Towards clinical significance of the <i>MUC5B</i> promoter variant and risk of rheumatoid arthritis-associated interstitial lung disease

Sparks, Jeffrey A

doi:10.1136/annrheumdis-2021-220856

Cited by 5 publications

(6 citation statements)

References 18 publications

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“…Of note, a similar magnitude of association was reported in individuals with interstitial lung abnormalities and without RA (35). Our findings are in good agreement with the results of the FinnGen epidemiologic cohort (19) and support a pivotal role of the MUC5B rs35705950 variant for both clinical and subclinical RA-ILD risk stratification and add to the possible interest for genotyping the risk variant in future clinical practice (36).…”

Section: Discussionsupporting

confidence: 88%

A Risk Score to Detect Subclinical Rheumatoid Arthritis–Associated Interstitial Lung Disease

Juge

Granger

Debray

et al. 2022

Arthritis & Rheumatology

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Objective Patients at high risk of rheumatoid arthritis–associated interstitial lung disease (RA‐ILD) would benefit from being identified before the onset of respiratory symptoms; this can be done by screening patients with the use of chest high‐resolution computed tomography (HRCT). Our objective was to develop and validate a risk score for patients who have subclinical RA‐ILD. Methods Our study included a discovery population and a replication population from 2 prospective RA cohorts (ESPOIR and TRANSLATE2, respectively) without pulmonary symptoms who had received chest HRCT scans. All patients were genotyped for MUC5B rs35705950. After multiple logistic regression, a risk score based on independent risk factors for subclinical RA‐ILD was developed in the discovery population and tested for validation in the replication population. Results The discovery population included 163 patients with RA, and the replication population included 89 patients with RA. The prevalence of subclinical RA‐ILD was 19.0% and 16.9%, respectively. In the discovery population, independent risk factors for subclinical RA‐ILD were presence of the MUC5B rs35705950 T allele (odds ratio [OR] 3.74 [95% confidence interval (95% CI) 1.37, 10.39]), male sex (OR 3.93 [95% CI 1.40, 11.39]), older age at RA onset (for each year, OR 1.10 [95% CI 1.04, 1.16]), and increased mean Disease Activity Score in 28 joints using the erythrocyte sedimentation rate (for each unit, OR 2.03 [95% CI 1.24, 3.42]). We developed and validated a derived risk score with receiver operating characteristic areas under the curve of 0.82 (95% CI 0.70–0.94) for the discovery population and 0.78 (95% CI 0.65–0.92) for the replication population. Excluding MUC5B rs35705950 from the model provided a lower goodness of fit (likelihood ratio test, P = 0.01). Conclusion We developed and validated a risk score that could help identify patients at high risk of subclinical RA‐ILD. Our findings support an important contribution of MUC5B rs35705950 to subclinical RA‐ILD risk.

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Section: Discussionsupporting

confidence: 88%

A Risk Score to Detect Subclinical Rheumatoid Arthritis–Associated Interstitial Lung Disease

Juge

Granger

Debray

et al. 2022

Arthritis & Rheumatology

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“…People with the MUC5B promoter variant produce higher quantities of MUC 5B in lung parenchyma and airways. The mechanisms that linking the MUC5B promoter variant with IPF risk are still under investigation, the relative overabundance of the MUC5B protein may lead to local recruitment of immune cells that leads to long-term damage and lung fibrosis [14].…”

Section: Discussionmentioning

confidence: 99%

MUC5B Mutation Causes Mucociliary Dysfunction and Primary Ciliary Dyskinesia Like Illness in a Saudi Girl: A Case Report

Mukhtar G,

Alzaid M,

Alsadoon H

et al. 2023

ACMCR

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1.1. Background: MUC5B is a major gel forming mucin in the lung that plays a key role in mucociliary clearance and host defense that is secreted from proximal submucosal glands and distal airway secretory cells. The MUC5B promoter variant is associated with enhanced expression of the MUC5B transcript in lung tissue from unaffected subjects and patients with idiopathic pulmonary fibrosis (IPF). In patients with IPF, excess MUC5B protein is especially observed in epithelial cells in the respiratory bronchiole and honeycomb cysts, regions of lung involved in lung fibrosis. However, it remains unclear how MUC5B leads to the development of IPF in adult. In mice, MUC5B is required for mucociliary clearance and for controlling inflammation after microbial exposure. The consequences of its loss in humans are unclear, however MUC5B homozygous variant has recently been reported in two affected siblings.

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“…The mortality associated with SSc, pSS, and DM with ILD is significantly higher than in CTDs without ILD ( 23 , 25 , 26 ). Although disease severity has been linked with SNPs in the promoter region of MUC5AC and MUC5B, which are the most abundant airway mucins ( 7 , 9 – 12 ), and MUC5AC protein levels in BALF ( 27 ), there have been no reports on the serum levels of MUC5AC and MUC5B in CTD-ILD patients.…”

Section: Discussionmentioning

confidence: 99%

“…The pathophysiology of CTD-ILD is unclear but genetic factors are thought to play an essential role in its development ( 8 ). Previous studies have demonstrated a strong relationship between ILDs and single nucleotide polymorphisms (SNPs) in the promoter regions of mucin 5B (MUC5B) ( 7 , 9 – 11 ) and mucin 5AC (MUC5AC) ( 12 ). MUC5AC and MUC5B, which account for approximately 90% of the mucoproteins ( 13 ), play a crucial role in the respiratory mucosal defense arsenal.…”

Section: Introductionmentioning

confidence: 99%

Serum MUC5AC protein levels are correlated with the development and severity of connective tissue disease-associated pulmonary interstitial lesions

Lin

Liu²,

Wang³

et al. 2022

Front. Immunol.

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Background: Mucin 5AC (MUC5AC) and mucin 5B (MUC5B) are the major components of airway mucins. The expression levels of MUC5AC and MUC5B are related to connective tissue disease-associated interstitial lung disease (CTD-ILD) in the promoter region of MUC5AC and MUC5B and the relevant bronchoalveolar lavage fluid. However, the serum protein levels of MUC5AC and MUC5B have not been tested in CTD-ILD patients. In this study, we tested the serum levels of MUC5AC and MUC5B proteins in CTD-ILD patients and assessed their relationship with the occurrence and development of ILD.Methods: Serum samples were obtained from 168 CTD and 80 healthy participants from the First Affiliated Hospital of Xiamen University. The serum levels of MUC5AC and MUC5B proteins were measured by enzyme-linked immunosorbent assay.Results: Of the 168 individuals with CTD, 70 had primary Sjögren's syndrome (pSS), 64 had systemic sclerosis (SSc), and 34 had polymyositis/ dermatomyositis (PM/DM). There were 116 cases with concurrent ILD; ILD scores were 1 (n=23), 2 (n=41), and 3 (n=52). Serum MUC5AC and MUC5B protein levels were considerably higher in CTD-ILD than CTD-only individuals or healthy controls (both p<0.005). Among the CTD subgroups, MUC5AC was higher in individuals with concurrent ILD than in those without ILD (all p<0.05). MUC5AC was positively correlated with ILD severity in all three CTD subgroups (all R>0.47 and all p<0.05). The MUC5B levels varied substantially between SSc Frontiers in Immunology frontiersin.org 01

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Towards clinical significance of the MUC5B promoter variant and risk of rheumatoid arthritis-associated interstitial lung disease

Cited by 5 publications

References 18 publications

A Risk Score to Detect Subclinical Rheumatoid Arthritis–Associated Interstitial Lung Disease

A Risk Score to Detect Subclinical Rheumatoid Arthritis–Associated Interstitial Lung Disease

MUC5B Mutation Causes Mucociliary Dysfunction and Primary Ciliary Dyskinesia Like Illness in a Saudi Girl: A Case Report

Serum MUC5AC protein levels are correlated with the development and severity of connective tissue disease-associated pulmonary interstitial lesions

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