## 4 Discussion  
In this single-center study, we evaluated the association between clinical, biological and functional characteristics of mild-to-severe asthmatics with the different genotypes of Bcll and A3669G polymorphisms. In this study, when dividing the population based on the dose of ICS (beclomethasone HFA \(\geq\) 400 ug/day), we observed that patients with moderate-to-severe asthma seem to have a T2-high phenotype, although blood eosinophils of more than 300 cells/\(\upmu\)L were the unique T2-high biomarker statistically different from the mild asthmatics. No difference was found between the groups regarding atopy and serum total IgE. In our asthmatic population, a few differences were reported when subdividing the population based on the SNP genotypes studied. Patients characterized by homozygous GG genotype for Bcll had a higher percentage of asthmatics with greater F\({}_{\text{E}}\)NO levels (>30 ppb) and a lower prevalence of asthmatics with elevated total serum IgE concentrations (>100 kU/L). Considering the A3669G genotypes, we found that patients with heterozygous AG genotypes were younger, characterized by atopy and higher IgE levels. Moreover, the AA genotype of A3669G was associated with lower BMI than the GG genotype. In the past years, different pharmacogenomics and genome-wide association studies focused their attention on the gene-encoding glucocorticoid receptor due to its central role in the GC-signaling pathway [26]. The NR3C1 gene is related to asthma inflammation, and the occurrence of polymorphisms can lead to resistance to glucocorticoids in asthmatics [27], causing difficult management of severe asthma patients [28]. Several studies analyzed the possible interaction between SNPs present within the NR3C1 gene and asthma, although the specific role of Bcll and A3369G SNPs in asthma is still under study. Considerable evidence indicates the involvement of GCs in regulating adipose tissue [15]. The work of [PERSON] and colleagues evaluated the possible association of the A3369G variant with obesity and revealed that the variant of this SNP did not correlate with obesity status, but with the waist-to-hip ratio and with waist circumference in a population of European women [15]. Here, we observed a possible contribution of the 3669G alleles with the obesity status in our asthmatic patients but the prevalence of BMI \(\geq\)30 is not associated with female asthmatics probably due to the smaller sample size of the GG group. For what concerns the Bcll SNP in our asthmatic population, we did not find significant differences in BMI even though the G-allele seems to be related to increased BMI, as reported by previous several studies [29]. In the literature, data regarding the interaction between Bcll SNP and response to GC was described in a study in which it was related to OCS response due to FEV\({}_{1}\)-predicted levels changing in adults [30]. Recently, another study suggested that in asthmatic children, the Bcll GG genotype was associated with ICS response due to an improvement of FEV\({}_{1}\) after 4 h upon high fluticasone propionate dose [31]. Here, no significant differences were observed between Bcll genotypes and pulmonary function levels, assuming that an association between Bcll SNP and GC sensitivity did not exist in our population. Considering the other SNP, for the first time, we describe an association between the AA genotype of A3669G SNP and worse lung function. Asthmatic patients carrying AA, after administration of 400 ug albuterol, did not improve their post-bronodilation FEV\({}_{1}\)/FVC ratio (airflow obstruction), implying a potential relationship between the allele A of A3669G SNP and the scarce response to GCs in our asthmatics. In the past, several studies connected the NR3C1 gene with asthma phenotypes suggesting a possible involvement of this gene in the identification of specific asthma phenotypes [32].