Association of the CFTR gene with asthma and airway mucus hypersecretion

Abstract

Introduction Asthma with airway mucus hypersecretion is an inadequately characterized variant of asthma. While several studies have reported that hypersecreting patients may carry genetic variants in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, many of those studies have been questioned for their numerous limitations and contradictory results. Objectives (1) To determine the presence of genetic variants of the CFTR gene in patients with asthma with and without airway mucus hypersecretion. (2) To identify the clinical, inflammatory and functional characteristics of the asthma phenotype with airway mucus hypersecretion. Method Comparative multicentre cross-sectional descriptive study that included 100 patients with asthma (39 hypersecretors and 61 non-hypersecretors). Asthmatic hypersecretion was defined as the presence of cough productive of sputum on most days for at least 3 months in 2 successive years. The patients were tested for fractional exhaled nitric oxide, spirometry, induced sputum cell count, total immunoglobulin E (IgE), peripheral blood eosinophil count, C-reactive protein, blood fibrinogen and blood albumin and underwent a skin prick test. Asthma control and quality of life were assessed by the Asthma Control Test and Mini Asthma Quality of Life questionnaires, respectively. Blood DNA samples were collected from the patients and next-generation sequencing using a MiSeq sequencer and the Illumina platform was used for the CFTR gene analysis. Results Genetic differences were observed in the c.1680-870T>A polymorphism of the CFTR gene, significantly more evident in hypersecretors than in non-hypersecretors: 78.94% vs. 59.32% in the majority allele and 21.05% vs. 40.67% in the minority allele (p = 0.036). Clinically, asthma hypersecretors compared to non-hypersecretors were older (57.4 years vs. 49.4 years; p = 0.004); had greater asthma severity (58.9% vs. 23.7%; p = 0.005); experienced greater airway obstruction (FEV1/FVC% 64.3 vs. 69.5; p = 0.041); had poorer asthma control (60% vs. 29%; p = 0.021); had lower IgE levels (126.4 IU/mL vs. 407.6 IU/mL; p = 0.003); and were less likely to have a positive prick test (37.5% vs. 68.85%; p = 0.011). Conclusion The results suggest that patients with asthma and with mucus hypersecretion (1) may have a different phenotype and disease mechanism produced by an intronic polymorphism in the CFTR gene (NM_000492.3:c.1680-870T>A), and (2) may have a poorer clinical outcome characterized by severe disease and poorer asthma control with a non-allergic inflammatory phenotype.

A review of the pathophysiology and the role of ion channels on bronchial asthma

“…These findings were supported by Crespo-Lessmann et al (2021) , who conducted a comparative multicenter cross-sectional descriptive study with 100 asthmatic patients, including those with the classic phenotype of asthma, without hypersecretion, and those with severe asthma (with hypersecretion). They observed that a significant number of these patients had polymorphisms in the CFTR gene, and these mutations coincided with more severe asthma and poorer clinical control.…”

Type 2-High Severe Asthma with and without Bronchiectasis: A Prospective Observational Multicentre Study

“… 40 , 41 The combination of these diseases may lead to a synergistic effect in sputum production. 42 , 43 To this extent, almost 60% of our T2-SA+BE patients reported CMH, often purulent or muco-purulent. The persistent accumulation of mucus can limit airflow, worsen asthma symptoms, trigger asthma exacerbations, and reduce the asthma control with the standard inhaled high dose ICS+LABA, often making chronic OCS intake necessary.…”

“…40,41 The combination of these diseases may lead to a synergistic effect in sputum production. 42,43 To this extent, almost 60% of our T2-SA+BE patients reported CMH, often purulent or muco-purulent. The persistent accumulation of mucus can limit airflow, worsen asthma Figure 2 Differences between Type-2 High Severe Asthma patients with and without Bronchiectasis with regard to chronic rhinosinusitis (A), chronic rhinosinusitis with nasal polyps (B), chronic sputum production (C), chronic oral corticosteroids intake (D) and asthma exacerbations in the previous year (E).…”

The Association between CFTR Gene Mutation Heterozygosity and Asthma Development: A Systematic Review

“…Genetic variants of CFTR gene may be possibly associated with certain asthma phenotypes. Crespo-Lessman et al showed that asthma phenotype with mucus hypersecretion may be related with an intronic polymorphism in the CFTR gene (NM_000492.3:c.1680-870T>A), and these patients may have a poorer clinical outcome characterized by severe disease and poorer asthma control with a non-allergic inflammatory phenotype [ 25 ]. Additionally, CFTR mutations have probably been linked to asthma severity.…”