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Mucin 5B Promoter Polymorphism Is Associated with Idiopathic

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Mucin 5B Promoter Polymorphism Is Associated with Idiopathic Thorax Online First, published on January 15, 2013 as 10.1136/thoraxjnl-2012-201786 Interstitial lung disease Thorax: first published as 10.1136/thoraxjnl-2012-201786 on 15 January 2013. Downloaded from ORIGINAL ARTICLE Mucin 5B promoter polymorphism is associated with idiopathic pulmonary fibrosis but not with development of lung fibrosis in systemic sclerosis or sarcoidosis Carmel J Stock,1 Hiroe Sato,1 Carmen Fonseca,2 Winston A S Banya,3 Philip L Molyneaux,1 Huzaifa Adamali,1 Anne-Marie Russell,1 Christopher P Denton,2 David J Abraham,2 David M Hansell,4 Andrew G Nicholson,5 Toby M Maher,1 Athol U Wells,1 Gisela E Lindahl,1 Elisabetta A Renzoni1 ▸ Additional material is ABSTRACT published online only. To view Background A polymorphism (rs35705950) 3 kb Key messages please visit the journal online (http://dx.doi.org/10.1136/ upstream of MUC5B, the gene encoding Mucin 5 thoraxjnl-2012-201786). subtype B, has been shown to be associated with familial and sporadic idiopathic pulmonary fibrosis (IPF). 1Interstitial Lung Disease Unit, What is the key question? Royal Brompton Hospital and We set out to verify whether this variant is also a risk ▸ Is the MUC5B rs35705950 polymorphism, National Heart and Lung factor for fibrotic lung disease in other settings and to recently reported as strongly associated with Institute, Imperial College confirm the published findings in a UK Caucasian IPF idiopathic pulmonary fibrosis, a risk factor for London, London, UK population. lung fibrosis in the context of systemic sclerosis 2Centre for Rheumatology and Connective Tissue Diseases, Methods Caucasian UK healthy controls (n=416) and and sarcoidosis? University College London patients with IPF (n=110), sarcoidosis (n=180) and Medical School, London, UK systemic sclerosis (SSc) (n=440) were genotyped to test What is the bottom line? 3Clinical Trials and Evaluation for association. The SSc and sarcoidosis cohorts were ▸ In our Caucasian UK based cohorts, we confirm Unit, Royal Brompton and subdivided according to the presence or absence of a significant association of the MUC5B variant Harefield NHS Foundation fibrotic lung disease. To assess correlation with disease with idiopathic pulmonary fibrosis. By contrast, Trust, London, UK fi 4Department of Radiology, progression, time to decline in forced vital capacity and/ we found no signi cant association with lung fi Royal Brompton Hospital and or lung carbon monoxide transfer factor was used in the brosis in the context of systemic sclerosis or fi National Heart and Lung IPF and SSc groups, while a persistent decline at 4 years sarcoidosis, although brotic subgroup http://thorax.bmj.com/ Institute, Imperial College since baseline was evaluated in patients with sarcoidosis. numbers may have resulted in insufficient London, London, UK power to detect an association, especially if 5Histopathology Department, Results A significant association of the MUC5B Royal Brompton Hospital and promoter single nucleotide polymorphism with IPF less pronounced than in IPF. National Heart and Lung (p=2.04×10–17; OR 4.90, 95% CI 3.42 to 7.03) was Institute, Imperial College Why read on? confirmed in this UK population. The MUC5B variant ▸ fi London, London, UK fi The lack of an association with lung brosis in was not a risk factor for lung brosis in patients with the context of systemic sclerosis and sarcoidosis Correspondence to SSc or sarcoidosis and did not predict more rapidly suggests that the MUC5B variant is associated Carmel Stock, Interstitial Lung on October 2, 2021 by guest. Protected copyright. progressive lung disease in any of the groups. Rather, a with an idiopathic pulmonary fibrosis-specific Disease Unit, Royal Brompton trend for a longer time to decline in forced vital capacity Hospital and National Heart pathway, differing from SSc- and was observed in patients with IPF. fi and Lung Institute, Imperial fi sarcoidosis-associated lung brosis which are College London, Emmanuel Conclusions We con rm the MUC5B variant likely to have distinct genetic and pathogenetic Kaye Building, 1B Manresa association with IPF. We did not observe an association risk factors. Road, London SW3 6LR, UK; with lung fibrosis in the context of SSc or sarcoidosis, [email protected] potentially highlighting fundamental differences in Received 17 February 2012 genetic susceptibility, although the limited subgroup numbers do not allow a definitive exclusion of an Revised 21 November 2012 in the respiratory tract.3 The IPF-associated SNP is Accepted 20 December 2012 association. located within a region highly conserved across ver- tebrate species and, based on a prediction algo- rithm, is potentially involved in gene regulation.4 INTRODUCTION By playing important roles in airway mucus rhe- A single nucleotide polymorphism (SNP) ology5 and mucosal immune defence,6 MUC5B is (rs35705950) located 3 kb upstream of the tran- essential in protecting the surface epithelium of the scriptional start site of MUC5B, the gene encoding airways. MUC5B overexpression was observed in To cite: Stock CJ, Sato H, Mucin 5 subtype B, has been shown to be strongly IPF lungs, with patchy staining of the epithelial Fonseca C, et al. Thorax 1 Published Online First: associated with both familial interstitial pneumo- cells lining honeycomb cysts. Although the [Please include Day Month nia1 and sporadic idiopathic pulmonary fibrosis mechanisms through which MUC5B dysregulation Year] doi:10.1136/thoraxjnl- (IPF) in US populations.12MUC5B is a gel- plays a part in the development of IPF are currently 2012-201786 forming mucin and a major component of mucus unknown, the strength of the genetic association CopyrightStock CJ, et alArticle. Thorax 2013; author0:1–6. (or doi:10.1136/thoraxjnl-2012-201786 their employer) 2013. Produced by BMJ Publishing Group Ltd (& BTS) under licence.1 Interstitial lung disease Thorax: first published as 10.1136/thoraxjnl-2012-201786 on 15 January 2013. Downloaded from suggests a pathogenetic role of mucins and/or mucin-producing Mann–Whitney U test), suggesting there was not a significant cells which was hitherto unsuspected. However, whether the imbalance between prevalent/incident cases according to MUC5B variant is a prognostic marker of IPF is currently MUC5B allele carriage. unknown. Fibrotic lung disease occurs in a large proportion of patients Clinical assessment with systemic sclerosis (SSc) and, together with pulmonary Pulmonary function tests and high-resolution CT (HRCT) were hypertension, represents the main cause of death in these performed as previously reported.23 All investigations were per- patients.7 In sarcoidosis the development of irreversible lung formed as part of a prospective routine clinical protocol. fibrosis, seen in 10–20% of patients, is associated with poorer Pulmonary function tests (expressed as percent predicted) from quality of life, the need for long-term treatment and a worse the time of first presentation at the Royal Brompton Hospital prognosis.8 A small number of genes associated with the devel- were available for patients with IPF (n=107), SSc-ILD (n=206) opment of lung fibrosis in the context of SSc9 or of sarcoid- and sarcoidosis (n=178). Among patients with SSc, ILD was – osis10 12 have been reported, highlighting a genetic component defined as a forced vital capacity (FVC) <75% and/or the pres- likely to involve several genes with small individual effects. ence of fibrosis on chest imaging (chest x-ray or HRCT). Although SSc-associated interstitial lung disease (SSc-ILD) and Patients with SSc were also classified into autoantibody sub- pulmonary sarcoidosis differ from IPF in many respects, includ- groups by previously described standard methods.24 25 The ing better survival for equivalent disease severity,13 there are patients with SSc for whom antibody status was known many similarities in the fibrotic process and alveolar epithelium (n=417) were grouped according to status for the two most abnormalities occur in all three diseases. In particular, the mem- common antibodies found in the cohort, anti-DNA topoisomer- brane tethered mucin MUC1 (also known as KL-6), a member ase 1 antibodies (ATA), which is known to be tightly linked to of the mucin family expressed by type II alveolar epithelial cells, the presence of ILD, and anti-centromere antibodies (ACA), has been suggested as a biomarker for disease activity in IPF,14 which is associated with limited skin disease and pulmonary pulmonary sarcoidosis15 and SSc-ILD,16 17 although large pro- hypertension but protective for ILD.26 spective studies are yet to be performed. We therefore investi- gated whether the MUC5B polymorphism increased the risk of Quantification of disease severity and progression lung fibrosis in the context of SSc and sarcoidosis and set out to in IPF and SSc-ILD confirm the reported association with IPF. We also assessed The composite physiological index (CPI), a functional index of whether this polymorphism was associated with the severity of disease severity, was calculated as: CPI=91.0−(0.65×TLCO% lung fibrosis and the likelihood of disease progression in the predicted)− (0.53×FVC% predicted)+(0.34×FEV1%pre- three fibrotic lung diseases. dicted), where TLCO is lung carbon monoxide transfer factor, and was used as a marker of lung disease severity in patients MATERIALS AND METHODS with IPF and SSc-ILD.27 Study populations Time to decline was quantified using serial pulmonary func- DNA samples were collected from consecutive newly presenting tional indices starting from first presentation to the Royal patients with IPF (n=110) and sarcoidosis
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