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Shared genetic predisposition in rheumatoid arthritis-interstitial lung disease and familial pulmonary fibrosis

2017; European Respiratory Society; Volume: 49; Issue: 5 Linguagem: Inglês

10.1183/13993003.02314-2016

1399-3003

Pierre‐Antoine Juge, Raphaël Borie, Caroline Kannengiesser, Steven Gazal, Patrick Revy, Lidwine Wémeau-Stervinou, Marie‐Pierre Debray, Sèbastien Ottaviani, S. Marchand‐Adam, Nadia Nathan, Gabriel Thabut, Christophe Richez, Hilario Nunès, Isabelle Callebaut, A. Justet, Nicolas Leulliot, Amélie Bonnefond, David Salgado, Pascal Richette, Jean-Pierre Desvignes, H. Lioté, Philippe Froguel, Yannick Allanore, Olivier Sand, Claire Dromer, René‐Marc Flipo, Annick Clément, Christophe Béroud, Jean Sibilia, Baptiste Coustet, Vincent Cottin, Marie‐Christophe Boissier, B. Wallaert, Thierry Schaeverbeke, F. Moal, Aline Frazier, Christelle Ménard, Martin Soubrier, Nathalie Saidenberg-Kermanac’h, Dominique Valeyre, Serge Amselem, Cathérine Boileau, Bruno Crestani, Philippe Dieudé,

Inflammasome and immune disorders

Despite its high prevalence and mortality, little is known about the pathogenesis of rheumatoid arthritis-associated interstitial lung disease (RA-ILD). Given that familial pulmonary fibrosis (FPF) and RA-ILD frequently share the usual pattern of interstitial pneumonia and common environmental risk factors, we hypothesised that the two diseases might share additional risk factors, including FPF-linked genes. Our aim was to identify coding mutations of FPF-risk genes associated with RA-ILD.We used whole exome sequencing (WES), followed by restricted analysis of a discrete number of FPF-linked genes and performed a burden test to assess the excess number of mutations in RA-ILD patients compared to controls.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 in RA-ILD patients (OR 3.17, 95% CI 1.53-6.12; p=9.45×10-4). Telomeres were shorter in RA-ILD patients with a TERT, RTEL1 or PARN mutation than in controls (p=2.87×10-2).Our results support the contribution of FPF-linked genes to RA-ILD susceptibility.