An FCER2 polymorphism is associated with increased oral leukotriene receptor antagonists and allergic rhinitis prescribing

is associated with increased receptor antagonists The Fc Fragment of IgE Receptor II (FCER2) is expressed in several cells, such as macrophages, eosinophils, B cells and platelets. Studies have suggested that FCER2 is involved in the regulation of IgE re -sponses, growth and differentiation of T and B cells, cellular adher ence and antigen presentation. 1,2 The activation of the receptor results in down- regulation of IgE- mediated immune responses. 2 Two studies found that individuals with asthma on inhaled corticoster oids (ICS) with the CC genotype of the rs28364072 polymorphism had a two- fold increased odds of asthma exacerbations and uncon trolled asthma compared with individuals with at least one copy of the T allele (CT/TT). 2,3 While the literature suggests an association between this FCER2 polymorphism and asthma exacerbations while on ICS, it is unclear whether the CC genotype of the rs28364072 polymorphism translates into different prescribing patterns. Thus, we explored the association between the FCER2 polymorphism and increased prescribing of medication for eczema, asthma, and allergic rhinitis, over a decade. We used of possi ble gene- interactions , a random adjusted Outcomes should be validated and harmonised to improve reproducibility and assessment of asthma severity, and guidelines for research using routine healthcare databases should be developed. 9 Our study also has uncontrolled confounding. It is unclear whether other genetic polymorphisms may be influencing or contributing to our results. Ideally, one should also have so cioeconomic and behavioural factors to control for confounding. However, albeit advantageous, this is also a limitation of using routine healthcare databases. Furthermore, all participants are assumed to be Caucasian, of European ancestry, according to phy -sicians. However, this information was not recorded and serves as a limitation as response to treatment varies between different ethnicities. Further studies are needed to replicate our results. This is an exploratory study, unrepresentative of the population. One should be aware of different behaviours across different subgroups regarding medication uptake. Ethnicity, comorbidities, such as obesity, and use of healthcare should, in future, be re corded to better understand the relationships we observed. However, more expensive, longitudinal studies should be con ducted to understand disease progression and evaluate the long-term effects of treatment. Individuals affected by chronic diseases, such as eczema and asthma can experience periods when they are well- controlled on no medication or preventive medicine alone. However, at any time, symptoms can reappear, and more intensive treatment may again be necessary. Hence, conducting longitudinal studies compared with cross- sectional studies is critical. A better understanding of the role of genetic biomarkers on pa tient prescribing might help us improve patients’ quality of life with chronic illnesses. The information from these studies may help de velop targeted therapies for these patients and lead to improved asthma- related clinical outcomes, such as asthma control and quality of life.


R E S E A R C H L E T T E R An FCER2 polymorphism is associated with increased oral leukotriene receptor antagonists and allergic rhinitis prescribing
The Fc Fragment of IgE Receptor II (FCER2) is expressed in several cells, such as macrophages, eosinophils, B cells and platelets. Studies have suggested that FCER2 is involved in the regulation of IgE responses, growth and differentiation of T and B cells, cellular adherence and antigen presentation. 1,2 The activation of the receptor results in down-regulation of IgE-mediated immune responses. 2 Two studies found that individuals with asthma on inhaled corticosteroids (ICS) with the CC genotype of the rs28364072 polymorphism had a two-fold increased odds of asthma exacerbations and uncontrolled asthma compared with individuals with at least one copy of the T allele (CT/TT). 2,3 While the literature suggests an association between this FCER2 polymorphism and asthma exacerbations while on ICS, it is unclear whether the CC genotype of the rs28364072 polymorphism translates into different prescribing patterns. Thus, we explored the association between the FCER2 polymorphism and increased prescribing of medication for eczema, asthma, and allergic rhinitis, over a decade.
We used the BREATHE dataset, a cross-sectional study of possible gene-environment interactions in 1100 children and adults with physician-diagnosed asthma, aged between 2 and 22 years, linked with the Community Pharmacy database. The outcomes considered were the annual number of asthma-, eczema-, and allergic rhinitisrelated prescriptions. We used generalised linear mixed models with a negative binomial family and a random effect for the participant, adjusted for age, gender and the FCER2 polymorphism. All analyses were performed on children and young adults with a physician diagnosis or self-report of the disease, except rhinitis. We decided to perform rhinitis-related analysis in the entire sample due to discrepant reporting in the data and add a sensitivity analysis, analysing only children and young adults that reported having rhinitis (see Supplementary Material for more details on the methodology).
Of the 1100 children and young adults in the dataset, 139 (12.6%) individuals did not have information about the FCER2 polymorphism and were excluded from the analysis. Thirty-four individuals (3.1%) were excluded due to missing clinical information. The final dataset included 927 children and adults with asthma.
The CC genotype was present in 76 (8.2%) of the participants, the TC genotype in 344 (37.1%) and the TT genotype in 507 (54.7%). Regarding dispensed asthma-related prescriptions, almost all participants (97.2%) had at least one short-acting β 2 -agonists (SABA) prescription dispensed over the period studied, followed by 79.6% of participants who were dispensed at least one prescription for ICS.   (Table S4).
There was no evidence of an association between the FCER2 polymorphism and the number of prescriptions dispensed for relievers, ICS, a combination of LABA and ICS, oral antihistamines, and eczema-related prescriptions ( Table 2).
This research demonstrates that children and adults with the CC genotype, for the rs28364072 polymorphism of the FCER2 gene, were dispensed more prescriptions for oral LTRA and allergic rhinitis, over more than a decade, than children and adults with the TT or TC genotype.
The exact role of the FCER2 gene in IgE regulation is still unknown. FCER2 expression has been shown to be induced specifically by interleukin 4 (IL-4). 5 Corticosteroids inhibit the transcription of IL-4, which could be one of the reasons for their efficacy in chronic allergic inflammation. 6 However, some studies have found that corticosteroids may be less effective in the presence of elevated levels of IgE and IL-4. Wu et al. 7 found that the use of glucocorticoids was associated with increased IgE levels in the presence of in vivo IL-4.
Another study found that the increase in IgE levels concerning glucocorticoid administration was only present in atopic asthmatic patients and not in non-atopic patients. 8 Variations in disease severity in conditions such as asthma may influence prescribing. People with more severe disease will often have more long-term medication, such as LABA, LTRA and oral steroids. However, we did not find an association between FCER2 and a higher number of dispensed prescriptions for SABA, ICS or OCS.
We only found an association between FCER2 and a higher number of LTRA prescriptions, which raises the possibility that the need

Key Messages
• We explored associations between genotype and prescriptions for allergic conditions in the BREATHE cohort.
• The low-affinity IgE receptor CC genotype was associated with increased prescriptions for allergic conditions.
• Associations were not all statistically significant, and these findings need replication in another cohort study. Our study also has several limitations. Dispensed prescriptions provide more information than prescribed prescriptions, as one knows that the prescription was dispensed, but it is impossible to determine whether the patient followed the doctor's recommendation and used the medicine or whether the medication was not used or shared among members of the household. It is also impossible to determine whether the patient bought additional over-thecounter medication or alternative medicine. We also considered the dispensing of medication as a proxy for severity, consequently using the medication, while other studies use self-report of medication. However, our study also suffers from self-report bias since eczema and rhinitis were self-reported by the participants. The self-report of rhinitis was inconsistent with rhinitis dispensing, which brings more uncertainty regarding the analysis. Although the association between allergic rhinitis prescribing and the FCER2 polymorphism was not statistically significant in children and adults who reported having rhinitis, the estimate was similar in both analyses. Outcomes should be validated and harmonised to improve reproducibility and assessment of asthma severity, and guidelines for research using routine healthcare databases should be developed. 9 Our study also has uncontrolled confounding. It is unclear whether other genetic polymorphisms may be influencing or contributing to our results. Ideally, one should also have socioeconomic and behavioural factors to control for confounding.

TA B L E 2 Association between the FCER2 polymorphism and asthma, rhinitis and eczema prescriptions
However, albeit advantageous, this is also a limitation of using

CO N FLI C T O F I NTE R E S T
The authors have no conflict of interest to report.

DATA AVA I L A B I L I T Y S TAT E M E N T
The data that support the findings of this study are available from the