MUC5B promoter Variant rs35705950 Is a Risk Factor for Rheumatoid Arthritis - Interstitial Lung Disease

Pierre-Antoine Juge¹, Joyce Sujin Lee², Esther Ebstein¹, Hiroshi Furukawa³, Evgenia Dobrinskikh⁴, Steven Gazal⁵, Caroline Kannengiesser⁵, Sébastien Ottaviani¹, Shomi Oka⁶, Shigeto Tohma⁷, Naoyuki Tsuchiya⁸, Jorge Rojas-Serrano⁹, Montserrat I. González-Pérez⁹, Mayra Mejía⁹, Ivette Buendía-Roldán⁹, Ramcés Falfan-Valencia¹⁰, Enrique Ambrocio-Ortiz¹⁰, Effrosyni Manali¹¹, Spyros A. Papiris¹¹, Theofanis Karageorgas¹², Dimitrios Boumpas¹², Katarina Antoniou¹³, Coline H.M. van Moorsel¹⁴, Joanne van der Vis¹⁴, Yaël A. de Man¹⁴, Jan C. Grutters¹⁴, Yaping Wang¹⁵, Raphaël Borie¹⁶, Lidwine Wemeau-Stervinou¹⁷, Benoit Wallaert¹⁸, René-Marc Flipo¹⁹, Hilario Nunes²⁰, Dominique Valeyre²⁰, Nathalie Saidenberg²¹, Marie-Christophe Boissier²², Sylvain Adam-Marchand²³, Aline Frazier²⁴, Pascal Richette²⁵, Yannick Allanore²⁶, Jean Sibilia²⁷, Claire Dromer²⁸, Christophe Richez²⁹, Thierry Schaeverbeke³⁰, Huguette Lioté³¹, Gabriel Thabut³², Nadia Nathan³³, Serge Amselem³⁴, Martin Soubrier³⁵, Vincent Cottin³⁶, Annick Clément³³, Kevin D. Deane³⁷, Avram D. Walts⁴, Tasha Fingerlin³⁸, Aryeh Fischer³⁹, Jay H. Ryu⁴⁰, Eric L. Matteson⁴¹, Timothy B. Niewold⁴², Deborah Assayag⁴³, Andrew Gross⁴⁴, Paul Wolters⁴⁵, Marvin I. Schwartz⁴⁶, V. Michael Holers⁴⁷, Joshua J. Solomon⁴⁸, Tracy Doyle⁴⁹, Ivan O. Rosas⁵⁰, Cornelis Blauwendraat⁵¹, Mike A. Nalls⁵², Marie-Pierre Debray¹⁶, Catherine Boileau⁵, Bruno Crestani¹⁶, David A. Schwartz⁴ and Philippe Dieude¹⁶, ¹Rhumatologie, Hôpital Bichat - Claude Bernard, Paris, France, ²SOM-MED, University of Colorado, Denver - Anschutz Medical Campus, Aurora, CO, ³University of Tsukuba, Graduate School of Comprehensive Human Sciences, Masters' Program in Medical Sciences, Tsukuba, Japan, ⁴Department of Medicine, University of Colorado School of Medicine, Aurora, CO, ⁵Génétique, Hôpital Bichat - Claude Bernard, Paris, France, ⁶Clinical Research Center for Allergy and Rheumatology, Sagamihara National Hopsital, Sagamihara, Japan, ⁷Clinical Research Center for Allergy and Rheumatology, Sagamihara National Hospital, Sagamihara, Japan, ⁸Faculty of Medicine, University of Tsukuba, Tsukuba, Japan, ⁹Interstitial Lung Disease & Rheumatology Unit, Instituto Nacional de Enfermedades Respiratorias, Mexico City, Mexico, ¹⁰HLA Laboratory, Instituto Nacional de Enfermedades Respiratorias, Mexico City, Mexico, ¹¹2nd Pulmonary Medicine Department, University Hospital of Athens "Attikon", Athens, Greece, ¹²Rheumatology and Clinical Immunology Unit, 4th Department of Internal Medicine, University Hospital of Athens "Attikon", Athens, Greece, ¹³PS Department of Respiratory Medicine & Laboratory of Molecular & Cellular Pneumonology, University of Crete, Crete, Greece, ¹⁴St Antonius ILD center of excellence, St Antonius ziekenhuis, Nieuwegein, Netherlands, ¹⁵Department of Medical Genetics, Nanjing University School of Medicine, Nanjing, China, ¹⁶Université Paris-Diderot, Paris, France, ¹⁷Pneumologie, CHRU de Lille, Lille, France, ¹⁸Pneumology, CHRU, Lille CEDEX, France, ¹⁹Hôpital Roger Salengro, Lille, France, ²⁰Pulmonary diseases department, Avicenne Hospital (AP-HP), Bobigny, France, ²¹Rhumatologie, Hôpital Avicenne, Paris, France, ²²74 rue Marcel Cachin, INSERM, Bobigny, France, ²³Pneumology, Centre Hospitalier Universitaire de Tours, Tours, France, ²⁴Rhumatologie, Hôpital Lariboisière, Paris, France, ²⁵Rheumatology, Université Paris Diderot, Paris, France, ²⁶Rhumatologie A, Hôpital Cochin, Paris, France, ²⁷Université de Strasbourg, Strasbourg, France, ²⁸Imagerie Thoracique et Cardiovasculaire, CHU Bordeaux, Bordeaux, France, ²⁹Department of Rheumatology, Bordeaux University Hospital, Bordeaux, France, ³⁰Department of Rheumatology, Bordeaux University Hospital, BORDEAUX, France, ³¹Pneumologie A, Hôpital Tenon, Paris, France, ³²Pneumologie B, Hôpital Bichat - Claude Bernard, Paris, France, ³³Pneumologie pédiatrique, Hôpital Trousseau, Paris, France, ³⁴Service de Pneumologie Pédiatrique et Centre de référence des maladies respiratoires rares, Hôpital Trousseau, Paris, France, ³⁵Rheumatology, Department of Rheumatology, CHU Gabriel Montpied, Clermont-Ferrand, France, ³⁶Lyon Louis Pradel, Lyon, France, ³⁷Division of Rheumatology, University of Colorado Denver, Aurora, CO, ³⁸Department of Biomedical Research, National Jewish Health, Denver, CO, ³⁹Rheumatology / ILD Program, National Jewish Health, Denver, CO, ⁴⁰Division of Pulmonary and Critical Care Medicine, Mayo Clinic College of Medicine and Science, Rochester, MN, ⁴¹Division of Rheumatology, Mayo Clinic College of Medicine and Science, Rochester, MN, ⁴²Colton Center for Autoimmunity, New York University School of Medicine, New York, NM, ⁴³McGill University, Department of Medicine, Montreal, QC, Canada, ⁴⁴Department of Medicine, University of California, San Francisco, CA, ⁴⁵Pulmonary Division, Department of Medicine, University of California, San Francisco, San Francisco, CA, ⁴⁶University of Colorado School of Medicine, Department of Medicine, Aurora, CO, ⁴⁷Division of Rheumatology, University of Colorado School of Medicine, Aurora, CO, ⁴⁸Division of Pulmonary and Critical Care Medicine, National Jewish Health, Denver, CO, ⁴⁹Brigham and Women's Hospital, Boston, MA, ⁵⁰BWH - Pulmonary, Brigham and Women's Hospital, Boston, MA, ⁵¹Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, ⁵²Data Tecnica International, Glen Echo, MD

Meeting: 2018 ACR/ARHP Annual Meeting

Keywords: genetics, interstitial lung disease and rheumatoid arthritis (RA)

Session Information

Date: Monday, October 22, 2018

Title: 4M042 ACR Abstract: Plenary Session II (1816–1821)

Session Type: ACR Plenary Session

Session Time: 11:00AM-12:30PM

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

Methods: Using a discovery population and multi-ethnic validation case series, we tested the association of the MUC5B promoter variant in RA-ILD (N=620), RA without ILD (N=614), and unaffected controls (N=5448).

Results: The discovery population revealed an association of the MUC5B promoter variant minor allele with RA-ILD when compared to unaffected controls (OR_adj=3.8 95%CI [2.8-5.2]; P=9.7×10^-17). Similar to the discovery population, the MUC5B promoter variant was significantly over-represented among the RA-ILD cases in the multi-ethnic study case series when compared to unaffected controls (OR_adj=5.5 95%CI[4.2-7.2]; P=4.7×10^-35), and when the discovery population and the multi-ethnic case series were combined (OR_combined=4.7 95%CI[3.9-5.8]; P=1.3×10^-49). Additionally, the MUC5B promoter variant was found to increase the risk of ILD among patients with RA (OR_combined=3.1 95%CI[1.8-5.4]; P=7.4×10^-5), however, no statistical association with the MUC5B promoter variant was observed for RA alone. The association of the MUC5B promoter variant with RA-ILD increased significantly when restricted to usual interstitial pneumonia (UIP) pattern by high-resolution computed tomography (OR_combined=6.1 95%CI[2.9-13.1]; P=2.5×10^-6). Given our results, we decided to explore 12 other common variants previously reported to be associated with IPF (LLRC34 rs6793295, FAM13A rs2609255, TERT rs2736100, EHMT2 rs7887, DSP rs2076295, rs4727443, OBFC1 rs11191865, TOLLIP rs5743890 and rs111521887, ATP11A rs1278769, IVD rs2034650 and DPP9 rs12610495). In this exploratory analyze, we found that 2 other IPF risk variants, TOLLIP rs5743890 and IVD rs2034650, were also preliminarily associated with RA-ILD (OR_combined=2.1 95%CI[1.1-4.1]; P=0.02 and OR_combined=0.59 95%CI[0.4-0.9]; P=0.01, respectively). These findings should be replicated to further conclude to their role in the RA-ILD genetic background.

Conclusion: Our findings demonstrate that the MUC5B promoter variant rs35705950 is a risk factor for RA-ILD specifically associated with radiologic evidence of the UIP pattern. Furthermore, other IPF related common variants may also participate in RA-ILD genetic susceptibility.

Disclosure: P. A. Juge, None; J. S. Lee, None; E. Ebstein, None; H. Furukawa, None; E. Dobrinskikh, None; S. Gazal, None; C. Kannengiesser, None; S. Ottaviani, None; S. Oka, None; S. Tohma, None; N. Tsuchiya, None; J. Rojas-Serrano, None; M. I. González-Pérez, None; M. Mejía, None; I. Buendía-Roldán, None; R. Falfan-Valencia, None; E. Ambrocio-Ortiz, None; E. Manali, None; S. A. Papiris, None; T. Karageorgas, None; D. Boumpas, None; K. Antoniou, None; C. H. M. van Moorsel, None; J. van der Vis, None; Y. A. de Man, None; J. C. Grutters, None; Y. Wang, None; R. Borie, None; L. Wemeau-Stervinou, None; B. Wallaert, None; R. M. Flipo, None; H. Nunes, None; D. Valeyre, None; N. Saidenberg, None; M. C. Boissier, None; S. Adam-Marchand, None; A. Frazier, None; P. Richette, None; Y. Allanore, None; J. Sibilia, None; C. Dromer, None; C. Richez, None; T. Schaeverbeke, None; H. Lioté, None; G. Thabut, None; N. Nathan, None; S. Amselem, None; M. Soubrier, None; V. Cottin, None; A. Clément, None; K. D. Deane, None; A. D. Walts, None; T. Fingerlin, None; A. Fischer, None; J. H. Ryu, None; E. L. Matteson, None; T. B. Niewold, None; D. Assayag, None; A. Gross, None; P. Wolters, None; M. I. Schwartz, None; V. M. Holers, None; J. J. Solomon, None; T. Doyle, None; I. O. Rosas, None; C. Blauwendraat, None; M. A. Nalls, None; M. P. Debray, None; C. Boileau, None; B. Crestani, None; D. A. Schwartz, None; P. Dieude, None.

To cite this abstract in AMA style:

Juge PA, Lee JS, Ebstein E, Furukawa H, Dobrinskikh E, Gazal S, Kannengiesser C, Ottaviani S, Oka S, Tohma S, Tsuchiya N, Rojas-Serrano J, González-Pérez MI, Mejía M, Buendía-Roldán I, Falfan-Valencia R, Ambrocio-Ortiz E, Manali E, Papiris SA, Karageorgas T, Boumpas D, Antoniou K, van Moorsel CHM, van der Vis J, de Man YA, Grutters JC, Wang Y, Borie R, Wemeau-Stervinou L, Wallaert B, Flipo RM, Nunes H, Valeyre D, Saidenberg N, Boissier MC, Adam-Marchand S, Frazier A, Richette P, Allanore Y, Sibilia J, Dromer C, Richez C, Schaeverbeke T, Lioté H, Thabut G, Nathan N, Amselem S, Soubrier M, Cottin V, Clément A, Deane KD, Walts AD, Fingerlin T, Fischer A, Ryu JH, Matteson EL, Niewold TB, Assayag D, Gross A, Wolters P, Schwartz MI, Holers VM, Solomon JJ, Doyle T, Rosas IO, Blauwendraat C, Nalls MA, Debray MP, Boileau C, Crestani B, Schwartz DA, Dieude P. MUC5B promoter Variant rs35705950 Is a Risk Factor for Rheumatoid Arthritis – Interstitial Lung Disease [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 9). https://acrabstracts.org/abstract/muc5b-promoter-variant-rs35705950-is-a-risk-factor-for-rheumatoid-arthritis-interstitial-lung-disease/. Accessed .

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