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, Pierre-Antoine Juge Université de Paris Cité, INSERM UMR 1152 , Paris, F-75018, France Service de Rhumatologie, Hôpital Bichat-Claude Bernard, AP-HP , Paris, F-75018, France Search for other works by this author on: Oxford Academic Jeffrey A Sparks Division of Rheumatology, Inflammation, and Immunity, Brigham and Women’s Hospital , Boston, MA, USA Harvard Medical School , Boston, MA, USA Search for other works by this author on: Oxford Academic Steven Gazal Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California , Los Angeles, CA, USA Center for Genetic Epidemiology, Keck School of Medicine, University of Southern California , Los Angeles, CA, USA Search for other works by this author on: Oxford Academic Esther Ebstein Service de Rhumatologie, Hôpital Bichat-Claude Bernard, AP-HP , Paris, F-75018, France Search for other works by this author on: Oxford Academic Raphaël Borie Université de Paris Cité, INSERM UMR 1152 , Paris, F-75018, France Service de Pneumologie, Hôpital Bichat-Claude Bernard, AP-HP , Paris, F-75018, France Search for other works by this author on: Oxford Academic Marie-Pierre Debray Service de Radiologie, Hôpital Bichat-Claude Bernard, AP-HP , Paris, F-75018, France Search for other works by this author on: Oxford Academic Caroline Kannengiesser Université de Paris Cité, INSERM UMR 1152 , Paris, F-75018, France Service de Génétique, Hôpital Bichat-Claude Bernard, AP-HP , Paris, F-75018, France Search for other works by this author on: Oxford Academic Gregory C McDermott Division of Rheumatology, Inflammation, and Immunity, Brigham and Women’s Hospital , Boston, MA, USA Harvard Medical School , Boston, MA, USA Search for other works by this author on: Oxford Academic Jing Cui Division of Rheumatology, Inflammation, and Immunity, Brigham and Women’s Hospital , Boston, MA, USA Harvard Medical School , Boston, MA, USA Search for other works by this author on: Oxford Academic Keigo Hayashi Division of Rheumatology, Inflammation, and Immunity, Brigham and Women’s Hospital , Boston, MA, USA Harvard Medical School , Boston, MA, USA Search for other works by this author on: Oxford Academic
, Tracy J Doyle Division of Pulmonary and Critical Care, Brigham and Women's Hospital , Boston, MA, USA Harvard Medical School , Boston, MA, USA Search for other works by this author on: Oxford Academic Coline H M van Moorsel Interstitial Lung Disease Center of Excellence, Department of Pulmonology, St Antonius Hospital, Nieuwegein, The Netherlands; Division of Heart and Lungs, University Medical Center Utrecht , Utrecht, The Netherlands Search for other works by this author on: Oxford Academic Joanne J van der Vis Interstitial Lung Disease Center of Excellence, Department of Pulmonology, St Antonius Hospital, Nieuwegein, The Netherlands; Division of Heart and Lungs, University Medical Center Utrecht , Utrecht, The Netherlands Search for other works by this author on: Oxford Academic Jan C Grutters Interstitial Lung Disease Center of Excellence, Department of Pulmonology, St Antonius Hospital, Nieuwegein, The Netherlands; Division of Heart and Lungs, University Medical Center Utrecht , Utrecht, The Netherlands Search for other works by this author on: Oxford Academic Rachel Knevel Department of Rheumatology, Leiden University Medical Center , Leiden, The Netherlands Search for other works by this author on: Oxford Academic Sascha L Heckert Department of Rheumatology, Leiden University Medical Center , Leiden, The Netherlands Search for other works by this author on: Oxford Academic Eirini Vasarmidi Laboratory of Molecular and Cellular Pneumonology, Department of Respiratory Medicine, School of Medicine, University of Crete , Heraklion, Greece Search for other works by this author on: Oxford Academic Katerina M Antoniou Laboratory of Molecular and Cellular Pneumonology, Department of Respiratory Medicine, School of Medicine, University of Crete , Heraklion, Greece Search for other works by this author on: Oxford Academic Annette H M van der Helm van Mil Department of Rheumatology, Leiden University Medical Center , Leiden, The Netherlands Department of Rheumatology, Erasmus MC , Rotterdam, the Netherlands Search for other works by this author on: Oxford Academic Catherine Boileau Service de Génétique, Hôpital Bichat-Claude Bernard, AP-HP , Paris, F-75018, France Search for other works by this author on: Oxford Academic Bruno Crestani Université de Paris Cité, INSERM UMR 1152 , Paris, F-75018, France Service de Pneumologie, Hôpital Bichat-Claude Bernard, AP-HP , Paris, F-75018, France Search for other works by this author on: Oxford Academic Philippe Dieudé Université de Paris Cité, INSERM UMR 1152 , Paris, F-75018, France Service de Rhumatologie, Hôpital Bichat-Claude Bernard, AP-HP , Paris, F-75018, France Corresponding author: Philippe Dieudé, Service de Rhumatologie, Hôpital Bichat-Claude Bernard, 46, rue Henri Huchard, 75018 Paris, France, philippe.dieude@aphp.fr Search for other works by this author on: Oxford Academic
Rheumatology Advances in Practice, rkae059, https://doi.org/10.1093/rap/rkae059
Published:
04 June 2024
Article history
Received:
11 October 2023
Accepted:
05 April 2024
Published:
04 June 2024
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Pierre-Antoine Juge, Jeffrey A Sparks, Steven Gazal, Esther Ebstein, Raphaël Borie, Marie-Pierre Debray, Caroline Kannengiesser, Gregory C McDermott, Jing Cui, Keigo Hayashi, Tracy J Doyle, Coline H M van Moorsel, Joanne J van der Vis, Jan C Grutters, Rachel Knevel, Sascha L Heckert, Eirini Vasarmidi, Katerina M Antoniou, Annette H M van der Helm van Mil, Catherine Boileau, Bruno Crestani, Philippe Dieudé, RPA3-UMAD1 rs12702634 and rheumatoid arthritis-associated interstitial lung disease in European ancestry, Rheumatology Advances in Practice, 2024;, rkae059, https://doi.org/10.1093/rap/rkae059
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Abstract
Objective
Recently, a genome-wide association identified an association between rheumatoid arthritis (RA)-associated interstitial lung disease (ILD) and RPA3-UMAD1 rs12702634 in the Japanese population, especially for patients with a usual interstitial pneumonia (UIP) pattern. We aimed to replicate this association in a European population and test for interaction with MUC5B rs35705950.
Methods
In this genetic case-control association study, cases with RA with ILD and controls with RA and no ILD were included from France, the US, and the Netherlands. Only cases and controls from European genetic ancestries determined by principal component analysis were included in the analyses. RA was defined by 1987 ACR or 2010 ACR/EULAR criteria and ILD by chest high-resolution CT scan, except in the control dataset from The Netherlands where the absence of ILD was determined by chart review. Patients were genotyped for RPA3-UMAD1 rs12702634 and MUC5B rs35705950. Associations were tested using logistic regression adjusted for sex, age at RA onset, age at ILD onset or at certified absence of ILD, tobacco smoking status, and country of origin.
Results
Among the 883 patients included, 322 were RA-ILD cases (36.5%). MUC5B rs35705950 was strongly associated with RA-ILD in all datasets: combined adjusted OR = 2.9, 95%CI [2.1–3.9], P = 1.1x1 0 −11. No association between RPA3-UMAD1 rs12702634 and RA-ILD was observed: combined OR = 1.2 95%CI [0.8–1.6], p = 0.31. No interaction was found between RPA3-UMAD1 rs12702634 and MUC5B rs35705950 (p = 0.70).
Conclusion
Our findings did not support a contribution of RPA3-UMAD1 rs12702634 to the overall RA-ILD susceptibility in the European population.
Lay Summary
What does this mean for patients?
Interstitial lung disease (ILD) can develop in 10–60% of patients with rheumatoid arthritis (RA) and is associated with an increased risk of death. We do not yet fully understand why RA-ILD occurs, but risk factors include genetics and environmental factors such as tobacco smoking. Identifying new genetic risk factors for RA-ILD may improve our understanding of how this disease occurs, help us categorise patients in terms of their risk level, and help us to potentially identify new drug targets. A previous Japanese genetic study identified the RPA3-UMAD1, rs12702634 common genetic variant as a risk factor for RA-ILD. However, a second Japanese study failed to replicate these findings. In this international study including patients with European ancestry, we did not find that RPA3-UMAD1 rs12702634 contributed to overall risk of RA-ILD. Our findings highlight the importance of conducting analyses that try to replicate the results of a study. We also emphasise that genetic associations—even those already reported—require rigorous testing in different groups of people before we can conclude that they contribute to disease risk. Ongoing collaboration and multi-ancestry genetic studies are essential in order to advance our understanding of the complex genetics underlying RA-ILD.
Rheumatoid arthritis, Interstitial lung disease, genetic
Accepted manuscripts
Accepted manuscripts are PDF versions of the author’s final manuscript, as accepted for publication by the journal but prior to copyediting or typesetting. They can be cited using the author(s), article title, journal title, year of online publication, and DOI. They will be replaced by the final typeset articles, which may therefore contain changes. The DOI will remain the same throughout.
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© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
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