MUC5B Promoter Variant and Rheumatoid Arthritis with Interstitial Lung Disease

Pierre-Antoine Juge¹, Joyce S Lee¹, Esther Ebstein¹, Hiroshi Furukawa¹, Evgenia Dobrinskikh¹, Steven Gazal¹, Caroline Kannengiesser¹, Sébastien Ottaviani¹, Shomi Oka¹, Shigeto Tohma¹, Naoyuki Tsuchiya¹, Jorge Rojas-Serrano¹, Montserrat I González-Pérez¹, Mayra Mejía¹, Ivette Buendía-Roldán¹, Ramcés Falfán-Valencia¹, Enrique Ambrocio-Ortiz¹, Effrosyni Manali¹, Spyros A Papiris¹, Theofanis Karageorgas¹, Dimitrios Boumpas¹, Katarina Antoniou¹, Coline H M van Moorsel¹, Joanne van der Vis¹, Yaël A de Man¹, Jan C Grutters¹, Yaping Wang¹, Raphaël Borie¹, Lidwine Wemeau-Stervinou¹, Benoît Wallaert¹, René-Marc Flipo¹, Hilario Nunes¹, Dominique Valeyre¹, Nathalie Saidenberg-Kermanac'h¹, Marie-Christophe Boissier¹, Sylvain Marchand-Adam¹, Aline Frazier¹, Pascal Richette¹, Yannick Allanore¹, Jean Sibilia¹, Claire Dromer¹, Christophe Richez¹, Thierry Schaeverbeke¹, Huguette Lioté¹, Gabriel Thabut¹, Nadia Nathan¹, Serge Amselem¹, Martin Soubrier¹, Vincent Cottin¹, Annick Clément¹, Kevin Deane¹, Avram D Walts¹, Tasha Fingerlin¹, Aryeh Fischer¹, Jay H Ryu¹, Eric L Matteson¹, Timothy B Niewold¹, Deborah Assayag¹, Andrew Gross¹, Paul Wolters¹, Marvin I Schwarz¹, Michael Holers¹, Joshua J Solomon¹, Tracy Doyle¹, Ivan O Rosas¹, Cornelis Blauwendraat¹, Mike A Nalls¹, Marie-Pierre Debray¹, Catherine Boileau¹, Bruno Crestani¹, David A Schwartz¹, Philippe Dieudé¹

Affiliations

Affiliation

¹ From Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Bichat-Claude Bernard, Departments of Rheumatology (P.-A.J., E.E., S. Ottaviani, P.D.), Genetics (C.K., C. Boileau), Pulmonology A (R.B., B.C.), Pulmonology B (G.T.), and Radiology (M.-P.D.), Département Hospitalo-Universitaire Fibrose Inflammation Remodelage, INSERM Unité Mixte de Recherche (UMR) 1152, Université Paris Diderot (P.-A.J., C.K., R.B., G.T., B.C., P.D.), Arthritis Recherche et Développement (P.-A.J.), AP-HP, Hôpital Lariboisière, Service de Rhumatologie (A. Frazier, P.R.), INSERM, UMR 1132 (P.R.), AP-HP, Hôpital Cochin, Service de Rhumatologie A, and INSERM, Unité 1016, UMR 8104 (Y.A.), AP-HP, Hôpital Tenon, Service de Pneumologie (H.L.), AP-HP, Service de Pneumologie Pédiatrique et Centre de Référence des Maladies Respiratoires Rares, and INSERM UMR S933 (N.N., S.A., A.C.), and AP-HP, Département de Génétique, Hôpital Trousseau (S.A.), Paris, Centre Hospitalier Régional Universitaire (CHRU) de Lille, Service de Pneumologie et Immuno-Allergologie, Centre de Compétence des Maladies Pulmonaires Rares, Fédératif Hospitalo-Universitaire Immune-Mediated Inflammatory Diseases and Targeted Therapies (L.W.-S., B.W.), and Centre Hospitalier Universitaire (CHU) de Lille, Service de Rhumatologie (R.-M.F.), Lille, the Departments of Pulmonology (H.N., D.V.) and Rheumatology (N.S.-K., M.-C.B.), Hôpital Avicenne, AP-HP, INSERM UMR 1125 (N.S.-K., M.-C.B.), and Université Paris 13, Sorbonne Paris Cité (N.S.-K., M.-C.B.), Bobigny, the Department of Pulmonology, CHRU Tours, Tours (S.M.-A.), CHRU de Strasbourg, Service de Rhumatologie, Hôpital de Hautepierre, INSERM UMR S1109, and Laboratoire d'Immuno-Rhumatologie Moléculaire, Centre de Recherche en Histoire des Idées, Fédération de Médecine Translationnelle de Strasbourg, Université de Strasbourg, Strasbourg (J. Sibilia), Service de Pneumologie (C.D.) and Service de Rhumatologie (C.R., T.S.), CHU de Bordeaux, and ImmunoConcEpT, Centre National de la Recherche Scientifique UMR 5164 (C.R., T.S.), Bordeaux, CHU Clermont-Ferrand, Service de Rhumatologie, Institut National de la Recherche Agronomique (INRA), UMR 1019, Unité de Nutrition Humaine, Centre de Recherche en Nutrition Humaine Auvergne, Clermont-Ferrand (M.S.), and Hospices Civils de Lyon, Hôpital Louis Pradel, Centre National de Référence des Maladies Pulmonaires Rares, and INRA, UMR 754, Université Claude Bernard Lyon 1, Lyon, (V.C.) - all in France; the Departments of Medicine (J.S.L., E.D., K.D., A.D.W., A. Fischer, M.I.S., M.H., D.A.S.) and Immunology and Microbiology (D.A.S.), University of Colorado School of Medicine, Aurora, and the Departments of Biomedical Research (T.F.) and Medicine (J.J. Solomon), National Jewish Health, Denver - both in Colorado; the Molecular and Genetic Epidemiology Laboratory, Faculty of Medicine, University of Tsukuba, Tsukuba (H.F., S. Oka, N.T.), and the Clinical Research Center for Allergy and Rheumatology, National Hospital Organization Sagamihara National Hospital, Sagamihara (H.F., S. Oka, S.T.) - both in Japan; the Department of Epidemiology, Harvard T.H. Chan School of Public Health (S.G.), and the Department of Medicine, Brigham and Women's Hospital (T.D., I.O.R.), Boston, and the Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge (S.G.) - all in Massachusetts; the Interstitial Lung Disease and Rheumatology Unit (J.R.-S., M.I.G.-P., M.M., I.B.-R.) and the HLA Laboratory (R.F.-V., E.A.-O.), Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, Mexico City; the 2nd Pulmonary Medicine Department (E.M., S.A.P.) and the Rheumatology and Clinical Immunology Unit, 4th Department of Internal Medicine (T.K., D.B.), University Hospital of Athens "Attikon," National and Kapodistrian University of Athens, Athens, and the Department of Respiratory Medicine and the Laboratory of Molecular and Cellular Pneumonology, Faculty of Medicine, University of Crete, Crete (K.A.) - both in Greece; St. Antonius ILD Center of Excellence, St. Antonius Ziekenhuis, Nieuwegein, the Netherlands (C.H.M.M., J.V., Y.A.M., J.C.G.); the Department of Medical Genetics, Nanjing University School of Medicine, Nanjing, China (Y.W.); the Divisions of Pulmonary and Critical Care Medicine (J.H.R.) and Rheumatology (E.L.M.), Mayo Clinic College of Medicine and Science, Rochester, MN; the Colton Center for Autoimmunity, New York University School of Medicine, New York (T.B.N.); the Department of Medicine, McGill University, Montreal (D.A.); the Department of Medicine, University of California, San Francisco, San Francisco (A.G., P.W.); and Data Tecnica International, Glen Echo, and the Laboratory of Neurogenetics, National Institute on Aging, Bethesda - both in Maryland (C. Blauwendraat, M.A.N.).

PMID: 30345907
PMCID: PMC6371965
DOI: 10.1056/NEJMoa1801562

MUC5B Promoter Variant and Rheumatoid Arthritis with Interstitial Lung Disease

Pierre-Antoine Juge et al. N Engl J Med. 2018.

. 2018 Dec 6;379(23):2209-2219.

doi: 10.1056/NEJMoa1801562. Epub 2018 Oct 20.

Authors

Affiliation

¹ From Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Bichat-Claude Bernard, Departments of Rheumatology (P.-A.J., E.E., S. Ottaviani, P.D.), Genetics (C.K., C. Boileau), Pulmonology A (R.B., B.C.), Pulmonology B (G.T.), and Radiology (M.-P.D.), Département Hospitalo-Universitaire Fibrose Inflammation Remodelage, INSERM Unité Mixte de Recherche (UMR) 1152, Université Paris Diderot (P.-A.J., C.K., R.B., G.T., B.C., P.D.), Arthritis Recherche et Développement (P.-A.J.), AP-HP, Hôpital Lariboisière, Service de Rhumatologie (A. Frazier, P.R.), INSERM, UMR 1132 (P.R.), AP-HP, Hôpital Cochin, Service de Rhumatologie A, and INSERM, Unité 1016, UMR 8104 (Y.A.), AP-HP, Hôpital Tenon, Service de Pneumologie (H.L.), AP-HP, Service de Pneumologie Pédiatrique et Centre de Référence des Maladies Respiratoires Rares, and INSERM UMR S933 (N.N., S.A., A.C.), and AP-HP, Département de Génétique, Hôpital Trousseau (S.A.), Paris, Centre Hospitalier Régional Universitaire (CHRU) de Lille, Service de Pneumologie et Immuno-Allergologie, Centre de Compétence des Maladies Pulmonaires Rares, Fédératif Hospitalo-Universitaire Immune-Mediated Inflammatory Diseases and Targeted Therapies (L.W.-S., B.W.), and Centre Hospitalier Universitaire (CHU) de Lille, Service de Rhumatologie (R.-M.F.), Lille, the Departments of Pulmonology (H.N., D.V.) and Rheumatology (N.S.-K., M.-C.B.), Hôpital Avicenne, AP-HP, INSERM UMR 1125 (N.S.-K., M.-C.B.), and Université Paris 13, Sorbonne Paris Cité (N.S.-K., M.-C.B.), Bobigny, the Department of Pulmonology, CHRU Tours, Tours (S.M.-A.), CHRU de Strasbourg, Service de Rhumatologie, Hôpital de Hautepierre, INSERM UMR S1109, and Laboratoire d'Immuno-Rhumatologie Moléculaire, Centre de Recherche en Histoire des Idées, Fédération de Médecine Translationnelle de Strasbourg, Université de Strasbourg, Strasbourg (J. Sibilia), Service de Pneumologie (C.D.) and Service de Rhumatologie (C.R., T.S.), CHU de Bordeaux, and ImmunoConcEpT, Centre National de la Recherche Scientifique UMR 5164 (C.R., T.S.), Bordeaux, CHU Clermont-Ferrand, Service de Rhumatologie, Institut National de la Recherche Agronomique (INRA), UMR 1019, Unité de Nutrition Humaine, Centre de Recherche en Nutrition Humaine Auvergne, Clermont-Ferrand (M.S.), and Hospices Civils de Lyon, Hôpital Louis Pradel, Centre National de Référence des Maladies Pulmonaires Rares, and INRA, UMR 754, Université Claude Bernard Lyon 1, Lyon, (V.C.) - all in France; the Departments of Medicine (J.S.L., E.D., K.D., A.D.W., A. Fischer, M.I.S., M.H., D.A.S.) and Immunology and Microbiology (D.A.S.), University of Colorado School of Medicine, Aurora, and the Departments of Biomedical Research (T.F.) and Medicine (J.J. Solomon), National Jewish Health, Denver - both in Colorado; the Molecular and Genetic Epidemiology Laboratory, Faculty of Medicine, University of Tsukuba, Tsukuba (H.F., S. Oka, N.T.), and the Clinical Research Center for Allergy and Rheumatology, National Hospital Organization Sagamihara National Hospital, Sagamihara (H.F., S. Oka, S.T.) - both in Japan; the Department of Epidemiology, Harvard T.H. Chan School of Public Health (S.G.), and the Department of Medicine, Brigham and Women's Hospital (T.D., I.O.R.), Boston, and the Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge (S.G.) - all in Massachusetts; the Interstitial Lung Disease and Rheumatology Unit (J.R.-S., M.I.G.-P., M.M., I.B.-R.) and the HLA Laboratory (R.F.-V., E.A.-O.), Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, Mexico City; the 2nd Pulmonary Medicine Department (E.M., S.A.P.) and the Rheumatology and Clinical Immunology Unit, 4th Department of Internal Medicine (T.K., D.B.), University Hospital of Athens "Attikon," National and Kapodistrian University of Athens, Athens, and the Department of Respiratory Medicine and the Laboratory of Molecular and Cellular Pneumonology, Faculty of Medicine, University of Crete, Crete (K.A.) - both in Greece; St. Antonius ILD Center of Excellence, St. Antonius Ziekenhuis, Nieuwegein, the Netherlands (C.H.M.M., J.V., Y.A.M., J.C.G.); the Department of Medical Genetics, Nanjing University School of Medicine, Nanjing, China (Y.W.); the Divisions of Pulmonary and Critical Care Medicine (J.H.R.) and Rheumatology (E.L.M.), Mayo Clinic College of Medicine and Science, Rochester, MN; the Colton Center for Autoimmunity, New York University School of Medicine, New York (T.B.N.); the Department of Medicine, McGill University, Montreal (D.A.); the Department of Medicine, University of California, San Francisco, San Francisco (A.G., P.W.); and Data Tecnica International, Glen Echo, and the Laboratory of Neurogenetics, National Institute on Aging, Bethesda - both in Maryland (C. Blauwendraat, M.A.N.).

PMID: 30345907
PMCID: PMC6371965
DOI: 10.1056/NEJMoa1801562

Abstract

Background: Given the phenotypic similarities between rheumatoid arthritis (RA)-associated interstitial lung disease (ILD) (hereafter, RA-ILD) and idiopathic pulmonary fibrosis, we hypothesized that the strongest risk factor for the development of idiopathic pulmonary fibrosis, the gain-of-function MUC5B promoter variant rs35705950, would also contribute to the risk of ILD among patients with RA.

Methods: Using a discovery population and multiple validation populations, we tested the association of the MUC5B promoter variant rs35705950 in 620 patients with RA-ILD, 614 patients with RA without ILD, and 5448 unaffected controls.

Results: Analysis of the discovery population revealed an association of the minor allele of the MUC5B promoter variant with RA-ILD when patients with RA-ILD were compared with unaffected controls (adjusted odds ratio, 3.8; 95% confidence interval [CI], 2.8 to 5.2; P=9.7×10^-17). The MUC5B promoter variant was also significantly overrepresented among patients with RA-ILD, as compared with unaffected controls, in an analysis of the multiethnic case series (adjusted odds ratio, 5.5; 95% CI, 4.2 to 7.3; P=4.7×10^-35) and in a combined analysis of the discovery population and the multiethnic case series (adjusted odds ratio, 4.7; 95% CI, 3.9 to 5.8; P=1.3×10^-49). In addition, the MUC5B promoter variant was associated with an increased risk of ILD among patients with RA (adjusted odds ratio in combined analysis, 3.1; 95% CI, 1.8 to 5.4; P=7.4×10^-5), particularly among those with evidence of usual interstitial pneumonia on high-resolution computed tomography (adjusted odds ratio in combined analysis, 6.1; 95% CI, 2.9 to 13.1; P=2.5×10^-6). However, no significant association with the MUC5B promoter variant was observed for the diagnosis of RA alone.

Conclusions: We found that the MUC5B promoter variant was associated with RA-ILD and more specifically associated with evidence of usual interstitial pneumonia on imaging. (Funded by Société Française de Rhumatologie and others.).

PubMed Disclaimer

Figures

**Figure 1.. Association of the *MUC5B* rs35705950 Promoter Variant with Rheumatoid Arthritis (RA)–Associated Interstitial Lung Disease (ILD) (RA-ILD).**
Shown are forest plots of odds ratios and 95% confidence intervals. The boxes indicate odds ratios, and the horizontal lines indicate 95% confidence intervals for the best-fitting genetic model (dominant or additive) for each association test. The black dashed line represents a mean odds ratio value of 1. The red boxes and red lines indicate the overall odds ratios and 95% confidence intervals, respectively. The case series from France represents the discovery population. For comparisons between patients with RA and controls, the associations were adjusted for the country of origin and sex. For comparisons among patients with RA, the associations were adjusted for the country of origin, sex, age at inclusion, and smoking status. Panel A shows a lack of association of the *MUC5B* promoter variant rs35705950 with RA without ILD. Panel B shows an additive genotypic association of the *MUC5B* promoter variant rs35705950 with RA-ILD. The red dashed line represents the mean overall odds ratio value. In Panels A and B, United States–1 indicates one of two case series from the United States. Panel C shows a dominant genotypic association of the *MUC5B* promoter variant rs35705950 with ILD among patients with RA and those with a pattern of usual interstitial pneumonia (UIP) or possible UIP. RA-UIP denotes RA-ILD and a UIP or possible UIP pattern, and RA-nonUIP denotes RA-ILD and a pattern inconsistent with UIP.

**Figure 2.. MUC5B Expression in Explanted Lung Tissue from Patients with RA-ILD and an Unaffected Control.**
Shown are representative lung-tissue images from an unaffected control with a GG genotype (Panel A), a patient with RA-ILD and a GG genotype (Panel B), and a patient with RA-ILD and a GT genotype (Panel C). Panel A includes a low-power view (left) of normal lung, top and middle insets with a high-power view of bronchiole with MUC5B staining, and a bottom inset with a high-power view of alveolar epithelia. Panels B and C each include a low-power view (left) of the UIP pattern in explanted lung tissue, a top inset with a high-power view of bronchiole with MUC5B staining, and middle and bottom insets with a high-power view of MUC5B staining in metaplastic epithelia lining honeycomb cysts and MUC5B staining of mucus in honeycomb cysts.

See this image and copyright information in PMC

Comment in

Breathing New Life into Interstitial Lung Disease in Rheumatoid Arthritis.
Gregersen PK, Gravallese EM. Gregersen PK, et al. N Engl J Med. 2018 Dec 6;379(23):2265-2266. doi: 10.1056/NEJMe1811767. Epub 2018 Oct 20. N Engl J Med. 2018. PMID: 30345908 No abstract available.
Advances in Interstitial Lung Disease Genetics.
Sclafani A, Worsham CM, McNeill J, Anandaiah A. Sclafani A, et al. Am J Respir Crit Care Med. 2019 Jul 15;200(2):247-249. doi: 10.1164/rccm.201902-0471RR. Am J Respir Crit Care Med. 2019. PMID: 31014082 No abstract available.

References

1. McInnes IB, Schett G. The pathogenesis of rheumatoid arthritis. N Engl J Med 2011; 365: 2205–19. - PubMed
1. Olson AL, Swigris JJ, Sprunger DB, et al. Rheumatoid arthritis-interstitial lung disease-associated mortality. Am J Respir Crit Care Med 2011; 183: 372–8. - PMC - PubMed
1. Bongartz T, Nannini C, Medina-Velasquez YF, et al. Incidence and mortality of interstitial lung disease in rheumatoid arthritis: a population-based study. Arthritis Rheum 2010; 62: 1583–91. - PMC - PubMed
1. Koduri G, Norton S, Young A, et al. Interstitial lung disease has a poor prognosis in rheumatoid arthritis: results from an inception cohort. Rheumatology (Oxford) 2010; 49: 1483–9. - PubMed
1. Gabbay E, Tarala R, Will R, et al. Inter-stitial lung disease in recent onset rheumatoid arthritis. Am J Respir Crit Care Med 1997; 156: 528–35. - PubMed

Publication types

Actions
Actions
Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

MUC5B Promoter Variant and Rheumatoid Arthritis with Interstitial Lung Disease

Affiliation

MUC5B Promoter Variant and Rheumatoid Arthritis with Interstitial Lung Disease

Authors

Affiliation

Abstract

Figures

Comment in

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Medical