MUC5B promoter variant and rheumatoid arthritis with interstitial lung disease

P. A. Juge; J. S. Lee; E. Ebstein; H. Furukawa; E. Dobrinskikh; S. Gazal; C. Kannengiesser; S. Ottaviani; S. Oka; S. Tohma; N. Tsuchiya; J. Rojas-Serrano; M. I. González-Pérez; M. Mejía; I. Buendía-Roldán; R. Falfán-Valencia; E. Ambrocio-Ortiz; E. Manali; S. A. Papiris; T. Karageorgas; D. Boumpas; K. Antoniou; C. H.M. Van Moorsel; J. Van Der Vis; Y. A. De Man; J. C. Grutters; Y. Wang; R. Borie; L. Wemeau-Stervinou; B. Wallaert; R. M. Flipo; H. Nunes; D. Valeyre; N. Saidenberg-Kermanac'H; M. C. Boissier; S. Marchand-Adam; A. Frazier; P. Richette; Y. Allanore; J. Sibilia; C. Dromer; C. Richez; T. Schaeverbeke; H. Lioté; G. Thabut; N. Nathan; S. Amselem; M. Soubrier; V. Cottin; A. Clément; K. Deane; A. D. Walts; T. Fingerlin; A. Fischer; J. H. Ryu; E. L. Matteson; T. B. Niewold; D. Assayag; A. Gross; P. Wolters; M. I. Schwarz; M. Holers; J. J. Solomon; T. Doyle; I. O. Rosas; C. Blauwendraat; M. A. Nalls; M. P. Debray; C. Boileau; B. Crestani; D. A. Schwartz; P. Dieudé

doi:10.1056/NEJMoa1801562

MUC5B promoter variant and rheumatoid arthritis with interstitial lung disease

P. A. Juge
, J. S. Lee
, E. Ebstein
, H. Furukawa
, E. Dobrinskikh
, S. Gazal
, C. Kannengiesser
, S. Ottaviani
, S. Oka
, S. Tohma
, N. Tsuchiya
, J. Rojas-Serrano
, M. I. González-Pérez
, M. Mejía
, I. Buendía-Roldán
, R. Falfán-Valencia
, E. Ambrocio-Ortiz
, E. Manali
, S. A. Papiris
, T. Karageorgas

D. Boumpas, K. Antoniou, C. H.M. Van Moorsel, J. Van Der Vis, Y. A. De Man, J. C. Grutters, Y. Wang, R. Borie, L. Wemeau-Stervinou, B. Wallaert, R. M. Flipo, H. Nunes, D. Valeyre, N. Saidenberg-Kermanac'H, M. C. Boissier, S. Marchand-Adam, A. Frazier, P. Richette, Y. Allanore, J. Sibilia, C. Dromer, C. Richez, T. Schaeverbeke, H. Lioté, G. Thabut, N. Nathan, S. Amselem, M. Soubrier, V. Cottin, A. Clément, K. Deane, A. D. Walts, T. Fingerlin, A. Fischer, J. H. Ryu, E. L. Matteson, T. B. Niewold, D. Assayag, A. Gross, P. Wolters, M. I. Schwarz, M. Holers, J. J. Solomon, T. Doyle, I. O. Rosas, C. Blauwendraat, M. A. Nalls, M. P. Debray, C. Boileau, B. Crestani, D. A. Schwartz^*, P. Dieudé

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

238 Citations (Scopus)

Abstract

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 = 9.7×10^-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 = 4.7×10^-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 = 1.3×10^-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 = 7.4×10^-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 = 2.5×10^-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.

Original language	English
Pages (from-to)	2209-2219
Number of pages	11
Journal	New England Journal of Medicine
Volume	379
Issue number	23
DOIs	https://doi.org/10.1056/NEJMoa1801562
Publication status	Published - 6 Dec 2018
Externally published	Yes

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10.1056/NEJMoa1801562

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Juge, P. A., Lee, J. S., Ebstein, E., Furukawa, H., Dobrinskikh, E., Gazal, S., Kannengiesser, C., Ottaviani, S., Oka, S., Tohma, S., Tsuchiya, N., Rojas-Serrano, J., González-Pérez, M. I., Mejía, M., Buendía-Roldán, I., Falfán-Valencia, R., Ambrocio-Ortiz, E., Manali, E., Papiris, S. A., ... Dieudé, P. (2018). MUC5B promoter variant and rheumatoid arthritis with interstitial lung disease. New England Journal of Medicine, 379(23), 2209-2219. https://doi.org/10.1056/NEJMoa1801562

@article{f08321c1fa2047d7a7189591cb8e689d,

title = "MUC5B promoter variant and rheumatoid arthritis with interstitial lung disease",

abstract = "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 = 9.7×10-17). 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 = 4.7×10-35) 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 = 1.3×10-49). 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 = 7.4×10-5), 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 = 2.5×10-6). 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.",

author = "Juge, \{P. A.\} and Lee, \{J. S.\} and E. Ebstein and H. Furukawa and E. Dobrinskikh and S. Gazal and C. Kannengiesser and S. Ottaviani and S. Oka and S. Tohma and N. Tsuchiya and J. Rojas-Serrano and Gonz{\'a}lez-P{\'e}rez, \{M. I.\} and M. Mej{\'i}a and I. Buend{\'i}a-Rold{\'a}n and R. Falf{\'a}n-Valencia and E. Ambrocio-Ortiz and E. Manali and Papiris, \{S. A.\} and T. Karageorgas and D. Boumpas and K. Antoniou and \{Van Moorsel\}, \{C. H.M.\} and \{Van Der Vis\}, J. and \{De Man\}, \{Y. A.\} and Grutters, \{J. C.\} and Y. Wang and R. Borie and L. Wemeau-Stervinou and B. Wallaert and Flipo, \{R. M.\} and H. Nunes and D. Valeyre and N. Saidenberg-Kermanac'H and Boissier, \{M. C.\} and S. Marchand-Adam and A. Frazier and P. Richette and Y. Allanore and J. Sibilia and C. Dromer and C. Richez and T. Schaeverbeke and H. Liot{\'e} and G. Thabut and N. Nathan and S. Amselem and M. Soubrier and V. Cottin and A. Cl{\'e}ment and K. Deane and Walts, \{A. D.\} and T. Fingerlin and A. Fischer and Ryu, \{J. H.\} and Matteson, \{E. L.\} and Niewold, \{T. B.\} and D. Assayag and A. Gross and P. Wolters and Schwarz, \{M. I.\} and M. Holers and Solomon, \{J. J.\} and T. Doyle and Rosas, \{I. O.\} and C. Blauwendraat and Nalls, \{M. A.\} and Debray, \{M. P.\} and C. Boileau and B. Crestani and Schwartz, \{D. A.\} and P. Dieud{\'e}",

note = "Funding Information: Supported by grants from Soci{\'e}t{\'e} Fran{\c c}aise de Rhumatologie; Fondation Arthritis; D{\'e}partement Hospitalo-Universitaire Fibrose Inflammation Remodelage; National Heart, Lung, and Blood Institute (UH2/3-HL123442, R01-HL097163, R21/R33-HL120770, P01-HL092870, and K23-HL138131); National Institute of Arthritis and Musculoskeletal and Skin Diseases (K23-AR051461); National Institute of Allergy and Infectious Diseases (U01-AI101981); U.S. Department of Defense (W81XWH-17-1-0597); National Center for Advancing Translational Science (UCSF-CTI KL2TR000143); the Nina Ireland Program for Lung Health; the Intramural Research Program of the National Institute on Aging, part of the National Institutes of Health, Department of Health and Human Services (Z01-AG000949-02); and the Japanese Society for the Promotion of Science. Publisher Copyright: Copyright {\textcopyright} 2018 Massachusetts Medical Society.",

year = "2018",

month = dec,

day = "6",

doi = "10.1056/NEJMoa1801562",

language = "English",

volume = "379",

pages = "2209--2219",

journal = "New England Journal of Medicine",

issn = "0028-4793",

publisher = "Massachussetts Medical Society",

number = "23",

}

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, Falfán-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-Kermanac'H, N, Boissier, MC, Marchand-Adam, 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, K, Walts, AD, Fingerlin, T, Fischer, A, Ryu, JH, Matteson, EL, Niewold, TB, Assayag, D, Gross, A, Wolters, P, Schwarz, MI, Holers, M, Solomon, JJ, Doyle, T, Rosas, IO, Blauwendraat, C, Nalls, MA, Debray, MP, Boileau, C, Crestani, B, Schwartz, DA & Dieudé, P 2018, 'MUC5B promoter variant and rheumatoid arthritis with interstitial lung disease', New England Journal of Medicine, vol. 379, no. 23, pp. 2209-2219. https://doi.org/10.1056/NEJMoa1801562

TY - JOUR

T1 - MUC5B promoter variant and rheumatoid arthritis with interstitial lung disease

AU - Juge, P. A.

AU - Lee, J. S.

AU - Ebstein, E.

AU - Furukawa, H.

AU - Dobrinskikh, E.

AU - Gazal, S.

AU - Kannengiesser, C.

AU - Ottaviani, S.

AU - Oka, S.

AU - Tohma, S.

AU - Tsuchiya, N.

AU - Rojas-Serrano, J.

AU - González-Pérez, M. I.

AU - Mejía, M.

AU - Buendía-Roldán, I.

AU - Falfán-Valencia, R.

AU - Ambrocio-Ortiz, E.

AU - Manali, E.

AU - Papiris, S. A.

AU - Karageorgas, T.

AU - Boumpas, D.

AU - Antoniou, K.

AU - Van Moorsel, C. H.M.

AU - Van Der Vis, J.

AU - De Man, Y. A.

AU - Grutters, J. C.

AU - Wang, Y.

AU - Borie, R.

AU - Wemeau-Stervinou, L.

AU - Wallaert, B.

AU - Flipo, R. M.

AU - Nunes, H.

AU - Valeyre, D.

AU - Saidenberg-Kermanac'H, N.

AU - Boissier, M. C.

AU - Marchand-Adam, S.

AU - Frazier, A.

AU - Richette, P.

AU - Allanore, Y.

AU - Sibilia, J.

AU - Dromer, C.

AU - Richez, C.

AU - Schaeverbeke, T.

AU - Lioté, H.

AU - Thabut, G.

AU - Nathan, N.

AU - Amselem, S.

AU - Soubrier, M.

AU - Cottin, V.

AU - Clément, A.

AU - Deane, K.

AU - Walts, A. D.

AU - Fingerlin, T.

AU - Fischer, A.

AU - Ryu, J. H.

AU - Matteson, E. L.

AU - Niewold, T. B.

AU - Assayag, D.

AU - Gross, A.

AU - Wolters, P.

AU - Schwarz, M. I.

AU - Holers, M.

AU - Solomon, J. J.

AU - Doyle, T.

AU - Rosas, I. O.

AU - Blauwendraat, C.

AU - Nalls, M. A.

AU - Debray, M. P.

AU - Boileau, C.

AU - Crestani, B.

AU - Schwartz, D. A.

AU - Dieudé, P.

N1 - Funding Information: Supported by grants from Société Française de Rhumatologie; Fondation Arthritis; Département Hospitalo-Universitaire Fibrose Inflammation Remodelage; National Heart, Lung, and Blood Institute (UH2/3-HL123442, R01-HL097163, R21/R33-HL120770, P01-HL092870, and K23-HL138131); National Institute of Arthritis and Musculoskeletal and Skin Diseases (K23-AR051461); National Institute of Allergy and Infectious Diseases (U01-AI101981); U.S. Department of Defense (W81XWH-17-1-0597); National Center for Advancing Translational Science (UCSF-CTI KL2TR000143); the Nina Ireland Program for Lung Health; the Intramural Research Program of the National Institute on Aging, part of the National Institutes of Health, Department of Health and Human Services (Z01-AG000949-02); and the Japanese Society for the Promotion of Science. Publisher Copyright: Copyright © 2018 Massachusetts Medical Society.

PY - 2018/12/6

Y1 - 2018/12/6

N2 - 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 = 9.7×10-17). 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 = 4.7×10-35) 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 = 1.3×10-49). 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 = 7.4×10-5), 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 = 2.5×10-6). 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.

AB - 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 = 9.7×10-17). 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 = 4.7×10-35) 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 = 1.3×10-49). 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 = 7.4×10-5), 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 = 2.5×10-6). 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.

UR - https://www.scopus.com/pages/publications/85058236740

U2 - 10.1056/NEJMoa1801562

DO - 10.1056/NEJMoa1801562

M3 - Article

C2 - 30345907

AN - SCOPUS:85058236740

SN - 0028-4793

VL - 379

SP - 2209

EP - 2219

JO - New England Journal of Medicine

JF - New England Journal of Medicine

IS - 23

ER -

MUC5B promoter variant and rheumatoid arthritis with interstitial lung disease

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