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 Renzoni 1 ▸ Additional material is published online only. To view please visit the journal online (http://dx.doi.org/10.1136/ thoraxjnl-2012-201786). 1 Interstitial Lung Disease Unit, Royal Brompton Hospital and National Heart and Lung Institute, Imperial College London, London, UK 2 Centre for Rheumatology and Connective Tissue Diseases, University College London Medical School, London, UK 3 Clinical Trials and Evaluation Unit, Royal Brompton and Harefield NHS Foundation Trust, London, UK 4 Department of Radiology, Royal Brompton Hospital and National Heart and Lung Institute, Imperial College London, London, UK 5 Histopathology Department, Royal Brompton Hospital and National Heart and Lung Institute, Imperial College London, London, UK Correspondence to Carmel Stock, Interstitial Lung Disease Unit, Royal Brompton Hospital and National Heart and Lung Institute, Imperial College London, Emmanuel Kaye Building, 1B Manresa Road, London SW3 6LR, UK; c.stock@imperial.ac.uk Received 17 February 2012 Revised 21 November 2012 Accepted 20 December 2012 Published Online First 15 January 2013 To cite: Stock CJ, Sato H, Fonseca C, et al. Thorax 2013;68:436–441. ABSTRACT Background A polymorphism (rs35705950) 3 kb upstream of MUC5B, the gene encoding Mucin 5 subtype B, has been shown to be associated with familial and sporadic idiopathic pulmonary fibrosis (IPF). We set out to verify whether this variant is also a risk factor for fibrotic lung disease in other settings and to confirm the published findings in a UK Caucasian IPF population. Methods Caucasian UK healthy controls (n=416) and patients with IPF (n=110), sarcoidosis (n=180) and systemic sclerosis (SSc) (n=440) were genotyped to test for association. The SSc and sarcoidosis cohorts were subdivided according to the presence or absence of fibrotic lung disease. To assess correlation with disease progression, time to decline in forced vital capacity and/ or lung carbon monoxide transfer factor was used in the IPF and SSc groups, while a persistent decline at 4 years since baseline was evaluated in patients with sarcoidosis. Results A significant association of the MUC5B promoter single nucleotide polymorphism with IPF ( p=2.04×10 –17 ; OR 4.90, 95% CI 3.42 to 7.03) was confirmed in this UK population. The MUC5B variant was not a risk factor for lung fibrosis in patients with SSc or sarcoidosis and did not predict more rapidly progressive lung disease in any of the groups. Rather, a trend for a longer time to decline in forced vital capacity was observed in patients with IPF. Conclusions We confirm the MUC5B variant association with IPF. We did not observe an association with lung fibrosis in the context of SSc or sarcoidosis, potentially highlighting fundamental differences in genetic susceptibility, although the limited subgroup numbers do not allow a definitive exclusion of an association. INTRODUCTION A single nucleotide polymorphism (SNP) (rs35705950) located 3 kb upstream of the tran- scriptional start site of MUC5B, the gene encoding Mucin 5 subtype B, has been shown to be strongly associated with both familial interstitial pneumo- nia 1 and sporadic idiopathic pulmonary fibrosis (IPF) in US populations. 1 2 MUC5B is a gel- forming mucin and a major component of mucus in the respiratory tract. 3 The IPF-associated SNP is located within a region highly conserved across ver- tebrate species and, based on a prediction algo- rithm, is potentially involved in gene regulation. 4 By playing important roles in airway mucus rhe- ology 5 and mucosal immune defence, 6 MUC5B is essential in protecting the surface epithelium of the airways. MUC5B overexpression was observed in IPF lungs, with patchy staining of the epithelial cells lining honeycomb cysts. 1 Although the mechanisms through which MUC5B dysregulation plays a part in the development of IPF are currently unknown, the strength of the genetic association ▸ http://dx.doi.org/10.1136/ thoraxjnl-2012-202957 Editor's choice Scan to access more free content Key messages What is the key question? ▸ Is the MUC5B rs35705950 polymorphism, recently reported as strongly associated with idiopathic pulmonary fibrosis, a risk factor for lung fibrosis in the context of systemic sclerosis and sarcoidosis? What is the bottom line? ▸ In our Caucasian UK based cohorts, we confirm a significant association of the MUC5B variant with idiopathic pulmonary fibrosis. By contrast, we found no significant association with lung fibrosis in the context of systemic sclerosis or sarcoidosis, although fibrotic subgroup numbers may have resulted in insufficient power to detect an association, especially if less pronounced than in IPF. Why read on? ▸ The lack of an association with lung fibrosis in the context of systemic sclerosis and sarcoidosis suggests that the MUC5B variant is associated with an idiopathic pulmonary fibrosis-specific pathway, differing from SSc- and sarcoidosis-associated lung fibrosis which are likely to have distinct genetic and pathogenetic risk factors. 436 Stock CJ, et al. Thorax 2013;68:436–441. doi:10.1136/thoraxjnl-2012-201786 Interstitial lung disease group.bmj.com on February 8, 2016 - Published by http://thorax.bmj.com/ Downloaded from