Nasal airway transcriptome-wide association study of asthma reveals genetically driven mucus pathobiology

Sajuthi, Satria; Jackson, Nathan D.; Saef, Benjamin; Rios, Cydney; Moore, Camille M.; Mak, Angel C. Y.; Eng, Celeste; Fairbanks-Mahnke, Ana; Salazar, Sandra; Elhawary, Jennifer R.; Huntsman, Scott; Medina, Vivian; Nickerson, Deborah A.; Germer, Søren; Zody, Michael C.; Abecasis, Gonçalo R.; Kang, Hyun Min; Rice, Ken; Kumar, Rajesh; Zaitlen, Noah; Oh, Sam S.; Rodríguez‐Santana, José; Burchard, Esteban G.; Seibold, Max A.

doi:10.1038/s41467-022-28973-7

Cited by 32 publications

(32 citation statements)

References 91 publications

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“…Recently, CRABP2 was shown to be increased in IPF airway cells [26]. In accord with mucin biogenesis, anterior gradient homolog 2 ( AGR2 ) has been shown to be essential for MUC2 production and FK506-binding protein 11 ( FKBP11 ) has been demonstrated to have a mucin secretory function [27]. Both AGR2 and FKBP11 are increased in the fibrotic HC airway cells.…”

Section: Resultsmentioning

confidence: 99%

The UIP honeycomb airway cells are the site of mucin biogenesis with deranged cilia

Herrera

Dingle

Montero

et al. 2022

Preprint

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Honeycombing (HC) is a histological pattern consistent with Usual Interstitial Pneumonia (UIP). HC refers to cystic airways (HC airways) located at sites of dense fibrosis with marked mucus accumulation. Utilizing laser capture microdissection coupled mass spectrometry (LCM-MS), we interrogated the fibrotic HC airway cells and fibrotic uninvolved airway cells (distant from sites of UIP and morphologically intact) in 10 UIP specimens; 6 non-fibrotic airway cell specimens served as controls. Furthermore, we performed LCM-MS on the mucus plugs found in 6 UIP and 6 mucinous adenocarcinoma (MA) specimens. The mass spectrometry data were subject to both qualitative and quantitative analysis and validated by immunohistochemistry. Surprisingly, fibrotic uninvolved airway cells share a similar protein profile to HC airway cells, showing deregulation of SLITs and ROBO pathway as the strongest category. We find that BPIFB1 is the most significantly increased secretome-associated protein in UIP, whereas MUC5AC is the most significantly increased in MA. We conclude that spatial proteomics demonstrates that the fibrotic uninvolved airway cells are abnormal. In addition, fibrotic HC airway cells are enriched in mucin biogenesis proteins with a marked derangement in proteins essential for ciliogenesis. This unbiased spatial proteomic approach will generate novel and testable hypotheses to decipher fibrosis progression.

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Section: Resultsmentioning

confidence: 99%

The UIP honeycomb airway cells are the site of mucin biogenesis with deranged cilia

Herrera

Dingle

Montero

et al. 2022

Preprint

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“…No other variants in the region were significantly associated with MUC5B expression (FDR = 0.497, Figure S7B). Additionally, rs140324259 was also not associated with MUC5B expression in the nasal epithelium of subjects with cystic fibrosis [16] or asthma [12], nor was it reported as an eQTL in any tissue in the GTEx dataset [17], including homogenized lung tissue.…”

Section: Resultsmentioning

confidence: 99%

Genetic Regulators of Sputum Mucin Concentration and Their Associations with COPD Phenotypes

Buren

Radicioni

Lester

et al. 2022

Preprint

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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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“…Recently, CRABP2 was shown to be increased in IPF airway cells [ 57 ]. In accord with mucin biogenesis, anterior gradient homolog 2 ( AGR2 ) has been shown to be essential for MUC2 production and FK506-binding protein 11 ( FKBP11 ) has been demonstrated to have a mucin secretory function [ 58 ]. Both AGR2 and FKBP11 are increased in the fibrotic honeycomb airway cells.…”

Section: Discussionmentioning

confidence: 99%

Morphologically intact airways in lung fibrosis have an abnormal proteome

et al. 2023

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Honeycombing is a histological pattern consistent with Usual Interstitial Pneumonia (UIP). Honeycombing refers to cystic airways located at sites of dense fibrosis with marked mucus accumulation. Utilizing laser capture microdissection coupled mass spectrometry (LCM-MS), we interrogated the fibrotic honeycomb airway cells and fibrotic uninvolved airway cells (distant from honeycomb airways and morphologically intact) in specimens from 10 patients with UIP. Non-fibrotic airway cell specimens from 6 patients served as controls. Furthermore, we performed LCM-MS on the mucus plugs found in 6 patients with UIP and 6 patients with mucinous adenocarcinoma. The mass spectrometry data were subject to both qualitative and quantitative analysis and validated by immunohistochemistry. Surprisingly, fibrotic uninvolved airway cells share a similar protein profile to honeycomb airway cells, showing deregulation of the slit and roundabout receptor (Slit and Robo) pathway as the strongest category. We find that (BPI) fold-containing family B member 1 (BPIFB1) is the most significantly increased secretome-associated protein in UIP, whereas Mucin-5AC (MUC5AC) is the most significantly increased in mucinous adenocarcinoma. We conclude that fibrotic uninvolved airway cells share pathological features with fibrotic honeycomb airway cells. In addition, fibrotic honeycomb airway cells are enriched in mucin biogenesis proteins with a marked derangement in proteins essential for ciliogenesis. This unbiased spatial proteomic approach generates novel and testable hypotheses to decipher fibrosis progression.

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Nasal airway transcriptome-wide association study of asthma reveals genetically driven mucus pathobiology

Cited by 32 publications

References 91 publications

The UIP honeycomb airway cells are the site of mucin biogenesis with deranged cilia

The UIP honeycomb airway cells are the site of mucin biogenesis with deranged cilia

Genetic Regulators of Sputum Mucin Concentration and Their Associations with COPD Phenotypes

Morphologically intact airways in lung fibrosis have an abnormal proteome

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