From Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Bichat-Claude Bernard, Departments of Rheumatology (P.-A.J., E.E., S. Ottaviani, P.D.), Genetics (C.K., C. Boileau), Pulmonology A (R.B., B.C.), Pulmonology B (G.T.), and Radiology (M.-P.D.), Département Hospitalo-Universitaire Fibrose Inflammation Remodelage, INSERM Unité Mixte de Recherche (UMR) 1152, Université Paris Diderot (P.-A.J., C.K., R.B., G.T., B.C., P.D.), Arthritis Recherche et Développement (P.-A.J.), AP-HP, Hôpital Lariboisière, Service de Rhumatologie (A. Frazier, P.R.), INSERM, UMR 1132 (P.R.), AP-HP, Hôpital Cochin, Service de Rhumatologie A, and INSERM, Unité 1016, UMR 8104 (Y.A.), AP-HP, Hôpital Tenon, Service de Pneumologie (H.L.), AP-HP, Service de Pneumologie Pédiatrique et Centre de Référence des Maladies Respiratoires Rares, and INSERM UMR S933 (N.N., S.A., A.C.), and AP-HP, Département de Génétique, Hôpital Trousseau (S.A.), Paris, Centre Hospitalier Régional Universitaire (CHRU) de Lille, Service de Pneumologie et Immuno-Allergologie, Centre de Compétence des Maladies Pulmonaires Rares, Fédératif Hospitalo-Universitaire Immune-Mediated Inflammatory Diseases and Targeted Therapies (L.W.-S., B.W.), and Centre Hospitalier Universitaire (CHU) de Lille, Service de Rhumatologie (R.-M.F.), Lille, the Departments of Pulmonology (H.N., D.V.) and Rheumatology (N.S.-K., M.-C.B.), Hôpital Avicenne, AP-HP, INSERM UMR 1125 (N.S.-K., M.-C.B.), and Université Paris 13, Sorbonne Paris Cité (N.S.-K., M.-C.B.), Bobigny, the Department of Pulmonology, CHRU Tours, Tours (S.M.-A.), CHRU de Strasbourg, Service de Rhumatologie, Hôpital de Hautepierre, INSERM UMR S1109, and Laboratoire d'Immuno-Rhumatologie Moléculaire, Centre de Recherche en Histoire des Idées, Fédération de Médecine Translationnelle de Strasbourg, Université de Strasbourg, Strasbourg (J. Sibilia), Service de Pneumologie (C.D.) and Service de Rhumatologie (C.R., T.S.), CHU de Bordeaux, and ImmunoConcEpT, Centre National de la Recherche Scientifique UMR 5164 (C.R., T.S.), Bordeaux, CHU Clermont-Ferrand, Service de Rhumatologie, Institut National de la Recherche Agronomique (INRA), UMR 1019, Unité de Nutrition Humaine, Centre de Recherche en Nutrition Humaine Auvergne, Clermont-Ferrand (M.S.), and Hospices Civils de Lyon, Hôpital Louis Pradel, Centre National de Référence des Maladies Pulmonaires Rares, and INRA, UMR 754, Université Claude Bernard Lyon 1, Lyon, (V.C.) - all in France; the Departments of Medicine (J.S.L., E.D., K.D., A.D.W., A. Fischer, M.I.S., M.H., D.A.S.) and Immunology and Microbiology (D.A.S.), University of Colorado School of Medicine, Aurora, and the Departments of Biomedical Research (T.F.) and Medicine (J.J. Solomon), National Jewish Health, Denver - both in Colorado; the Molecular and Genetic Epidemiology Laboratory, Faculty of Medicine, University of Tsukuba, Tsukuba (H.F., S. Oka, N.T.), and the Clinical Research Center for Allergy and Rheumatology, National Hospital Organization Sagamihara National Hospital, Sagamihara (H.F., S. Oka, S.T.) - both in Japan; the Department of Epidemiology, Harvard T.H. Chan School of Public Health (S.G.), and the Department of Medicine, Brigham and Women's Hospital (T.D., I.O.R.), Boston, and the Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge (S.G.) - all in Massachusetts; the Interstitial Lung Disease and Rheumatology Unit (J.R.-S., M.I.G.-P., M.M., I.B.-R.) and the HLA Laboratory (R.F.-V., E.A.-O.), Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, Mexico City; the 2nd Pulmonary Medicine Department (E.M., S.A.P.) and the Rheumatology and Clinical Immunology Unit, 4th Department of Internal Medicine (T.K., D.B.), University Hospital of Athens "Attikon," National and Kapodistrian University of Athens, Athens, and the Department of Respiratory Medicine and the Laboratory of Molecular and Cellular Pneumonology, Faculty of Medicine, University of Crete, Crete (K.A.) - both in Greece; St. Antonius ILD Center of Excellence, St. Antonius Ziekenhuis, Nieuwegein, the Netherlands (C.H.M.M., J.V., Y.A.M., J.C.G.); the Department of Medical Genetics, Nanjing University School of Medicine, Nanjing, China (Y.W.); the Divisions of Pulmonary and Critical Care Medicine (J.H.R.) and Rheumatology (E.L.M.), Mayo Clinic College of Medicine and Science, Rochester, MN; the Colton Center for Autoimmunity, New York University School of Medicine, New York (T.B.N.); the Department of Medicine, McGill University, Montreal (D.A.); the Department of Medicine, University of California, San Francisco, San Francisco (A.G., P.W.); and Data Tecnica International, Glen Echo, and the Laboratory of Neurogenetics, National Institute on Aging, Bethesda - both in Maryland (C. Blauwendraat, M.A.N.).
N Engl J Med. 2018 Dec 6;379(23):2209-2219. doi: 10.1056/NEJMoa1801562. Epub 2018 Oct 20.
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.
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.
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). 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) 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). 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), 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). However, no significant association with the MUC5B promoter variant was observed for the diagnosis of RA alone.
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 Société Française de Rhumatologie and others.).
鉴于类风湿关节炎（RA）相关间质性肺病（ILD）（以下简称 RA-ILD）和特发性肺纤维化之间的表型相似性，我们假设特发性肺纤维化最强的风险因素，即功能获得性 MUC5B 启动子变异 rs35705950，也会导致 RA 患者发生 ILD。
使用发现人群和多个验证人群，我们检测了 620 例 RA-ILD 患者、614 例 RA 无 ILD 患者和 5448 例未受影响的对照者中 MUC5B 启动子变异 rs35705950 的相关性。
发现人群的分析显示，当 RA-ILD 患者与未受影响的对照者相比时，MUC5B 启动子变异的次要等位基因与 RA-ILD 相关（调整后的优势比，3.8；95%置信区间[CI]，2.8 至 5.2；P=9.7×10）。在多民族病例系列分析中（调整后的优势比，5.5；95%CI，4.2 至 7.3；P=4.7×10）和发现人群与多民族病例系列的综合分析中（调整后的优势比，4.7；95%CI，3.9 至 5.8；P=1.3×10），MUC5B 启动子变异在 RA-ILD 患者中也明显高于未受影响的对照者。此外，MUC5B 启动子变异与 RA 患者的 ILD 风险增加相关（综合分析中的调整后优势比，3.1；95%CI，1.8 至 5.4；P=7.4×10），尤其是在高分辨率计算机断层扫描（HRCT）上有典型间质性肺炎证据的患者中（综合分析中的调整后优势比，6.1；95%CI，2.9 至 13.1；P=2.5×10）。然而，对于 RA 的单独诊断，与 MUC5B 启动子变异无显著相关性。
我们发现 MUC5B 启动子变异与 RA-ILD 相关，更具体地说，与影像学上的典型间质性肺炎相关。（由法国风湿病学会等资助）。
