RMD Open (Aug 2025)
Assessing the MUC5B promoter variant in a large cohort of systemic sclerosis-associated interstitial lung disease
- ,
- Yannick Allanore,
- Marialbert Acosta-Herrera,
- Martin Kerick,
- Oliver Distler,
- Christopher P Denton,
- Alexandre E Voskuyl,
- Mandana Nikpour,
- Lorenzo Beretta,
- Javier Martin,
- Maureen D Mayes,
- Shervin Assassi,
- Ariane L Herrick,
- Alexander Kreuter,
- Nicolas Hunzelmann,
- P Airò,
- A Barton,
- G Riemekasten,
- Susanna M Proudman,
- F J López-Longo,
- E Beltrán,
- C Fonseca,
- B Fernandez-Gutierrez,
- A Nordin,
- M Freire,
- L Rodriguez-Rodriguez,
- G Major,
- Jeska K de Vries-Bouwstra,
- M A Gonzalez-Gay,
- G ESPINOSA,
- T R D J Radstake,
- A Gabrielli,
- F Diaz,
- V Ortiz-Santamaria,
- L Padyukov,
- G Orozco,
- T Witte,
- J Walker,
- W Stevens,
- C Lunardi,
- N Oreiro,
- José Luis Callejas,
- P Carreira,
- I Castellvi,
- R Ríos,
- R García Portales,
- A Fernández-Nebro,
- F J García-Hernández,
- M A Aguirre,
- P García de la Peña,
- E Vicente,
- J L Andreu,
- M Fernández de Castro,
- V Fonollosa,
- A Pros,
- M Rodríguez Carballeira,
- F J Narváez,
- M Rubio Rivas,
- A B Madroñero,
- B Díaz,
- L Trapiella,
- M V Egurbide,
- P Fanlo-Mateo,
- L Saez-Comet,
- J A Roman-Ivorra,
- J J Alegre Sancho,
- F J Blanco Garcia,
- C Magro,
- M C Vonk,
- R Hesselstrand,
- A Hoffmann-Vold,
- J H W Distler,
- J Sahhar,
- N Ortego-Centeno,
- B P C Koeleman,
- D Hansen,
- A Apostolopoulos,
- L Ross,
- G Moroncini,
- Alfredo Guillén-Del-Castillo,
- Carmen P Simeon-Aznar,
- Carlos Rosa-Baez,
- Carlos Rangel-Pelaez,
- Inmaculada Rodriguez-Martin,
- L Tío,
- N Ferdowsi,
- L V Host,
- G S Ngian,
- A Quinlivan,
- M Tabesh
Affiliations
- Yannick Allanore
- Department of Rheumatology, Université Paris Cité UFR de Médecine, Paris, France
- Marialbert Acosta-Herrera
- Department of Cell Biology and Immunology, Institute of Parasitology and Biomedicine Lopez-Neyra, CSIC, Granada, Spain
- Martin Kerick
- Department of Cell Biology and Immunology, Institute of Parasitology and Biomedicine Lopez-Neyra, CSIC, Granada, Spain
- Oliver Distler
- Department of Rheumatology, University Hospital Zürich Center of Experimental Rheumatology, Zürich, Switzerland
- Christopher P Denton
- Division of Medicine, University College London, London, UK
- Alexandre E Voskuyl
- Department of Rheumatology and Clinical Immunology, Amsterdam Rheumatology and immunology Center, Amsterdam UMC, Amsterdam, Netherlands
- Mandana Nikpour
- University of Sydney School of Public Health, Royal Prince Alfred Hospital Sydney, and Sydney MSK Research Flagship Centre, University of Sydney, Sydney, New South Wales, Australia
- Lorenzo Beretta
- Referral Center for Systemic Autoimmune Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico di Milano, Milan, Italy
- Javier Martin
- Department of Cell Biology and Immunology, Institute of Parasitology and Biomedicine Lopez-Neyra, CSIC, Granada, Spain
- Maureen D Mayes
- Division of Rheumatology, Department of internal medicine, The University of Texas Health Science Center at Houston, Houston, Texas, USA
- Shervin Assassi
- Division of Rheumatology, Department of internal medicine, The University of Texas Health Science Center at Houston, Houston, Texas, USA
- Ariane L Herrick
- NIHR Manchester Biomedical Research Centre, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK
- Alexander Kreuter
- Department of Dermatology, Venereology, and Allergology, Helios St. Elisabeth Klinik Oberhausen, University Witten-Herdecke, Oberhausen, Germany
- Nicolas Hunzelmann
- Department of Dermatology and Venereology, University Hospital Cologne, Cologne, Germany
- P Airò
- A Barton
- G Riemekasten
- Susanna M Proudman
- Rheumatology Unit, Royal Adelaide Hospital and University of Adelaide, Adelaide, Victoria, Australia
- F J López-Longo
- E Beltrán
- C Fonseca
- B Fernandez-Gutierrez
- A Nordin
- M Freire
- L Rodriguez-Rodriguez
- G Major
- Jeska K de Vries-Bouwstra
- Department of Rheumatology, Leiden University Medical Center, Leiden, Netherlands
- M A Gonzalez-Gay
- G ESPINOSA
- T R D J Radstake
- A Gabrielli
- F Diaz
- V Ortiz-Santamaria
- L Padyukov
- G Orozco
- T Witte
- J Walker
- W Stevens
- C Lunardi
- N Oreiro
- José Luis Callejas
- Department of Internal Medicine, Hospital San Cecilio, Granada, Spain
- P Carreira
- I Castellvi
- R Ríos
- R García Portales
- A Fernández-Nebro
- F J García-Hernández
- M A Aguirre
- P García de la Peña
- E Vicente
- J L Andreu
- M Fernández de Castro
- V Fonollosa
- A Pros
- M Rodríguez Carballeira
- F J Narváez
- M Rubio Rivas
- A B Madroñero
- B Díaz
- L Trapiella
- M V Egurbide
- P Fanlo-Mateo
- L Saez-Comet
- J A Roman-Ivorra
- J J Alegre Sancho
- F J Blanco Garcia
- C Magro
- M C Vonk
- R Hesselstrand
- A Hoffmann-Vold
- J H W Distler
- J Sahhar
- N Ortego-Centeno
- B P C Koeleman
- D Hansen
- A Apostolopoulos
- L Ross
- G Moroncini
- Alfredo Guillén-Del-Castillo
- Unit of Autoimmune Diseases, Department of Internal Medicine, Hospital Universitario Vall d’Hebron, Barcelona, Spain
- Carmen P Simeon-Aznar
- Unit of Autoimmune Diseases, Department of Internal Medicine, Hospital Universitario Vall d’Hebron, Barcelona, Spain
- Carlos Rosa-Baez
- Department of Cell Biology and Immunology, Institute of Parasitology and Biomedicine Lopez-Neyra, CSIC, Granada, Spain
- Carlos Rangel-Pelaez
- Department of Cell Biology and Immunology, Institute of Parasitology and Biomedicine Lopez-Neyra, CSIC, Granada, Spain
- Inmaculada Rodriguez-Martin
- Department of Cell Biology and Immunology, Institute of Parasitology and Biomedicine Lopez-Neyra, CSIC, Granada, Spain
- L Tío
- N Ferdowsi
- L V Host
- G S Ngian
- A Quinlivan
- M Tabesh
- DOI
- https://doi.org/10.1136/rmdopen-2025-005754
- Journal volume & issue
-
Vol. 11,
no. 3
Abstract
Objective The common gain-of-function variant rs35705950, located in the promoter of MUC5B gene, has been strongly associated with interstitial lung diseases (ILDs) of different aetiology, such as idiopathic pulmonary fibrosis (IPF) and rheumatoid arthritis-associated ILD (RA-ILD). In this study, we aimed to investigate the association of this variant and its nearby single nucleotide polymorphisms (SNPs) in the largest cohort of systemic sclerosis-associated ILD (SSc-ILD) to date.Methods Samples were collected from blood/saliva, followed by DNA extraction and genotyping using SNP arrays. Data for rs35705950 and additional 903 variants within 100 Kb were obtained using genomic imputation. Subsequently, we tested their association in a meta-analysis to increase the consistency of the results, including 10 European ancestry cohorts comprising 2363 patients with SSc-ILD, 3526 SSc patients without ILD and 15 076 controls.Results Meta-analysis showed no significant association between rs35705950 and SSc-ILD, either comparing patients with SSc with and without ILD (p value: 0.588, OR: 1.05, 95% CI: 0.87 to 1.27) nor patients with SSc-ILD with controls (p value: 0.061, OR: 1.16, 95% CI: 0.99 to 1.36). Moreover, none of the additional 903 variants tested in the genomic region reached statistical significance.Conclusion Despite analysing the largest and most statistically powered SSc-ILD cohort to date, we found no evidence of association between the MUC5B promoter variant rs35705950 and its surrounding SNPs with SSc-ILD. These results suggest that the pathogenic mechanisms underlying SSc-ILD may only partially overlap with those of other similar ILDs, such as IPF or RA-ILD. This highlights the need for further studies regarding their genetic architecture.
