67.9% vs. −55.1%, P=0.004), rhinorrhea (AA vs. GG: −71.4% vs. −61.8%, P=0.031; AG vs. GG: −72.7% vs. −61.8%, P=0.006), and sneezing (AA vs. GG: −68.9% vs. −52.8%, P=0.001; AG vs. GG: −72.4% vs. −52.8%, P=0.000). The improvements in the nasal symptoms (obstruction, rhinorrhea, and sneezing) were significantly fewer for the GG group than for the AA and AG groups after INCS treatment for 4 weeks. Correlation between GLCCI1 rs37973 and the INCS treatment response The distribution frequency of treatment response was as follows: AA (good response/poor response=56/20), AG (115/31), and GG (33/31). The percentage of patients with good responses on week 4 is presented in Figure 4. The effective rate of the GG group was significantly lower than those of the AA and AG groups (AA vs. GG: 73.7% vs. 51.6%, P=0.007; AG vs. GG: 78.8% vs. 51.6%, P=0.000) and was not affected by smoking history or family history of SAR. Meanwhile, the rs37973 genotype showed a correlation with the INCS treatment response by univariate analysis (OR=0.598, 95% CI: 0.41 to 0.87, P=0.007). The multivariate analysis is presented in Table 3, after adjustments for demographic characteristics and the TNSS at baseline. The results indicate that the therapeutic effect of INCS might decrease gradually along with the increase in the G allele frequency. In addition, age may be a factor that affects efficacy according to the logistic regression analysis (OR=0.97, 95% CI: 0.95 to 1.00, P=0.033), and older patients may have poor treatment outcomes. Associations between other SNPs and the INCS treatment response The assessments of the other SNPs, namely, the SNPs of TBX21 (rs9910408), ABCB1 (rs1045642), and NR3C1 (rs41423247), showed no connections with the INCS response (Table 4). Discussion Glucocorticoid resistance is an important issue in the management of allergic diseases (e.g., allergic dermatitis, asthma, and allergic rhinitis) and may lead to treatment failure. Several pharmacogenetic studies have been performed to investigate genetic effects on glucocorticoid resistance, and several candidate genes have been identified (e.g., CRHR1, FCER2, TBX21, and NR3C1) [6,16–21]. However, correlation studies have not precisely approximated clinical relevance. The expression product of GLCCI1 was presumed to reduce the apoptosis of inflammatory cells [22]. Related SNP mutations may decrease GLCCI1 expression, which may inhibit inflammatory cell apoptosis and lead to glucocorticoid resistance. More recently, a genome-wide association study (GWAS) by Tantisira et al. revealed that GLCCI1 acts as a candidate gene in the response to ICS therapy in asthmatic patients. The G allele of rs37973 might downregulate GLCCI1 expression and decrease patient corticoid sensitivity [10]. Since this report, further studies have confirmed the association between GLCCI1 gene polymorphisms and the glucocorticoid response [23–25], though the findings of other relevant studies were not consistent with those of the original findings [26,27]. In 2016, Hu C et al. successfully repeated the finding in a Chinese adult population [25]. However, these studies were mostly limited to a disease model of asthma, and the conclusion needs to be extended to other allergic diseases. Our study showed that SAR patients with the GG genotype at the rs37973 locus of the GLCCI1 gene might have poor responses to INCS short-term treatment as measured by changes in the TNSS, TOSS, and VAS score. In this study, all assessments of nasal and ocular symptoms showed less improvement in the GG group than in the AA or AG groups. For example, the mean TNSS of the GG patients decreased by approximate 58% from baseline to week 4 compared with a decrease of 68% for the same period for the AA patients. However, no significant difference regarding the improvement in nasal itching was evident in the rs37973 group. Our study suggested that the therapeutic effect of INCS might decrease gradually along with the increase in the G allele frequency (OR=0.598, 95% CI: 0.41 to 0.87, P=0.007). This result was similar to that the study by Tantisira et al., which suggested that patients with GG were approximately two and a half times more likely to have poor responses to ICS than those with AA in a non-Hispanic white asthmatic population [10]. Hence, we can reasonably conceive that GLCCI1 variations may affect the INCS responses of SAR patients. Some studies have concluded that smoking may affect the therapeutic effect of ICS on asthma [24], but our findings suggested that the smoking and family histories of SAR patients did not affect the therapeutic effect of INCS. In addition, according to our research, older patients may have poor treatment outcomes. This association with age may be because the anatomical structure of the nasal cavity changes as age increases, resulting in changes to nasal airflow and a reduction in the nasal mucosa cilia beat frequency, leading to a decreased ability to eliminate allergens. Based on the hypothesis that the GLCCI1 variant influences the effects of endogenous hormones, the GG genotype of rs37973 is expected to be associated with worse symptoms at baseline. Hu C et al. found that the rs37973 variant was associated with a higher baseline forced expiratory volume in 1 second (FEV1) in a Chinese population [25]. However, our study did not find any association between the rs37973 polymorphism and baseline clinical severity. The baseline TNSS, TOSS, and VAS score showed no statistical significance among the groups. Anton Lopert et al. showed that the TBX21 gene might be associated with improvements in pulmonary function after ICS treatment for at least 3 years in asthmatic patients [7]. The rs41423247 polymorphism of the NR3C1 gene was reported to be associated with improvements in FEV1 at 4 h in children with moderate to severe asthma who were treated with high-dose ICS [8]. In addition, the ABCB1 gene polymorphism may influence the efficacy of the salmeterol/fluticasone combination therapy in stable chronic obstructive pulmonary patients [9]. However, those SNPs did not show any association with INCS effect in our study. There were several limitations in our study design. First, no healthy control group was set up to explore the association between rs37973 and SAR susceptibility. Second, the correction for confounding factors was not as strict as that of clinical trials because of non-intervention. Third, the study lacked objective indicators for the evaluation of clinical symptoms. Despite these limitations, this gene correlation study will be meaningful toward shedding light on further research. Conclusions In conclusion, the GLCCI1 rs37973 polymorphism may be a pharmacogenetic factor in the response to INCS treatment in Chinese SAR patients. Acknowledgments The authors would like to thank all patients and otolaryngologists for their contributions to this study. We are sincerely grateful to the Center for Human Genetics Research, Shanghai Genesky Biotechnology Company for technical support. Conflicts of interest None. Source of support: This work was supported by the National Science and Technology Major Project of China (2011ZX09302-007-05) Figure 1 Inclusion-exclusion flow chart. Figure 2 Changes in the TNSS, TOSS, and VAS before and after treatment. The TNSS, TOSS, and VAS decreased significantly after INCS treatment. The GG genotype was associated with poor improvements in the TNSS, TOSS, and VAS, relative to the AA or AG genotype. Data are presented as the mean ±SD. * P<0.05; ** P<0.01. Figure 3 Changes in the nasal symptoms before and after treatment. After INCS treatment, all nasal symptoms were significantly improved. The GG genotype was associated with poor improvements in obstruction, rhinorrhea and sneezing, relative to the AA or AG genotype. No significant differences between genotypes were observed for itching. Data are presented as the mean. * P<0.05; ** P<0.01. Figure 4 Assessment of treatment response according to rs37973. The effective rate of the GG genotype was significantly lower than those of the AA and AG genotypes and was not affected by the smoking history or family history of the SAR patients. * P<0.05; ** P<0.01. Table 1 Patient characteristics according to GLCCI1 rs37973 genotype. rs37973 AA (n=76) AG (n=146) GG (n=64) Gender (male/female), n 42/34 74/72 29/35 Age, years 34.6 (10.5) 35.2 (10.3) 34.7 (10.4) BMI, kg/m2 21.1 (2.1) 21.9 (2.0) 21.6 (2.1) Smoking history (never), % 75.0 74.7 78.1 Family history of SAR (none), % 75.0 73.3 65.6 TNSS at baseline, scores 7.38 (1.52) 7.38 (1.36) 7.81 (1.71)  Obstruction, scores 1.95 (0.69) 1.96 (0.63) 2.05 (0.58)  Rhinorrhea, scores 2.59 (0.66) 2.56 (0.73) 2.67 (0.62)  Itching, scores 1.53 (0.81) 1.40 (0.67) 1.50 (0.71)  Sneezing, scores 1.32 (0.80) 1.54 (0.79) 1.59 (0.96) TOSS at baseline, scores 2.25 (1.95) 2.14 (1.99) 2.56 (2.06) VAS at baseline, scores 7.71 (0.99) 7.5 (0.97) 7.66 (1.17) Results were presented as mean (SD). P>0.05 for all characteristics according to the Kruskal-Wallis or Chi-Square test. BMI – body mass index; TNSS – total nasal symptoms score; TOSS – total ocular symptoms score; VAS – visual analogue scale. Table 2 Assessment of AR severity before and after treatment according to rs37973. Assessment Rs37973 AA (n=76) AG (n=146) GG (n=64) Mean SD Change Mean SD Change Mean SD Change TNSS  Baseline 7.38 1.52 −5.05 (−68.4%) 7.38 1.36 −5.13(−69.5%) 7.81 1.71 −4.54(−58.1%)  4w 2.33 1.72 2.25 1.81 3.27 2.37 P value* AA vs. AG: p=0.782 AA vs. GG: p=0.004 AG vs. GG: p=0.001 TOSS  Baseline 2.25 1.95 −2.11(−93.8%) 2.14 1.99 −1.81 (−84.6%) 2.56 2.06 −2.08 (−81.3%)  4w 0.14 0.42 0.33 0.67 0.48 0.78 P value* AA vs. AG: p=0.043 AA vs. GG: p=0.002 AG vs. GG: p=0.105 VAS  Baseline 7.71 0.99 −5.00 (−64.9%) 7.50 0.97 −5.03 (−67.1%) 7.66 1.17 −4.43 (−57.8%)  4w 2.71 1.90 2.47 1.87 3.23 2.02 P value* AA vs. AG: p=0.379 AA vs. GG: p=0.107 AG vs. GG: p=0.008 * One-Way ANOVA test comparing treatment means of rs37973 groups. Table 3 Effects of clinical indices and GLCCI1 rs37973 on the treatment response. Multivariate analysis OR 95% C.I. P’ value rs37973 genotype 0.58 0.40 to 0.86 0.007** Gender 0.95 0.52 to 1.75 0.87 Age 0.97 0.95 to 1.00 0.033* BMI 1.04 0.91 to 1.19 0.58 Smoking history 1.56 0.75 to 3.22 0.23 Family history of SAR 0.76 0.43 to 1.35 0.35 TNSS at baseline 1.09 0.91 to 1.31 0.33 * p<0.05; ** p<0.01. C.I. – confidence interval; BMI – body mass index; TNSS – total nasal symptoms score. Table 4 Effects of other SNPs on INCS treatment response. SNP OR 95% C.I. P value P’ value* rs9910408 1.335 0.88 to 2.02 0.172 0.199 rs1045642 0.918 0.63 to 1.33 0.653 0.455 rs41423247 0.901 0.57 to 1.42 0.653 0.700 * Effects were adjusted for gender, age, BMI, smoking history, family history of SAR, and TNSS at enrollment. C.I. – confidence interval. ==== Refs References 1 Skoner DP Allergic rhinitis: Definition, epidemiology, pathophysiology, detection, and diagnosis J Allergy Clin Immunol 2001 108 2 8 2 Meltzer EO Bukstein DA The economic impact of allergic rhinitis and current guidelines for treatment Ann Allergy Asthma Immunol 2011 106 12 16 3 Seidman MD Gurgel RK Lin SY Clinical practice guideline: Allergic rhinitis Otolaryngol Head Neck Surg 2015 152 1 43 4 Mccoll A Michlewska S Dransfield I Effects of glucocorticoids on apoptosis and clearance of apoptotic cells Sci World J 2007 7 1165 81 5 Ahmadiafshar A Ahmadiafshar S Efficacy and safety of inhaled and intranasal corticosteroids Antiinflamm Antiallergy Agents Med Chem 2014 13 83 87 25175908 6 Leung DY Bloom JW Update on glucocorticoid action and resistance J Allergy Clin Immunol 2003 111 3 22 12532089 7 Lopert A Rijavec M Zavbi M Asthma treatment outcome in adults is associated with rs9910408 in TBX21 gene Sci Rep 2013 3 2915 24107858 8 Keskin Ö Uluca Ü Birben E Genetic associations of the response to inhaled corticosteroids in children during an asthma exacerbation Pediatr Allergy Immunol 2016 27 507 13 27003716 9 Wang XW Zhang YL Xiong Y Impact of ABCB1 single-nucleotide polymorphisms on treatment outcomes with salmeterol/fluticasone combination therapy for stable chronic obstructive pulmonary disease Genet Test Mol Biomarkers 2015 19 566 72 26327575 10 Tantisira KG Lasky-Su J Harada M Genomewide association between GLCCI1 and response to glucocorticoid therapy in asthma N Engl J Med 2011 365 1173 83 21991891 11 Taramarcaz P Gibson PG The effectiveness of intranasal corticosteroids in combined allergic rhinitis and asthma syndrome Clin Exp Allergy 2004 34 1883 89 15663563 12 Canonica GW Baena-Cagnani CE Bousquet J Recommendations for standardization of clinical trials with allergen specific immunotherapy for respiratory allergy. A statement of a world allergy organization (WAO) taskforce Allergy 2010 62 317 24 13 Senti G Vavricka BM Graf N Evaluation of visual analog scales for the assessment of symptom severity in allergic rhinoconjunctivitis Ann Allergy Asthma Immunol 2007 98 134 38 17304879 14 Barnes ML Vaidyanathan S Williamson PA The minimal clinically important difference in allergic rhinitis Clin Exp Allergy 2010 40 242 50 19895590 15 Zhang Z Xu G Zhu W PRKCH 1425G/A polymorphism predicts recurrence of ischemic stroke in a Chinese population Mol Neurobiol 2015 52 1648 53 25370935 16 Kazani S Wechsler ME The role of pharmacogenomics in improving the management of asthma J Allergy Clin Immunol 2010 125 295 302 20159237 17 Tse SM Tantisira K Weiss ST The pharmacogenetics and pharmacogenomics of asthma therapy Pharmacogenomics J 2011 11 383 92 21987090 18 Koster ES Zee MVD Tavendale R FCER2 T2206C variant associated with chronic symptoms and exacerbations in steroid-treated asthmatic children Allergy 2011 66 1546 52 21958076 19 Panek M Pietras T Antczak A The N363S and I559N single nucleotide polymorphisms of the h-GR/NR3C1, gene in patients with bronchial asthma Int J Mol Med 2012 30 142 50 22469783 20 Tantisira KG Hwang ES Raby BA TBX21: A functional variant predicts improvement in asthma with the use of inhaled corticosteroids Proc Natl Acad Sci USA 2004 101 18099 104 15604153 21 Mcgeachie MJ Wu AC Chang HH Predicting inhaled corticosteroid response in asthma with two associated SNPs Pharmacogenomics J 2013 13 306 11 22641026 22 Chapman MS Qu N Pascoe S Isolation of differentially expressed sequence tags from steroid-responsive cells using mRNA differential display Mol Cell Endocrinol 1995 108 1 7 7758821 23 Maitland-van der Zee AH Raaijmakers JA Variation at GLCCI1 and FCER2 : One step closer to personalized asthma treatment Pharmacogenomics 2012 13 243 45 22304573 24 Izuhara Y Matsumoto H Kanemitsu Y GLCCI1 variant accelerates pulmonary function decline in patients with asthma receiving inhaled corticosteroids Allergy 2014 69 668 73 24673601 25 Hu C Xun Q Li X GLCCI1 variation is associated with asthma susceptibility and inhaled corticosteroid response in a Chinese Han population Arch Med Res 2016 47 118 25 27133712 26 Hosking L Bleecker E Ghosh S GLCCI1 rs37973 does not influence treatment response to inhaled corticosteroids in white subjects with asthma J Allergy Clin Immunol 2014 133 587 89 24131825 27 Vijverberg SJ Tavendale R Leusink M Pharmacogenetic analysis of glcci1 in three north European pediatric asthma populations with a reported use of inhaled corticosteroids Pharmacogenomics 2014 15 799 806 24897287