BACKGROUND AND OBJECTIVE: The minor T-allele of the MUC5B promoter polymorphism rs35705950 is strongly associated with idiopathic pulmonary fibrosis (IPF). However, conflicting results have been reported on the relationship between the MUC5B minor allele and survival and it is unknown whether a specific subgroup of IPF patients might benefit from MUC5B minor allele carriage. We investigated the association between MUC5B rs35705950, survival and patient characteristics in a real-world population of European IPF patients. METHODS: In this retrospective study, 1751 patients with IPF from 8 European centres were included. MUC5B rs35705950 genotype, demographics, clinical characteristics at diagnosis and survival data were analysed. RESULTS: In a multi-variate Cox proportional hazard model the MUC5B minor allele was a significant independent predictor of survival when adjusted for age, sex, high resolution computed tomography pattern, smoking behaviour and pulmonary function tests in IPF. MUC5B minor allele carriers were significantly older at diagnosis (p = 0.001). The percentage of MUC5B minor allele carriers increased significantly with age from 44% in patients aged <56 year, to 63% in patients aged >75. In IPF patients aged <56, the MUC5B minor allele was not associated with survival. In IPF patients aged ≥56, survival was significantly better for MUC5B minor allele carriers (45 months [CI: 42-49]) compared to non-carriers (29 months [CI: 26-33]; p = 4 × 10-12 ). CONCLUSION: MUC5B minor allele carriage associates with a better median transplant-free survival of 16 months in the European IPF population aged over 56 years. MUC5B genotype status might aid disease prognostication in clinical management of IPF patients.

Center for Interstitial and Rare Lung Diseases Pneumology Department Ruhrlandklinik University Hospital University of Duisburg Essen Essen Germany

Division of Heart and Lungs University Medical Center Utrecht Utrecht the Netherlands

Division of Pulmonology Hannover Medical School and DZL BREATH Hannover Germany

European Reference Network ILD core Network center

Faculty of Medicine and Dentistry Palacky University Pathophysiology Molecular and Translational Medicine Olomouc Czech Republic

Fraunhofer Institute ITEM Hannover Germany

Interstitial Lung Disease Unit Royal Brompton and Harefield Clinical Group Guy's and St Thomas' NHS Foundation Trust London UK

Keck Medicine of University of Southern California Los Angeles California USA

Laboratoire d'excellence INFLAMEX Inserm U1152 Paris France

Margaret Turner Warwick Centre for Fibrosing Lung Disease National Heart and Lung Institute Imperial College London London UK

National Heart and Lung Institute Imperial College London London UK

Service de Pneumologie A Hôpital Bichat Paris France

St Antonius ILD Center of Excellence Department of Clinical Chemistry St Antonius Hospital Nieuwegein the Netherlands

St Antonius ILD Center of Excellence Department of Pulmonology St Antonius Hospital Nieuwegein the Netherlands

Unit for Interstitial Lung Diseases Department of Respiratory Medicine University Hospitals Leuven Belgium

University Hospital Olomouc Experimental Medicine Olomouc Czech Republic

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Raghu G, Remy-Jardin M, Myers JL, Richeldi L, Ryerson CJ, Lederer DJ, et al. Diagnosis of idiopathic pulmonary fibrosis. An official ATS/ERS/JRS/ALAT clinical practice guideline. Am J Respir Crit Care Med. 2018 Sep 1;198(5):e44-68.

Raghu G, Rochwerg B, Zhang Y, Garcia CAC, Azuma A, Behr J, et al. An official ATS/ERS/JRS/ALAT clinical practice guideline: treatment of idiopathic pulmonary fibrosis. An update of the 2011 clinical practice guideline. Am J Respir Crit Care Med. 2015 Jul 15;192(2):e3-19.

Seibold MA, Wise AL, Speer MC, Steele MP, Brown KK, Loyd JE, et al. A common MUC5B promoter polymorphism and pulmonary fibrosis. N Engl J Med. 2011;364:1503-12.

Wu X, Li W, Luo Z, Chen Y. The minor T allele of the MUC5B promoter rs35705950 associated with susceptibility to idiopathic pulmonary fibrosis: a meta-analysis. Sci Rep. 2021 Dec 14;11(1):24007.

Peljto AL, Zhang Y, Fingerlin TE, Ma S-F, Garcia JGN, Richards TJ, et al. Association between the MUC5B promoter polymorphism and survival in patients with idiopathic pulmonary fibrosis. JAMA. 2013 Jun 5;309(21):2232-9.

Biondini D, Cocconcelli E, Bernardinello N, Lorenzoni G, Rigobello C, Lococo S, et al. Prognostic role of MUC5B rs35705950 genotype in patients with idiopathic pulmonary fibrosis (IPF) on antifibrotic treatment. Respir Res. 2021 Dec 1;22(1):98.

Van Der Vis JJ, Snetselaar R, Kazemier KM, Ten Klooster L, Grutters JC, Van Moorsel CHM. Effect of Muc5b promoter polymorphism on disease predisposition and survival in idiopathic interstitial pneumonias. Respirology. 2016 May 1;21(4):712-7.

Bonella F, Campo I, Zorzetto M, Boerner E, Ohshimo S, Theegarten D, et al. Potential clinical utility of MUC5B und TOLLIP single nucleotide polymorphisms (SNPs) in the management of patients with IPF. Orphanet J Rare Dis. 2021;16(1):111.

Stock C, Molyneaux P, Saunders P, Kokosi M, George P, Kouranos V, et al. MUC2 MUC5B and TOLLIP variants: no association with disease progression and survival in an IPF cohort. Eur Respir J. 2020 Sep 7;56(Suppl 64):736.

Doubkova M, Kriegova E, Littnerova S, Schneiderova P, Sterclova M, Bartos V, et al. DSP rs2076295 variants influence nintedanib and pirfenidone outcomes in idiopathic pulmonary fibrosis: a pilot study. Ther Adv Respir Dis. 2021 Jan;13(15):175346662110425.

Dudbridge F, Allen RJ, Sheehan NA, Schmidt AF, Lee JC, Jenkins RG, et al. Adjustment for index event bias in genome-wide association studies of subsequent events. Nat Commun. 2019;10(1):1561.

Raghu G, Collard HR, Egan JJ, Martinez FJ, Behr J, Brown KK, et al. An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med. 2011;183(6):788-824.

Dressen A, Abbas AR, Cabanski C, Reeder J, Ramalingam TR, Neighbors M, et al. Analysis of protein-altering variants in telomerase genes and their association with MUC5B common variant status in patients with idiopathic pulmonary fibrosis: a candidate gene sequencing study. Lancet Respir Med. 2018 Aug 1;6(8):603-14.

Platenburg MGJP, Wiertz IA, van der Vis JJ, Crestani B, Borie R, Dieude P, et al. The MUC5B promoter risk allele for idiopathic pulmonary fibrosis predisposes to asbestosis. Eur Respir J. 2020;55(4):1902361.

Ley B, Newton CA, Arnould I, Elicker BM, Henry TS, Vittinghoff E, et al. The MUC5B promoter polymorphism and telomere length in patients with chronic hypersensitivity pneumonitis: an observational cohort-control study. Lancet Respir Med. 2017 Aug;5(8):639-47.

Newton CA, Oldham JM, Ley B, Anand V, Adegunsoye A, Liu G, et al. Telomere length and genetic variant associations with interstitial lung disease progression and survival. Eur Respir J. 2019 Apr 1;53(4):1801641.

Juge P-A, Solomon JJ, van Moorsel CHM, Garofoli R, Lee JS, Louis-Sydney F, et al. MUC5B promoter variant rs35705950 and rheumatoid arthritis associated interstitial lung disease survival and progression. Semin Arthritis Rheum. 2021 Oct;51(5):996-1004.

Furusawa H, Cardwell JH, Okamoto T, Walts AD, Konigsberg IR, Kurche JS, et al. Chronic hypersensitivity pneumonitis, an interstitial lung disease with distinct molecular signatures. Am J Respir Crit Care Med. 2020 Nov 15;202(10):1430-44.

Palomäki A, FinnGen Rheumatology Clinical Expert Group FRCE, Palotie A, Koskela J, Eklund KK, Pirinen M, et al. Lifetime risk of rheumatoid arthritis-associated interstitial lung disease in MUC5B mutation carriers. Ann Rheum Dis. 2021 Aug 3;80(12):1530-6.

Gally F, Sasse SK, Kurche JS, Gruca MA, Cardwell JH, Okamoto T, et al. The MUC5B-associated variant rs35705950 resides within an enhancer subject to lineage- and disease-dependent epigenetic remodeling. JCI Insight. 2021 Jan 25;6(2):e144294.

Benayoun BA, Pollina EA, Brunet A. Epigenetic regulation of ageing: linking environmental inputs to genomic stability. Nat Rev Mol Cell Biol. 2015 Oct 25;16(10):593-610.

Fadista J, Kraven LM, Karjalainen J, Andrews SJ, Geller F, COVID-19 Host Genetics Initiative, et al. Shared genetic etiology between idiopathic pulmonary fibrosis and COVID-19 severity. EBioMedicine. 2021 Mar;65:103277.

van Moorsel CHM, van der Vis JJ, Duckworth A, Scotton CJ, Benschop C, Ellinghaus D, et al. The MUC5B promoter polymorphism associates with severe COVID-19 in the European population. Front Med. 2021 Nov;23:8.

Grubb BR, Livraghi-Butrico A, Rogers TD, Yin W, Button B, Ostrowski LE. Reduced mucociliary clearance in old mice is associated with a decrease in Muc5b mucin. Am J Physiol Lung Cell Mol Physiol. 2016 Mar 1;310(9):L860-7.

Svartengren M, Falk R, Philipson K. Long-term clearance from small airways decreases with age. Eur Respir J. 2005 Oct;26(4):609-15.

Helling BA, Yang IV. Epigenetics in lung fibrosis: from pathobiology to treatment perspective. Curr Opin Pulm Med. 2015 Jul 1;21(5):454-62.

Borie R, Kannengiesser C, de Fontbrune FS, Gouya L, Nathan N, Crestani B. Management of suspected monogenic lung fibrosis in a specialised centre. Eur Respir Rev. 2017 Jun 30;26(144):160122.

gnomAD browser [Internet]. Available from: https://gnomad.broadinstitute.org/

Dahabreh IJ, Kent DM. Index event bias as an explanation for the paradoxes of recurrence risk research. JAMA. 2011 Feb 23;305(8):822-3.

Ley B, Ryerson CJ, Vittinghoff E, Ryu JH, Tomassetti S, Lee JS, et al. A multidimensional index and staging system for idiopathic pulmonary fibrosis. Ann Intern Med. 2012;156(10):684-95.

Ley B, Collard HR, King TE. Clinical course and prediction of survival in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2011 Feb 15;183(4):431-40.

Chung JH, Peljto AL, Chawla A, Talbert JL, McKean DF, Rho BH, et al. CT imaging phenotypes of pulmonary fibrosis in the MUC5B promoter site polymorphism. Chest. 2016 May 1;149(5):1215-22.