Frontiers in Medicine (Aug 2023)
Genetic and geographic influence on phenotypic variation in European sarcoidosis patients
- Sandra Freitag-Wolf,
- Jonas C. Schupp,
- Jonas C. Schupp,
- Jonas C. Schupp,
- Björn C. Frye,
- Annegret Fischer,
- Raihanatul Anwar,
- Robert Kieszko,
- Violeta Mihailović-Vučinić,
- Janusz Milanowski,
- Dragana Jovanovic,
- Gernot Zissel,
- Elena Bargagli,
- Paola Rottoli,
- Dragos Bumbacea,
- René Jonkers,
- Ling-Pei Ho,
- Karoline I. Gaede,
- Anna Dubaniewicz,
- Ben G. Marshall,
- Andreas Günther,
- Martin Petrek,
- Michael P. Keane,
- Sigridur O. Haraldsdottir,
- Francesco Bonella,
- Christian Grah,
- Tatjana Peroš-Golubičić,
- Zamir Kadija,
- Stefan Pabst,
- Christian Grohé,
- János Strausz,
- Martina Safrankova,
- Ann Millar,
- Jiří Homolka,
- Wim A. Wuyts,
- Lisa G. Spencer,
- Michael Pfeifer,
- Dominique Valeyre,
- Venerino Poletti,
- Hubertus Wirtz,
- Antje Prasse,
- Antje Prasse,
- Stefan Schreiber,
- Stefan Schreiber,
- Astrid Dempfle,
- Joachim Müller-Quernheim
Affiliations
- Sandra Freitag-Wolf
- Institute of Medical Informatics and Statistics, Kiel University, Kiel, Germany
- Jonas C. Schupp
- Department of Pneumology, Faculty of Medicine, University Medical Centre, Freiburg, Germany
- Jonas C. Schupp
- Department of Respiratory Medicine, Hannover Medical School, German Center for Lung Research (DZL), Hannover, Germany
- Jonas C. Schupp
- Biomedical Research in End-Stage and Obstructive Lung Disease (BREATH), Hannover Medical School (MHH), German Center for Lung Research (DZL), Hannover, Germany
- Björn C. Frye
- Department of Pneumology, Faculty of Medicine, University Medical Centre, Freiburg, Germany
- Annegret Fischer
- Institute of Clinical Molecular Biology, Kiel University, Kiel, Germany
- Raihanatul Anwar
- Institute of Medical Informatics and Statistics, Kiel University, Kiel, Germany
- Robert Kieszko
- Department of Pneumonology, Oncology and Allergology, Medical University of Lublin, Lublin, Poland
- Violeta Mihailović-Vučinić
- Department of Pneumology, University Hospital, Belgrade, Serbia
- Janusz Milanowski
- Department of Pneumonology, Oncology and Allergology, Medical University of Lublin, Lublin, Poland
- Dragana Jovanovic
- Department of Pneumology, University Hospital, Belgrade, Serbia
- Gernot Zissel
- Department of Pneumology, Faculty of Medicine, University Medical Centre, Freiburg, Germany
- Elena Bargagli
- Respiratory Diseases and Lung Transplant Unit, University Hospital, Siena, Italy
- Paola Rottoli
- Respiratory Diseases and Lung Transplant Unit, University Hospital, Siena, Italy
- Dragos Bumbacea
- Department of Cardio-Thoracic Medicine, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
- René Jonkers
- 0Pulmonology Department, Academic Medical Center Amsterdam, Amsterdam, Netherlands
- Ling-Pei Ho
- 1Oxford Sarcoidosis Service, Oxford University Hospitals NHS Foundation Trust, Churchill Hospital, Oxford, United Kingdom
- Karoline I. Gaede
- 2Medical Hospital, Research Center Borstel, Borstel, Germany
- Anna Dubaniewicz
- 3Department of Pulmonology, Medical University of Gdansk, Gdansk, Poland
- Ben G. Marshall
- 4Department of Respiratory Medicine, University Hospital, Southampton, United Kingdom
- Andreas Günther
- 5Department of Pneumology and Intensive Care, University Hospital, Giessen, Germany
- Martin Petrek
- 6Faculty of Medicine and Dentistry, Palacký University and University Hospital Olomouc, Olomouc, Czechia
- Michael P. Keane
- 7Division of Pulmonary and Critical Care Medicine, University College Dublin and St Vincent’s University Hospital, Dublin, Ireland
- Sigridur O. Haraldsdottir
- 8Landspitali, University Hospital, Reykjavik, Iceland
- Francesco Bonella
- 9Ruhrlandklinik, Westdeutsches Lungenzentrum am Universitätsklinikum Essen, Universitätsklinik Essen, Essen, Germany
- Christian Grah
- 0Hospital Berlin-Havelhöhe, Berlin, Germany
- Tatjana Peroš-Golubičić
- 1Pulmonary Department, University Hospital Jordanovac, Zagreb, Croatia
- Zamir Kadija
- 2Foundation IRCCS Policlinico San Matteo - Pulmonology Unit, Pavia, Italy
- Stefan Pabst
- 3Department of Pneumology, University Hospital, Bonn, Germany
- Christian Grohé
- 4Evangelische Lungenklinik Berlin, Berlin, Germany
- János Strausz
- 5National Koranyi Institute, Budapest, Hungary
- Martina Safrankova
- 6Thomayer Hospital and 1st Faculty of Medicine, Charles University, Praha, Czechia
- Ann Millar
- 7Pulmonary Department, University Hospital, Bristol, United Kingdom
- Jiří Homolka
- 8Prague General Hospital, Charles University, Prague, Czechia
- Wim A. Wuyts
- 9Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), University Hospital, Leuven, Belgium
- Lisa G. Spencer
- 0Liverpool Interstitial Lung Disease Service, Aintree Chest Centre, Liverpool University Hospitals NHS FT, Liverpool, United Kingdom
- Michael Pfeifer
- 1Department of Pneumology, University Hospital Regensburg, Regensburg, Germany
- Dominique Valeyre
- 2Groupe Hospitalier Avicenne-Jean Verdier-René Muret, Service de Pneumologie, Bobigny, France
- Venerino Poletti
- 3Pulmonary Unit, Department of Thoracic Diseases, Azienda USL Romagna, GB Morgagni-L-Pierantoni Hospital, Forlì, Italy
- Hubertus Wirtz
- 4Department of Pneumology, University Hospital Leipzig, Leipzig, Germany
- Antje Prasse
- Department of Pneumology, Faculty of Medicine, University Medical Centre, Freiburg, Germany
- Antje Prasse
- Department of Respiratory Medicine, Hannover Medical School, German Center for Lung Research (DZL), Hannover, Germany
- Stefan Schreiber
- Institute of Clinical Molecular Biology, Kiel University, Kiel, Germany
- Stefan Schreiber
- 5Department of Internal Medicine I, University Hospital Schleswig-Holstein, Kiel, Germany
- Astrid Dempfle
- Institute of Medical Informatics and Statistics, Kiel University, Kiel, Germany
- Joachim Müller-Quernheim
- Department of Pneumology, Faculty of Medicine, University Medical Centre, Freiburg, Germany
- DOI
- https://doi.org/10.3389/fmed.2023.1218106
- Journal volume & issue
-
Vol. 10
Abstract
IntroductionSarcoidosis is a highly variable disease in terms of organ involvement, type of onset and course. Associations of genetic polymorphisms with sarcoidosis phenotypes have been observed and suggest genetic signatures.MethodsAfter obtaining a positive vote of the competent ethics committee we genotyped 1909 patients of the deeply phenotyped Genetic-Phenotype Relationship in Sarcoidosis (GenPhenReSa) cohort of 31 European centers in 12 countries with 116 potentially disease-relevant single-nucleotide polymorphisms (SNPs). Using a meta-analysis, we investigated the association of relevant phenotypes (acute vs. sub-acute onset, phenotypes of organ involvement, specific organ involvements, and specific symptoms) with genetic markers. Subgroups were built on the basis of geographical, clinical and hospital provision considerations.ResultsIn the meta-analysis of the full cohort, there was no significant genetic association with any considered phenotype after correcting for multiple testing. In the largest sub-cohort (Serbia), we confirmed the known association of acute onset with TNF and reported a new association of acute onset an HLA polymorphism. Multi-locus models with sets of three SNPs in different genes showed strong associations with the acute onset phenotype in Serbia and Lublin (Poland) demonstrating potential region-specific genetic links with clinical features, including recently described phenotypes of organ involvement.DiscussionThe observed associations between genetic variants and sarcoidosis phenotypes in subgroups suggest that gene–environment-interactions may influence the clinical phenotype. In addition, we show that two different sets of genetic variants are permissive for the same phenotype of acute disease only in two geographic subcohorts pointing to interactions of genetic signatures with different local environmental factors. Our results represent an important step towards understanding the genetic architecture of sarcoidosis.
Keywords
- genetic polymorphism
- genetic risk factors
- sarcoidosis
- genotype–phenotype-relationship
- region-specific genetic links
