Polymorphisms in the FCER2 gene have associations with asthma and chronic obstructive pulmonary disease

Introduction

Asthma and chronic obstructive pulmonary disease (COPD) are the major health problems worldwide (1,2). Airway obstruction occurs in both diseases with asthma showing reversible and COPD being irreversible. However, persistent airflow limitation could present in severe asthma and partially reversible airflow obstruction may occur in COPD (3). Despite the differences in pathogenic factors and endotypes (4,5), the two diseases showed many phenotypic similarities. Typically, chronic inflammation in asthmatic airways is featured by infiltration of CD4 (+) lymphocytes and eosinophils, while CD8 (+) lymphocytes, macrophages, and neutrophils are elevated in COPD airways (6). However, the endotypes of chronic inflammation could be represented by neutrophilia in asthma (7) and eosinophilia in COPD (8). A recent study reported that the Th2 inflammation-related genetic signature, a typical feature in asthma, co-occurred in COPD (9).

“Dutch hypothesis” was proposed by Orie and colleagues that asthma and COPD are two different manifestations of one disease entity called “chronic non-specific lung disease” (CNSLD), which resulted from the interactions between genetic predisposition and exposure to similar environmental factors, further leading to the clinical presentations of the disease (10,11). By contrast, the “British hypothesis” stated that asthma and COPD are two distinct disease entities with different clinical syndromes, inflammatory processes, therapy responses, genetic substrate, and atopy status (4).

In recent years, growing evidence supported the Dutch hypothesis by showing the commonalities between asthma and COPD (12-14). Both diseases have common environmental risk exposure, such as maternal smoking during pregnancy, environmental tobacco exposure, and air pollution (14). Airway hyperresponsiveness (AHR) and atopy defined by IgE level are two important characteristics of asthma (15). Previous studies have reported that AHR led to chronic COPD-associated respiratory symptoms and worse lung function in COPD (15,16), while IgE correlated with development, exacerbations, and lung function decline (17,18). Importantly, several single nucleotide polymorphisms (SNPs) of specific genes were reported to be associated with both asthma and COPD, including CHI3L1, CHIT1, IL-13, ADAM33, MMP12, and others (19-25). Besides, Hayden and colleagues suggested that childhood asthma was associated with a higher risk for COPD, while the known childhood asthma loci like IL1RL1, IL13, and GSDMB, correlated with COPD (26). However, a genome-wide association study (GWAS) suggested that no common genetic component was found in asthma and COPD (27). So far, a consensus on the origins of these two disorders has not been reached (28).

The present study aims to investigate whether asthma and COPD share the possible common genetic susceptibility in Chinese patients by selecting 10 SNPs within 7 candidate genes (FCER1A, FCGR2A, FCGR2B, CHI3L1, ADRB2, STAT6, and FCER2), that are mainly expressed in airway epithelial cells. We present the following article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-22-820/rc).

Methods

Study participants

This case-control study included 848 patients, 251 with COPD and 597 with asthma, and 632 healthy controls, who were recruited from August 2017 to September 2019 from two medical centers, Peking Union Medical College Hospital and Beijing Aviation General Hospital. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The research protocol was reviewed and approved by the Ethics Committee for Human Research of Peking Union Medical College Hospital (S-767) and Beijing Aviation General Hospital (MHZYY 2014-05-01) and informed written consent was obtained from all participants.

Inclusion and exclusion criteria

All participants were aged 18 years or older. Asthma was diagnosed based on Global Initiative for Asthma (GINA) criteria (29): (I) history of variable respiratory symptoms; (II) variable expiratory airflow limitation, e.g., increase in forced expiratory volume in the first second (FEV₁) of >12% and >200 mL after salbutamol (albuterol) inhalation; (III) effective of medications for asthma. COPD was diagnosed according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) (30): FEV₁ to forced vital capacity (FVC) of <0.7 after salbutamol (albuterol) inhalation. COPD patients with asthma were excluded from our study.

Healthy controls were eligible for this study according to the following criteria: (I) without a diagnosis of COPD, asthma, or any other respiratory diseases; (II) no history of respiratory allergic diseases or any other respiratory symptom, like wheezing, shortness of breath; (III) no use of medications for asthma and COPD. Spirometry without bronchodilation was performed for all healthy controls.

Individuals were excluded from the study if they (I) were diagnosed with asthma-COPD overlap syndrome; (II) had a suspected acute inflammatory or infectious disease; (III) had a history of stroke or acute coronary syndrome; (IV) experienced venous thromboembolism; (V) received anticoagulant therapy; (VI) were diagnosed with cancer within the last 5 years; (VII) were pregnant or under hormone-replacement therapy.

Demographic and clinical measurements

We collected the following variables: age, gender, and smoking status. Fasting venous blood samples were drawn into tubes and transported to the laboratory within 4 hours to test blood eosinophil and serum IgE levels. The missing data were less than 5% and replaced using linear interpolation.

According to the GINA, participants were stratified into three groups based on age: (I) age between 18 and 40 years; (II) age between 40 and 65 years; (III) and age ≥65 years.

Genotyping

Genomic DNA was extracted from peripheral blood leukocytes by standard protocols. After a comprehensive literature search and consultation with a respiratory established geneticist, a total of 10 SNPs of interest within 7 genes which are mainly expressed in airway epithelial cells were selected, including FCER1A (rs2427837), FCGR2A (rs1801274), FCGR2B (rs1050501), CHI3L1 (rs4950928), ADRB2 (rs1042713 and rs1042714), STAT6 (rs12368672) and FCER2 (rs28364072, rs2228137, and rs3760687). These SNPs were to some extent the most frequently reported candidates in the two diseases according to our literature review. Genotyping was done using SNaPshot as previously described (31). The PCR products were sequenced and analyzed using ABI 3730XL DNA Analyzer (Applied Biosystems) and GeneMapper 4 software, respectively. Hardy-Weinberg equilibrium was tested as shown in Table S1 (P cutoff-value =0.05).

Statistical analysis

The baseline characteristics of the participants were compared using a chi-square test (discrete variables) and Student’s t-test (continuous variables). The odds ratio (OR) and 95% confidence interval (CI) were calculated for evaluating differences in genotype distributions and haplotype disease analysis by binary logistic regression with adjusting for age and sex. SNK-q test and Student’s t-test were used to assess the associations between polymorphisms and phenotypes. Results were expressed as mean ± SD. Multiple factors analysis of variance (ANOVA) was used to evaluate the relationship between each haplotype and phenotypes. We used multiple-factor analysis such as binary logistic regression and multiple factors ANOVA to control the population stratification as a confounder. A P<0.05 was considered statistically significant. All analyses were performed using SPSS 22.0 (SPSS Inc., Chicago, IL, USA).

Results

Baseline characteristics of the study population

Baseline characteristics were presented in Table 1. The average age of participants with COPD and asthma was significantly higher than those of healthy controls (both P<0.001). Compared with the controls, the percentage of male participants was significantly higher in the COPD group (P<0.001), while no significant differences were found between asthma groups (P=0.78). The percentage of total smokers (ex-smokers and current smokers) in COPD patients was 71.3%, higher than those in asthma patients (12.9%). There was a higher percentage of blood eosinophil in asthma but not in COPD as compared to those in controls. Additionally, patients with COPD/asthma displayed significantly higher levels of serum IgE than those of the controls (both P<0.001). Moreover, we found significantly higher levels of blood eosinophil in asthma patients than those in controls (P<0.001). As expected, the two key spirometry indices FEV₁% predicted and FEV₁/FVC were significantly lower in the patients with COPD or asthma than those in controls (both P<0.001).

Genotype analysis and single-locus analysis

Table 2 showed the genotype distributions of selected polymorphisms between asthma/COPD patients and controls. Genotype analyses showed that, of 10 variants within 7 genes, only one SNP rs28364072 (FCER2) was significantly different between COPD patients and controls (P=0.009), while 3 SNPs (rs1801274 in FCGR2A, rs12368672 in STAT6, rs2228137 in FCER2) differed significantly between asthma and controls (P=0.004, 0.007 and 0.01, respectively). Additionally, single-locus analysis showed that polymorphisms of rs1801274 (FCGR2A), rs12368672 (STAT6) and rs2228137 (FCER2) were significantly associated with asthma (OR =1.302, P=0.004; OR =1.276, P=0.007; and OR =1.502, P=0.010, respectively). No SNP was found to be associated with COPD. Our results suggested that the FCER2 gene was a common hereditary factor in COPD or asthma.

Polymorphism-phenotype analysis

Since only polymorphisms of the FCER2 gene were found to be associated with asthma and COPD, three included SNPs (rs28364072, rs2228137, and rs3760687) in the FCER2 gene were selected for further analysis. Table 3 showed the associations between polymorphisms of the FCER2 gene and blood eosinophil and serum IgE levels in COPD/asthma patients. We observed that asthma patients carrying homozygote CC genotype of rs2228137 had a lower level of blood eosinophils counts than those carrying heterozygote CT (5.4%±4.3% vs. 7.0%±4.7%, P=0.034). Additionally, asthma patients carrying homozygote CC genotype of rs3760687 had a significantly higher level of serum IgE than those with homozygote TT (391.0±655.9 vs. 184.3±169.1 U/L, P=0.009). However, no significant difference was observed between the three SNPs and COPD.

Haplotype-disease analysis

To identify the combined effects of these three polymorphisms of the FCER2 gene on the risk of COPD or asthma, we performed haplotype analysis. As shown in Table 4, we focused only on the haplotypes related to the target SNPs detected at frequencies ≥3%. Using haplotype C-A-C (allele of rs28364072, rs2228137, and rs4950928, respectively) as a reference and adjusting for age and gender, only haplotypes T-G-T were found to be significantly associated with a higher risk of asthma (OR =2.25, 95% CI: 1.26–4.01, P=0.006).

Haplotype-phenotype analysis

The associations of phenotypes with FCER2 haplotypes in COPD and asthma patients were presented in Table 5. We found C-A-C was associated with FEV₁/FVC, blood eosinophil, and serum IgE levels in asthma patients (P=0.033, <0.001, and 0.002, respectively), while it was related with blood eosinophils in COPD patients (P=0.034). In addition, C-G-C was associated with blood eosinophils and serum IgE levels in asthma patients (P<0.001 and P=0.041, respectively). Moreover, C-G-T was related to blood eosinophils both in COPD and asthma patients (P=0.040 and 0.049, respectively). T-A-C was associated with FEV₁/FVC and blood eosinophils in asthma patients (P<0.001 and P=0.005, respectively), whereas it correlated with FEV₁% predicted in COPD patients (P=0.003). Meanwhile, T-G-C was associated with FEV₁% predicted, blood eosinophil, and serum IgE levels in asthma patients (P=0.029, 0.004, and 0.004, respectively), and it was also associated with FEV₁/FVC in COPD patients (P=0.004).

Overall, FECR2 was associated with blood eosinophils, FEV1/FVC, FEV1% predicted, and serum IgE levels in asthma patients, while FECR2 was associated with blood eosinophils, FEV1/FVC, and FEV1% predicted in COPD patients.

Discussion

Although many SNPs of genes are associated with both asthma and COPD, to the best of our knowledge, no study has so far demonstrated associations between FCER2 polymorphisms and COPD. The present study suggested that rs28364072 (FCER2) was a risk factor in COPD predisposition, while rs2228137 (FCER2) conferred asthma susceptibility. Haplotype analyses suggested that FCER2 haplotypes C-A-C and C-G-T were associated with blood eosinophils in both diseases, while a haplotype T-A-C correlated with FEV₁% predicted in COPD and FEV₁/FVC ratio in asthma, haplotype T-G-C correlated with FEV₁/FVC ratio in COPD and FEV₁% predicted in asthma. Our results suggested that FCER2 polymorphisms may genetically play a role in both overall asthma and COPD susceptibility, partly supporting the Dutch hypothesis that asthma and COPD share common genetic backgrounds.

FCER2 gene is an 11-exon gene located at chromosome 19p13.3, encoding the low-affinity receptor for IgE (CD23) (32). CD23 interacts with IgE with low affinity, playing a dual role in regulating IgE synthesis in activated B lymphocytes and facilitating allergen-specific activation in T lymphocytes (33,34). Previous studies have demonstrated the role of FCER2/CD23 polymorphisms in exacerbations, lung function, regulation of IgE synthesis, and immunotherapy in asthma (35-37). The rs28364072, rs2228137 and rs3760687, are the three most frequently reported SNPs in FCER2 (38). The rs2228137, encoding a nonsynonymous amino acid change (R62W), produced increased IgE binding and Egr-1 expression in human B cells, which may responsible for the atopic phenotypes (39).

Consistently, our results suggested that a SNP rs2228137 in FCER2 was associated with higher blood eosinophils in asthma patients, while several FCER2 haplotypes were associated with declines in FEV₁/FVC and FEV₁% predicted, elevated eosinophils, and serum IgE levels. Interestingly, we found that serum IgE levels in asthma patients carrying allele T were significantly lower than those carrying homozygote CC, suggesting that rs3760687 might be involved in the regulation of serum IgE. In contrast to our results, rs3760687 was reported to be associated with increased total serum IgE in the randomly selected population (40). However, no significant association was observed between IgE levels and rs3760687 in asthmatics (40). Functionally, the marker rs3760687, a promoter SNP in the FCER2 gene, was reported to alter transcriptional activity by binding transcription factors Sp1 and Sp3, leading to the regulation of CD23 expression (38).

The rs28364072, also known as the FCER2 T2206C variant, was associated with asthma severity (37,41). A previous study found that the percentage of rs28364072 of FCER2 was significantly higher in patients with controlled asthma than those in patients with uncontrolled asthma (40). However, no prior studies correlated FCER2 with COPD. In the present study, we first reported that rs28364072 (FCER2) was associated with COPD susceptibility after adjusting for age and sex. Although no association between FCER2 polymorphisms and COPD susceptibility was demonstrated previously, the rs28364072 has been well demonstrated to be genetically linked to asthma. Positive associations between rs28364072 and lower levels of fractional exhaled nitric oxide (FENO) and poor responsiveness to inhaled corticosteroids (ICS) were presented in asthmatic children (35,37,42,43).

Recent evidence has indicated that atopy is also a feature of COPD (18,44). 25–47.3% of COPD patients had atopy, as defined by elevated specific IgE for any inhaled antigen (3,45). Additionally, COPD patients with higher serum total IgE levels showed worse clinical symptoms (17,46). Therefore, it is hypothesized that FCER2 polymorphisms may involve COPD pathogenesis. Consistently, we found that serum IgE levels in COPD patients carrying alternative variants of FCER2 polymorphisms (rs28364072 and rs3760687) were slightly higher than those with corresponding reference homozygote genotype, although statistical significance was not reached. Our results suggested that the FCER2 gene was the common genetic factor shared by asthma and COPD, indicating that CD23 could be a therapeutic target in allergic diseases and COPD. A recent cohort study found that increased plasma IgE correlated with a higher risk of severe exacerbation and all-cause mortality in COPD patients after adjusting for blood eosinophils, suggesting that anti-IgE antibody, such as a famous commercial drugs omalizumab, may be effective for patients with COPD (47,48).

Genotype analysis showed significant associations between FCER2 polymorphisms and blood eosinophils or serum IgE levels in COPD. However, haplotype analyses in association with phenotypes suggested that certain haplotypes were involved in FEV₁/FVC, FEV₁% predicted, and the percentage of eosinophils in COPD. The interactions among different polymorphisms may regulate FCER2/CD23 expression at different levels and in interacting manners (38).

FCGR2A gene encodes low-affinity IgG Fc receptors, which play critical roles in immune processes (49). STAT6 gene is an important factor in Th2 response and allergic inflammation. Previous studies have indicated that genetic variants in the STAT6 gene were associated with serum IgE levels and asthma (50,51). In line with previous studies (49,50), we found that rs1801274 (FCGR2A) was linked to asthma. Previous studies showed that rs2427837 (FCER1A) and rs1050501 (FCGR2B) are associated with asthma (49,52), while CHI3L1 polymorphism (rs4950928) ADRB2 polymorphisms (rs1042713 and rs1042714) correlated with both asthma and COPD susceptibility (20,53). However, no statistically significant associations were found in patients with asthma and COPD in this study. The reasons for the inconsistencies may be due to different environmental exposure, ethnic differences, and the sample size of the population studied.

Notably, the present study showed that the FCER2 gene was genetically associated with asthma and COPD, providing evidence for the common genetic origins of the two diseases. Although the mechanisms remain unclear, our results suggested that FCER2 SNPs might be involved in regulating pulmonary function and blood eosinophils in COPD.

There are several limitations to this study. First, as a case-control study, the causality could not be determined between FCER2 variants and COPD. Second, only 1 to 3 SNPs of 7 genes were evaluated in our study, which may underestimate potential common genes associated with asthma and COPD. More variants and candidate genes are warranted in future studies to justify the Dutch hypothesis. Third, the sample size of some groups with homozygote alternative variants was small (less than 10), leading to potential biases, studies with larger populations are needed to identify more common genes between asthma and COPD. Fourth, because this study was a case-control investigation aiming to compare the similarities and differences in the genetic background of two common airway diseases, we didn’t include data regarding the allergic status, antigen exposure, therapy intensification, and adherence to therapy, when recruitment. Future studies focusing on how the environmental factors interacting with genes influence disease expression are needed. Fifth, we did not adjust for the smoking status in the logistic regression because of lacking related information on the control subjects. However, we found that several manuscripts similar to our study did not adjust for smoking status (20,54), indicating that adjusting for smoking status may have a limited influence on the conclusion. Last, our sample compromised exclusively on northern Chinese. The generalization of the findings to other populations with different demographics should be cautious.

Conclusions

In conclusion, the current study suggested that the FCER2 gene was a potential candidate gene for asthma and COPD susceptibility, and haplotypes in the FCER2 gene were associated with pulmonary function and blood eosinophils in both diseases. Our findings may provide evidence for further studies to demonstrate the mechanisms and causality of the FCER2 gene in asthma and COPD.

Acknowledgments

Funding: This work was supported by the National Natural Science Foundation of China (No. 81970025, No. 81470229, and No. 81170040).

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-22-820/rc

Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-22-820/dss

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-22-820/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-22-820/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The research protocol was reviewed and approved by the Ethics Committee for Human Research of Peking Union Medical College Hospital (S-767) and Beijing Aviation General Hospital (MHZYY 2014-05-01) and informed written consent was obtained from all participants.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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