Shared Genetic Predisposition in Rheumatoid Arthritis–Interstitial Lung Disease and Idiopathic Pulmonary Fibrosis: A Genetic Association Study

Pierre-Antoine Juge¹, Raphaël Borie², Caroline Kannengiesser³, Steven Gazal³, Patrick Revy⁴, Lidwine Wemeau-Stervinou⁵, Marie-Pierre Debray⁶, Sébastien Ottaviani⁷, Sylvain Adam-Marchand⁸, Nadia Nathan⁹, Gabriel Thabut¹⁰, Christophe Richez¹¹, Hilario Nunes¹², Isabelle Callebaut¹³, Aurélien Justet², Nicolas Leulliot¹⁴, Amélie Bonnefond¹⁵, David Salgado¹⁶, Pascal Richette¹⁷, Jean-Pierre Desvignes¹⁶, Huguette Lioté¹⁸, Philippe Froguel¹⁵, Yannick Allanore¹⁹, Olivier Sand¹⁵, Claire Dromer²⁰, René-Marc Flipo²¹, Annick Clément⁹, Christophe Béroud²², Jean Sibilia²³, Baptiste Coustet^1,24, Vincent Cottin²⁵, Marie-Christophe Boissier²⁶, Benoit Wallaert²⁷, Thierry Schaeverbeke²⁸, Florence Dasto le Moal²⁹, Aline Frazier¹⁷, Christelle Ménard³⁰, Martin Soubrier³¹, Nathalie Saidenberg²⁹, Dominique Valeyre³², Serge Amselem⁹, Catherine Boileau³, Bruno Crestani² and Philippe Dieudé¹, ¹Rhumatologie, Hôpital Bichat - Claude Bernard, Paris, France, ²Pneumologie A, Hôpital Bichat - Claude Bernard, Paris, France, ³Génétique, Hôpital Bichat - Claude Bernard, Paris, France, ⁴Laboratory of Genome Dynamics in the Immune System, Institut Imagine, Paris, France, ⁵Pneumologie, CHRU de Lille, Lille, France, ⁶Université Paris-Diderot, Paris, France, ⁷Rheumatologie, Hôpital Bichat - Claude Bernard, Paris, France, ⁸Pneumology, Centre Hospitalier Universitaire de Tours, Tours, France, ⁹Pneumologie pédiatrique, Hôpital Trousseau, Paris, France, ¹⁰Pneumologie B, Hôpital Bichat - Claude Bernard, Paris, France, ¹¹Rhumatologie, Department of Rheumatology, Bordeaux University Hospital, Bordeaux, France, ¹²Pneumologie B, Hôpital Avicenne, Paris, France, ¹³CNRS UMR_7590, Paris, France, ¹⁴Laboratoire de cristallographie et RMN biologiques, UMR CNRS 8015, Paris, France, ¹⁵CNRS UMR_8199, Lille, France, ¹⁶UMR_S 910, Marseille, France, ¹⁷Rhumatologie, Hôpital Lariboisière, Paris, France, ¹⁸Pneumologie A, Hôpital Tenon, Paris, France, ¹⁹Rhumatologie A, Hôpital Cochin, Paris, France, ²⁰Imagerie Thoracique et Cardiovasculaire, CHU Bordeaux, Bordeaux, France, ²¹Rhumatologie, CHU Lille, Lille, France, ²²INSERM UMR_S 910, Marseille, France, ²³Department of Rheumatology, Strasbourg University Hospital, Strasbourg, France, ²⁴Rheumatology, Université Paris Descartes, Hopital Cochin, Paris, France, ²⁵Louis Pradel Hospital, Claude Bernard University Lyon 1, Lyon, France, ²⁶Li2P, University of Paris 13, Sorbonne Paris Cité, Bobigny, France, ²⁷Pneumology, CHRU, Lille CEDEX, France, ²⁸Rheumatology, CHU Bordeaux, Bordeaux, France, ²⁹Rhumatologie, Hôpital Avicenne, Paris, France, ³⁰Pneumologie Pédiatrique, Hôpital Trousseau, Paris, France, ³¹Rheumatology, Department of Rheumatology, CHU Gabriel Montpied, Clermont-Ferrand, France, ³²Department of Pneumology, Avicenne Hospital (AP-HP), Bobigny, France

Meeting: 2016 ACR/ARHP Annual Meeting

Date of first publication: September 28, 2016

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

Session Information

Date: Monday, November 14, 2016

Session Title: Rheumatoid Arthritis – Human Etiology and Pathogenesis - Poster II

Session Type: ACR Poster Session B

Session Time: 9:00AM-11:00AM

Background/Purpose: Interstitial lung disease (ILD) is one of the leading causes of mortality for rheumatoid arthritis (RA) patients. Despite its high prevalence and mortality, little is known about the pathogenesis of RA–associated ILD (RA-ILD). Given that idiopathic pulmonary fibrosis (IPF) and RA–ILD share the usual interstitial pneumonia pattern and common environmental risk factors such as tobacco smoking, we hypothesized that the two diseases may share additional risk factors including familial pulmonary fibrosis (FPF) susceptibility genes.

Methods: We used whole-exome sequencing (WES) followed by restricted analysis of a discrete number of FPF-linked genes to compare mutations among consecutive RA–ILD patients collected by a French network of pulmonologists and rheumatologists. A burden test was used to assess the excess number of mutations in RA–ILD patients.

Results: Among the 101 RA–ILD patients included, 12 (11.9%) had 13 WES-identified heterozygous mutations in the TERT, RTEL1, PARN or SFTPC coding regions. The burden test, based on 81 RA–ILD patients and 1010 controls of European ancestry, revealed an excess of TERT, RTEL1, PARN or SFTPC mutations for RA–ILD patients compared to controls (p=9.45x10^–4, odds ratio [OR] 3.17 95% CI 1.53–6.12). Telomeres were shorter for RA-ILD patients with a TERT, RTEL1 or PARN mutation than controls (p=2.87×10^-2).

Conclusion: Our results support the contribution of FPF-linked genes to RA–ILD susceptibility, linking RA–ILD and IPF pathogeneses. Recent therapeutic advances in IPF may open new avenues for treatment of ILD, the most severe RA manifestation for which effective drugs are lacking.

Disclosure: P. A. Juge, None; R. Borie, None; C. Kannengiesser, None; S. Gazal, None; P. Revy, None; L. Wemeau-Stervinou, None; M. P. Debray, None; S. Ottaviani, None; S. Adam-Marchand, None; N. Nathan, None; G. Thabut, None; C. Richez, None; H. Nunes, None; I. Callebaut, None; A. Justet, None; N. Leulliot, None; A. Bonnefond, None; D. Salgado, None; P. Richette, None; J. P. Desvignes, None; H. Lioté, None; P. Froguel, None; Y. Allanore, None; O. Sand, None; C. Dromer, None; R. M. Flipo, None; A. Clément, None; C. Béroud, None; J. Sibilia, None; B. Coustet, None; V. Cottin, None; M. C. Boissier, None; B. Wallaert, None; T. Schaeverbeke, None; F. Dasto le Moal, None; A. Frazier, None; C. Ménard, None; M. Soubrier, None; N. Saidenberg, None; D. Valeyre, None; S. Amselem, None; C. Boileau, None; B. Crestani, None; P. Dieudé, None.

To cite this abstract in AMA style:

Juge PA, Borie R, Kannengiesser C, Gazal S, Revy P, Wemeau-Stervinou L, Debray MP, Ottaviani S, Adam-Marchand S, Nathan N, Thabut G, Richez C, Nunes H, Callebaut I, Justet A, Leulliot N, Bonnefond A, Salgado D, Richette P, Desvignes JP, Lioté H, Froguel P, Allanore Y, Sand O, Dromer C, Flipo RM, Clément A, Béroud C, Sibilia J, Coustet B, Cottin V, Boissier MC, Wallaert B, Schaeverbeke T, Dasto le Moal F, Frazier A, Ménard C, Soubrier M, Saidenberg N, Valeyre D, Amselem S, Boileau C, Crestani B, Dieudé P. Shared Genetic Predisposition in Rheumatoid Arthritis–Interstitial Lung Disease and Idiopathic Pulmonary Fibrosis: A Genetic Association Study [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/shared-genetic-predisposition-in-rheumatoid-arthritis-interstitial-lung-disease-and-idiopathic-pulmonary-fibrosis-a-genetic-association-study/. Accessed June 3, 2020.

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