Genome-wide association study of chronic sputum production implicates loci involved in mucus production and infection

Packer, Richard; Shrine, Nick; Hall, Robert J.; Melbourne, Carl; Thompson, Rebecca; Williams, Alex T.; Paynton, Megan L.; Guyatt, Anna L; Lee, Paul H.; John, Catherine; Campbell, Archie; Hayward, Caroline; Vries, Maaike de; Vonk, Judith M.; Davitte, Jonathan; Hessel, Edith M.; Michalovich, David; Betts, Joanna; Sayers, Ian; Yeo, Astrid; Hall, Ian P.; Tobin, Martin D.; Wain, Louise V.

doi:10.1183/13993003.01667-2022

Cited by 6 publications

(9 citation statements)

References 91 publications

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“…A role for FUT2 is supported by findings in Fut2 gene disrupted mice that lack fucosylated airway mucins and are protected from AHR and airway mucus plugging (see Figures 3-5). These findings provide a translational link to prior reports showing associations between mucin fucosylation in human asthma and animal models (13,21,22) FUT2 and mucin gene loci are linked to chronic sputum production (23), and people with asthma who lack FUT2 are protected from severe exacerbations (13). Over extended periods, these could be explained by effects on host defense and inflammation, which are complex and are likely both organism and tissue specific.…”

Section: Discussionsupporting

confidence: 74%

Requirement for Fucosyltransferase 2 in Allergic Airway Hyperreactivity and Mucus Obstruction

Hara,

Raclawska,

Morgan

et al. 2024

Preprint

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Mucus hypersecretion is an important pathological problem in respiratory diseases. Mucus accumulates in the airways of people with asthma, and it contributes to airflow limitation by forming plugs that occlude airways. Current treatments have minimal effects on mucus or its chief components, the polymeric mucin glycoproteins MUC5AC and MUC5B. This treatment gap reflects a poor molecular understanding of mucins that could be used to determine how they contribute to airway obstruction. Due to the prominence of glycosylation as a defining characteristic of mucins, we investigated characteristics of mucin glycans in asthma and in a mouse model of allergic asthma. Mucin fucosylation was observed in asthma, and in healthy mice it was induced as part of a mucous metaplastic response to allergic inflammation. In allergically inflamed mouse airways, mucin fucosylation was dependent on the enzyme fucosyltransferase 2 (Fut2). Fut2 gene deficient mice were protected from asthma-like airway hyperreactivity and mucus plugging. These findings provide mechanistic and translational links between observations in human asthma and a mouse model, which can help in therapeutic targeting of airway mucus.

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Section: Discussionsupporting

confidence: 74%

Requirement for Fucosyltransferase 2 in Allergic Airway Hyperreactivity and Mucus Obstruction

Hara,

Raclawska,

Morgan

et al. 2024

Preprint

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“…The UK Biobank analysis, while supportive of our results, did not have the same degree of detailed respiratory phenotypes and was performed in a general population sample. Additional analyses adjusting for disease state and other covariates could be beneficial [ 27 ]. Further attempts to replicate these finding in other populations would also be useful, in particular to address the question of generalizability across populations of different genetic ancestries.…”

Section: Discussionmentioning

confidence: 99%

“…While we examined associations between loci associated with mucins, CB, and AE in COPD patients specifically, others have examined the genetics of CB/chronic mucin hypersecretion in combined analysis of the general population and patients with COPD [ 27 , 29 ] or in smokers without COPD [ 30 ]. In the study with COPD cases and the general population [ 29 ], the most consistent association signal was for rs6577641, which was also shown to act as an eQTL for the gene SATB1 .…”

Section: Discussionmentioning

confidence: 99%

“…In look up analysis, this variant was not associated with either sputum MUC5B concentration or CB in the SPIROMICS population, nor was the lead variant (rs10461985) from another study [ 30 ]. The most recent study reported an association of variants on proximal Chr 11 (near MUC2 ) with chronic sputum production using the same UK Biobank phenotype codes we used [ 27 ], but the LD between lead variant in that study (rs779167905) and rs140324259 is minimal (R 2 = 0.08), making it unlikely that these are the same signals.…”

Section: Discussionmentioning

confidence: 99%

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Genetic regulators of sputum mucin concentration and their associations with COPD phenotypes

et al. 2023

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Hyper-secretion and/or hyper-concentration of mucus is a defining feature of multiple obstructive lung diseases, including chronic obstructive pulmonary disease (COPD). Mucus itself is composed of a mixture of water, ions, salt and proteins, of which the gel-forming mucins, MUC5AC and MUC5B, are the most abundant. Recent studies have linked the concentrations of these proteins in sputum to COPD phenotypes, including chronic bronchitis (CB) and acute exacerbations (AE). We sought to determine whether common genetic variants influence sputum mucin concentrations and whether these variants are also associated with COPD phenotypes, specifically CB and AE. We performed a GWAS to identify quantitative trait loci for sputum mucin protein concentration (pQTL) in the Sub-Populations and InteRmediate Outcome Measures in COPD Study (SPIROMICS, n = 708 for total mucin, n = 215 for MUC5AC, MUC5B). Subsequently, we tested for associations of mucin pQTL with CB and AE using regression modeling (n = 822–1300). Replication analysis was conducted using data from COPDGene (n = 5740) and by examining results from the UK Biobank. We identified one genome-wide significant pQTL for MUC5AC (rs75401036) and two for MUC5B (rs140324259, rs10001928). The strongest association for MUC5B, with rs140324259 on chromosome 11, explained 14% of variation in sputum MUC5B. Despite being associated with lower MUC5B, the C allele of rs140324259 conferred increased risk of CB (odds ratio (OR) = 1.42; 95% confidence interval (CI): 1.10–1.80) as well as AE ascertained over three years of follow up (OR = 1.41; 95% CI: 1.02–1.94). Associations between rs140324259 and CB or AE did not replicate in COPDGene. However, in the UK Biobank, rs140324259 was associated with phenotypes that define CB, namely chronic mucus production and cough, again with the C allele conferring increased risk. We conclude that sputum MUC5AC and MUC5B concentrations are associated with common genetic variants, and the top locus for MUC5B may influence COPD phenotypes, in particular CB.

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“…Tobacco smoking induces MUC5AC expression and MUC5AC expression is elevated in the airways of patients with chronic obstructive pulmonary disease (COPD) (16). Variants in MUC5AC have been associated with chronic sputum production (17), asthma (18) and pulmonary fibrosis (19). Forkhead box protein J1 (FOXJ1) is a transcription factor involved in the late stages of ciliogenesis and, in the airways, is expressed uniquely by multiciliated cells (20).…”

Section: Introductionmentioning

confidence: 99%

A lentiviral toolkit to monitor airway epithelial cell differentiation using bioluminescence

Orr,

Laali,

Durrenberger

et al. 2024

Preprint

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Basal cells are adult stem cells in the airway epithelium and regenerate differentiated cell populations, including the mucosecretory and ciliated cells that enact mucociliary clearance. Human airway basal cells can proliferate and produce differentiated epitheliumin vitro. However, studies of airway epithelial differentiation mostly rely on immunohistochemical or immunofluorescence-based staining approaches, meaning that a quantitative approach is lacking. Here, we use a lentiviral reporter gene approach to transduce primary human basal cells with bioluminescence-based reporter constructs to monitor airway epithelial differentiation longitudinally. We generated three constructs driven by promoter sequences from theTP63,MUC5ACandFOXJ1genes to quantitatively assess basal cell, ciliated cell and mucosecretory cell abundance, respectively. We validated these constructs by tracking differentiation of basal cells in air-liquid interface and organoid (‘bronchosphere’) cultures. Transduced cells also responded appropriately to stimulation with interleukin 13 (IL-13; to increase mucosecretory differentiation and mucus production) and IL-6 (to increase ciliated cell differentiation). We anticipate that these constructs will be a valuable resource for researchers monitoring airway epithelial cell differentiation in primary epithelial and/or induced pluripotent stem cell (iPSC) cell cultures.Graphical Abstract

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Genome-wide association study of chronic sputum production implicates loci involved in mucus production and infection

Cited by 6 publications

References 91 publications

Requirement for Fucosyltransferase 2 in Allergic Airway Hyperreactivity and Mucus Obstruction

Requirement for Fucosyltransferase 2 in Allergic Airway Hyperreactivity and Mucus Obstruction

Genetic regulators of sputum mucin concentration and their associations with COPD phenotypes

A lentiviral toolkit to monitor airway epithelial cell differentiation using bioluminescence

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