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Eur Respir J. 2017 May 11;49(5). pii: 1602314. doi: 10.1183/13993003.02314-2016. Print 2017 May.

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

Juge PA1,2,3, Borie R2,4,5,3, Kannengiesser C2,6,7,3, Gazal S2,8,9, Revy P10,11, Wemeau-Stervinou L12,13, Debray MP2,14, Ottaviani S1,2, Marchand-Adam S15,16,17, Nathan N18,19,20, Thabut G2,5,21, Richez C22,23,24, Nunes H25,26, Callebaut I20,27, Justet A2,4, Leulliot N11,28, Bonnefond A13,29,30, Salgado D31,32, Richette P2,33,34, Desvignes JP31,32, Lioté H35, Froguel P13,29,36, Allanore Y11,37,38, Sand O13,29,30, Dromer C24,39, Flipo RM13,40, Clément A18,19,20, Béroud C31,32,41, Sibilia J42,43,44, Coustet B1,2, Cottin V45,46, Boissier MC26,47,48, Wallaert B12,13, Schaeverbeke T22,23,24, Dastot le Moal F18,20,49, Frazier A2,33, Ménard C18,19,20, Soubrier M50, Saidenberg N26,48, Valeyre D25,26, Amselem S18,19,49; FREX consortium, Boileau C2,6,51, Crestani B2,4,5, Dieudé P52,2,7.

Author information

1
APHP, Hôpital Bichat, Service de Rhumatologie, DHU FIRE, Paris, France.
2
Université Paris Diderot, Sorbonne Paris Cité, Paris, France.
3
These authors contributed equally.
4
APHP, Hôpital Bichat, Service de Pneumologie A, DHU FIRE, Paris, France.
5
INSERM U1152, Paris, France.
6
APHP, Service de Génétique, Hôpital Bichat, Paris, France.
7
INSERM, UMR_1149 Centre de Recherches sur l'Inflammation Paris, Paris, France.
8
INSERM, IAME, UMR_1137, Paris, France.
9
APHP, Plateforme de génomique constitutionnelle du GHU Nord, Hôpital Bichat, Paris, France.
10
INSERM UMR_1163, Laboratory of Genome Dynamics in the Immune System, Institut Imagine, Paris, France.
11
Université Paris Descartes, Sorbonne Cité, Paris, France.
12
CHRU de Lille, Service de Pneumologie et Immuno-Allergologie, Centre de compétence maladies pulmonaires rares, FHU IMMINENT, Lille, France.
13
Université Lille 2, Lille, France.
14
APHP, Hôpital Bichat, Service de Radiologie, Paris, France.
15
CHRU Tours, Service de Pneumologie, Tours, France.
16
Université Francois Rabelais, Tours, France.
17
INSERM, U1100, Tours, France.
18
APHP, Service de Pneumologie Pédiatrique et Centre de référence des maladies respiratoires rares, Hôpital Trousseau, Paris, France.
19
INSERM UMR_S933, Paris, France.
20
Université Pierre et Marie Curie, Sorbonne Paris Cité, Paris, France.
21
APHP, Hôpital Bichat, Service de Pneumologie B, DHU FIRE, Paris, France.
22
CHU de Bordeaux, service de rhumatologie, Bordeaux, France.
23
Immuno ConcEpT, CNRS UMR_5164, Bordeaux, France.
24
Université de Bordeaux, Bordeaux, France.
25
AP-HP, Hôpital Avicenne, Service de Pneumologie, Bobigny, France.
26
Université Paris 13, Sorbonne Paris Cité, Paris, France.
27
CNRS UMR_7590, MNHM-IRD-IUC, Paris, France.
28
Laboratoire de Cristallographie et RMN Biologiques, UMR CNRS 8015, Faculté de Pharmacie, Paris, France.
29
CNRS, UMR_8199, Lille, France.
30
European Genomic Institute for Diabetes, Lille, France.
31
Aix-Marseille Université, GMGF, Marseille, France.
32
INSERM, UMR_S 910, Marseille, France.
33
AP-HP, hôpital Lariboisière, Service de Rhumatologie, Paris, France.
34
INSERM, UMR_1132, Paris, France.
35
APHP, Hôpital Tenon, Service de Pneumologie, Paris, France.
36
Dept of Genomics of Common Diseases, School of Public Health, Imperial College London, Hammersmith Hospital, London, UK.
37
APHP, Hôpital Cochin, Service de Rhumatologie A, Paris, France.
38
INSERM, U1016, UMR_8104, Paris, France.
39
CHU de Bordeaux, Service d'Imagerie Thoracique et Cardiovasculaire, Pessac, France.
40
CHU de Lille, Service de Rhumatologie, Lille, France.
41
APHM, Hôpital La Timone Enfants, Laboratoire de Génétique Moléculaire, Marseille, France.
42
CHRU de Strasbourg, Service de Rhumatologie, Hôpital de Hautepierre, Strasbourg, France.
43
INSERM UMR_S1109, Laboratoire d'Immuno-Rhumatologie Moléculaire, CRHI, FMTS, Université de Strasbourg, Strasbourg, France.
44
Fédération Hospitalo-Universitaire OMICARE, Strasbourg, France.
45
Hospices Civils de Lyon, Hôpital Louis Pradel, Centre national de référence des maladies pulmonaires rares, Lyon, France.
46
INRA, UMR_754, Université Claude Bernard Lyon 1, Lyon, France.
47
INSERM U1125, Bobigny, France.
48
APHP, GH HUPSSD, Service de Rhumatologie, Bobigny, France.
49
APHP, Département de Génétique, Hôpital Trousseau, Paris, France.
50
CHU Clermont-Ferrand, Service de Rhumatologie, INRA, UMR1019, UNH, CRNH Auvergne, Clermont-Ferrand, France.
51
INSERM, UMR_1148, Maladies structurelles cardiovasculaires, Paris, France.
52
APHP, Hôpital Bichat, Service de Rhumatologie, DHU FIRE, Paris, France philippe.dieude@aphp.fr.

Abstract

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.

PMID:
28495692
DOI:
10.1183/13993003.02314-2016
[Indexed for MEDLINE]

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