INTRODUCTION: Sarcoidosis 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. METHODS: After 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. RESULTS: In 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. DISCUSSION: The 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.

Biomedical Research in End Stage and Obstructive Lung Disease Hannover Germany

Department of Cardio Thoracic Medicine Carol Davila University of Medicine and Pharmacy Bucharest Romania

Department of Internal Medicine 1 University Hospital Schleswig Holstein Kiel Germany

Department of Pneumology and Intensive Care University Hospital Giessen Germany

Department of Pneumology Faculty of Medicine University Medical Centre Freiburg Germany

Department of Pneumology University Hospital Belgrade Serbia

Department of Pneumology University Hospital Bonn Germany

Department of Pneumology University Hospital Leipzig Leipzig Germany

Department of Pneumology University Hospital Regensburg Regensburg Germany

Department of Pneumonology Oncology and Allergology Medical University of Lublin Lublin Poland

Department of Pulmonology Medical University of Gdansk Gdansk Poland

Department of Respiratory Medicine Hannover Medical School German Center for Lung Research Hannover Germany

Department of Respiratory Medicine University Hospital Southampton United Kingdom

Division of Pulmonary and Critical Care Medicine University College Dublin and St Vincent's University Hospital Dublin Ireland

Evangelische Lungenklinik Berlin Berlin Germany

Faculty of Medicine and Dentistry Palacký University and University Hospital Olomouc Olomouc Czechia

Foundation IRCCS Policlinico San Matteo Pulmonology Unit Pavia Italy

Groupe Hospitalier Avicenne Jean Verdier René Muret Service de Pneumologie Bobigny France

Hospital Berlin Havelhöhe Berlin Germany

Institute of Clinical Molecular Biology Kiel University Kiel Germany

Institute of Medical Informatics and Statistics Kiel University Kiel Germany

Laboratory of Respiratory Diseases and Thoracic Surgery University Hospital Leuven Belgium

Landspitali University Hospital Reykjavik Iceland

Liverpool Interstitial Lung Disease Service Aintree Chest Centre Liverpool University Hospitals NHS FT Liverpool United Kingdom

Medical Hospital Research Center Borstel Borstel Germany

National Koranyi Institute Budapest Hungary

Oxford Sarcoidosis Service Oxford University Hospitals NHS Foundation Trust Churchill Hospital Oxford United Kingdom

Prague General Hospital Charles University Prague Czechia

Pulmonary Department University Hospital Bristol United Kingdom

Pulmonary Department University Hospital Jordanovac Zagreb Croatia

Pulmonary Unit Department of Thoracic Diseases Azienda USL Romagna GB Morgagni L Pierantoni Hospital Forlì Italy

Pulmonology Department Academic Medical Center Amsterdam Amsterdam Netherlands

Respiratory Diseases and Lung Transplant Unit University Hospital Siena Italy

Ruhrlandklinik Westdeutsches Lungenzentrum am Universitätsklinikum Essen Universitätsklinik Essen Essen Germany

Thomayer Hospital and 1st Faculty of Medicine Charles University Praha Czechia

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