RATIONALE: Genetic variation plays a significant role in the etiology of sarcoidosis. However, only a small fraction of its heritability has been explained so far. OBJECTIVES: To define further genetic risk loci for sarcoidosis, we used the Immunochip for a candidate gene association study of immune-associated loci. METHODS: Altogether the study population comprised over 19,000 individuals. In a two-stage design, 1,726 German sarcoidosis cases and 5,482 control subjects were genotyped for 128,705 single-nucleotide polymorphisms using the Illumina Immunochip for the screening step. The remaining 3,955 cases, 7,514 control subjects, and 684 parents of affected offspring were used for validation and replication of 44 candidate and two established risk single-nucleotide polymorphisms. MEASUREMENTS AND MAIN RESULTS: Four novel susceptibility loci were identified with genome-wide significance in the European case-control populations, located on chromosomes 12q24.12 (rs653178; ATXN2/SH2B3), 5q33.3 (rs4921492; IL12B), 4q24 (rs223498; MANBA/NFKB1), and 2q33.2 (rs6748088; FAM117B). We further defined three independent association signals in the HLA region with genome-wide significance, peaking in the BTNL2 promoter region (rs5007259), at HLA-B (rs4143332/HLA-B*0801) and at HLA-DPB1 (rs9277542), and found another novel independent signal near IL23R (rs12069782) on chromosome 1p31.3. CONCLUSIONS: Functional predictions and protein network analyses suggest a prominent role of the drug-targetable IL23/Th17 signaling pathway in the genetic etiology of sarcoidosis. Our findings reveal a substantial genetic overlap of sarcoidosis with diverse immune-mediated inflammatory disorders, which could be of relevance for the clinical application of modern therapeutics.

1st Lung Department Prague General Hospital Charles University Prague Czech Republic

Arthritis and Clinical Immunology Research Program Oklahoma Medical Research Foundation Oklahoma City Oklahoma

Clinic of Internal Medicine 1 University Hospital Schleswig Holstein Campus Kiel Kiel Germany

Department of Dermatology Allergology and Venerology and

Department of Gastroenterology Hepatology and Endocrinology Charité Campus Mitte Berlin Germany

Department of Genomics Life and Brain Center University of Bonn Bonn Germany

Department of Internal Medicine 1 Ulm University Medical Centre Ulm Germany

Department of Medicine 2 Grosshadern Ludwig Maximilians University Munich Germany

Department of Medicine Upstate Medical University Syracuse New York

Department of Neurology MRI and

Department of Pneumology University of Freiburg Freiburg Germany

Department of Public Health Sciences Henry Ford Hospital Detroit Michigan

Department of Respiratory Medicine Evangelische Lungenklinik Berlin Buch Berlin Germany

Department of Respiratory Medicine Thomayer Hospital and 1 Medical Faculty and

Department of Sarcoidosis and Other Granulomatous Diseases and

Faculty of Medicine and Dentistry Palacky University Olomouc Czech Republic

Genomics Group Medical Genetics Department of Biomedicine University of Basel Basel Switzerland

Graduate School of Information Science in Health Technische Universität München Munich Germany

Imperial College London London United Kingdom

Institute of Clinical Molecular Biology Kiel University and University Hospital Schleswig Holstein Kiel Germany

Institute of Epidemiology 2 and

Institute of Epidemiology and Popgen Biobank Kiel University Kiel Germany; and

Institute of Genetic Epidemiology and

Institute of Human Genetics and

Institute of Human Genetics Helmholtz Center Munich German Research Center for Environmental Health Neuherberg Germany

Institute of Human Genetics MRI

Institute of Human Genetics University of Lübeck Lübeck Germany

Institute of Medical Informatics Biometry and Epidemiology and

LKCMedicine Nanyang Technological University Singapore

Pneumologische Praxis Bonn Germany

Research Unit of Molecular Epidemiology Helmholtz Center Munich Munich Germany

Respiratory Medicine Unit Department of Medicine and CMM Karolinska Institutet and Karolinska University Hospital Stockholm Sweden

Rheumatology Unit Department of Medicine Karolinska Institutet Stockholm Sweden

Thoracic Oncology and ILD Department University Hospital of Pulmonology Clinical Center of Serbia Belgrade Serbia

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Am J Respir Crit Care Med. 2015 Sep 15;192(6):652-4. doi: 10.1164/rccm.201506-1235ED. PubMed

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Association between sarcoidosis and HLA polymorphisms in a Czech population from Central Europe: focus on a relationship with clinical outcome and treatment

Genetic control of CCL24, POR, and IL23R contributes to the pathogenesis of sarcoidosis

Whole-exome sequencing identifies rare genetic variations in German families with pulmonary sarcoidosis