MUC5B Promoter Variant and Rheumatoid Arthritis with Interstitial Lung Disease
Pierre-Antoine Juge
(1, 2)
,
Joyce S. Lee
(3)
,
Esther Ebstein
(1)
,
Hiroshi Furukawa
(4, 5)
,
Evgenia Dobrinskikh
(3)
,
Steven Gazal
(6, 7)
,
Caroline Kannengiesser
(1, 2)
,
Sebastien Ottaviani
(1)
,
Shomi Oka
(5, 4)
,
Shigeto Tohma
(5)
,
Naoyuki Tsuchiya
(4)
,
Jorge Rojas-Serrano
,
Montserrat I. Gonzalez-Perez
,
Mayra Mejia
,
Ivette Buendia-Roldan
,
Ramces Falfan-Valencia
,
Enrique Ambrocio-Ortiz
,
Effrosyni Manali
(8, 9)
,
Spyros A. Papiris
(8, 9)
,
Theofanis Karageorgas
(8, 9)
,
Dimitrios Boumpas
(8, 9)
,
Katarina Antoniou
(10)
,
Coline H. M. van Moorsel
(11)
,
Joanne van der Vis
(11)
,
Yael A. de Man
(11)
,
Jan C. Grutters
(11)
,
Yaping Wang
(12)
,
Raphael Borie
(1, 2)
,
Lidwine Wemeau-Stervinou
(13)
,
Benoit Wallaert
(13)
,
René-Marc Flipo
(13)
,
Hilario Nunes
(14)
,
Dominique Valeyre
(14)
,
Nathalie Saidenberg-Kermanac'H
(14, 15)
,
Marie-Christophe Boissier
(14, 15)
,
Sylvain Marchand-Adam
(16)
,
Aline Frazier
(17)
,
Pascal Richette
(17, 18)
,
Yannick Allanore
(19, 20)
,
Jean Sibilia
(21, 22, 23)
,
Claire Dromer
(24)
,
Christophe Richez
(24, 25)
,
Thierry Schaeverbeke
(24, 25)
,
Huguette Liote
(26)
,
Gabriel Thabut
(1, 2)
,
N. Nathan
(27, 28)
,
S. Amselem
(27, 28)
,
M. Soubrier
(29, 30)
,
Vincent Cottin
(31, 32)
,
Annick Clement
(27, 28)
,
Kevin Deane
(3)
,
Avram D. Walts
(3)
,
Tasha Fingerlin
(33)
,
Aryeh Fischer
(3)
,
Jay H. Ryu
(34)
,
Eric L. Matteson
(34)
,
Timothy B. Niewold
(35)
,
Deborah Assayag
(36)
,
Andrew Gross
(37)
,
Paul Wolters
(37)
,
Marvin I. Schwarz
(3)
,
Michael Holers
(3)
,
Joshua J. Solomon
(33)
,
Tracy Doyle
(38)
,
Ivan O. Rosas
(38)
,
Cornelis Blauwendraat
(39)
,
Mike A. Nalls
(39)
,
Marie-Pierre Debray
(1)
,
Catherine Boileau
(1)
,
Bruno Crestani
(1, 2)
,
David A. Schwartz
(3)
,
P. Dieude
(2, 1)
1
AP-HP - Hôpital Bichat - Claude Bernard [Paris]
2 PHERE (UMR_S_1152 / U1152) - Physiopathologie et Epidémiologie des Maladies Respiratoires
3 University of Colorado School of Medicine
4 Université de Tsukuba = University of Tsukuba
5 Sagamihara National Hospital [Kanagawa, Japan]
6 Harvard T.H. Chan School of Public Health
7 BROAD INSTITUTE - Broad Institute of MIT and Harvard
8 “Attikon” University Hospital
9 NKUA - National and Kapodistrian University of Athens
10 UOC - University of Crete [Heraklion]
11 St. Antonius Hospital [Nieuwegein]
12 Nanjing Medical University
13 CHRU Lille - Centre Hospitalier Régional Universitaire [CHU Lille]
14 Hôpital Avicenne [AP-HP]
15 Physiopathologie, Cibles et Thérapies de la Polyarthrite Rhumatoïde
16 CHRU Tours - Centre Hospitalier Régional Universitaire de Tours
17 Hôpital Lariboisière-Fernand-Widal [APHP]
18 BIOSCAR (UMR_S_1132 / U1132) - Biologie de l'Os et du Cartilage : Régulations et Ciblages Thérapeutiques
19 AP-HP - Hôpital Cochin Broca Hôtel Dieu [Paris]
20 IC UM3 (UMR 8104 / U1016) - Institut Cochin
21 Hôpital de Hautepierre [Strasbourg]
22 IRM - Immuno-Rhumatologie Moléculaire
23 UNISTRA - Université de Strasbourg
24 CHU Bordeaux
25 ImmunoConcept - Immunology from Concept and Experiments to Translation
26 CHU Tenon [AP-HP]
27 U933 - Maladies génétiques d'expression pédiatrique
28 CHU Trousseau [APHP]
29 CHU Clermont-Ferrand
30 UNH - Unité de Nutrition Humaine
31 IVPC - Infections Virales et Pathologie Comparée - UMR 754
32 Hôpital Louis Pradel [CHU - HCL]
33 NJH - National Jewish Health
34 Mayo Clinic and Mayo College of Medicine
35 New York University School of Medicine
36 McGill University = Université McGill [Montréal, Canada]
37 UC San Francisco - University of California [San Francisco]
38 BWH - Brigham & Women’s Hospital [Boston]
39 NIA - National Institute on Aging [Bethesda, USA]
2 PHERE (UMR_S_1152 / U1152) - Physiopathologie et Epidémiologie des Maladies Respiratoires
3 University of Colorado School of Medicine
4 Université de Tsukuba = University of Tsukuba
5 Sagamihara National Hospital [Kanagawa, Japan]
6 Harvard T.H. Chan School of Public Health
7 BROAD INSTITUTE - Broad Institute of MIT and Harvard
8 “Attikon” University Hospital
9 NKUA - National and Kapodistrian University of Athens
10 UOC - University of Crete [Heraklion]
11 St. Antonius Hospital [Nieuwegein]
12 Nanjing Medical University
13 CHRU Lille - Centre Hospitalier Régional Universitaire [CHU Lille]
14 Hôpital Avicenne [AP-HP]
15 Physiopathologie, Cibles et Thérapies de la Polyarthrite Rhumatoïde
16 CHRU Tours - Centre Hospitalier Régional Universitaire de Tours
17 Hôpital Lariboisière-Fernand-Widal [APHP]
18 BIOSCAR (UMR_S_1132 / U1132) - Biologie de l'Os et du Cartilage : Régulations et Ciblages Thérapeutiques
19 AP-HP - Hôpital Cochin Broca Hôtel Dieu [Paris]
20 IC UM3 (UMR 8104 / U1016) - Institut Cochin
21 Hôpital de Hautepierre [Strasbourg]
22 IRM - Immuno-Rhumatologie Moléculaire
23 UNISTRA - Université de Strasbourg
24 CHU Bordeaux
25 ImmunoConcept - Immunology from Concept and Experiments to Translation
26 CHU Tenon [AP-HP]
27 U933 - Maladies génétiques d'expression pédiatrique
28 CHU Trousseau [APHP]
29 CHU Clermont-Ferrand
30 UNH - Unité de Nutrition Humaine
31 IVPC - Infections Virales et Pathologie Comparée - UMR 754
32 Hôpital Louis Pradel [CHU - HCL]
33 NJH - National Jewish Health
34 Mayo Clinic and Mayo College of Medicine
35 New York University School of Medicine
36 McGill University = Université McGill [Montréal, Canada]
37 UC San Francisco - University of California [San Francisco]
38 BWH - Brigham & Women’s Hospital [Boston]
39 NIA - National Institute on Aging [Bethesda, USA]
Jorge Rojas-Serrano
- Fonction : Auteur
Montserrat I. Gonzalez-Perez
- Fonction : Auteur
Mayra Mejia
- Fonction : Auteur
Ivette Buendia-Roldan
- Fonction : Auteur
Ramces Falfan-Valencia
- Fonction : Auteur
Enrique Ambrocio-Ortiz
- Fonction : Auteur
Sylvain Marchand-Adam
- Fonction : Auteur
- PersonId : 989455
Christophe Richez
- Fonction : Auteur
- PersonId : 756184
- ORCID : 0000-0002-3029-8739
N. Nathan
- Fonction : Auteur
- PersonId : 1029287
- IdHAL : nadianathan
- ORCID : 0000-0001-5149-7975
S. Amselem
- Fonction : Auteur
- PersonId : 936326
- IdHAL : serge-amselem
- ORCID : 0000-0001-9506-3968
- IdRef : 066957761
M. Soubrier
- Fonction : Auteur
- PersonId : 760322
- ORCID : 0000-0001-9349-0720
- IdRef : 074723375
Annick Clement
- Fonction : Auteur
- PersonId : 1196743
Résumé
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=9.7x10(-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=4.7x10(-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=1.3x10(-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=7.4x10(-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=2.5x10(-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 Societe Francaise de Rhumatologie and others.).
Mots clés
Promoter Regions
Rheumatoid/complications/*genetics
Female
Humans
Male
Aged
Middle Aged
Genetic Predisposition to Disease
Genotype
Arthritis
Lung Diseases
Genetic
*Gain of Function Mutation
Idiopathic Pulmonary Fibrosis/genetics
Interstitial/complications/*genetics
Lung/chemistry/pathology
Mucin-5B/analysis/*genetics
Odds Ratio