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Fischer, A.* ; Ellinghaus, D.* ; Nutsua, M.* ; Hofmann, S.* ; Montgomery, C.G.* ; Iannuzzi, M.C.* ; Rybicki, B.A.* ; Petrek, M.* ; Mrazek, F.* ; Pabst, S.* ; Grohe, C.* ; Grunewald, J.* ; Ronninger, M.* ; Eklund, A.* ; Padyukov, L.* ; Mihailovic-Vucinic, V.* ; Jovanovic, D.L.* ; Sterclova, M.* ; Homolka, J.* ; Nöthen, M.M.* ; Herms, S.* ; Gieger, C. ; Strauch, K. ; Winkelmann, J. ; Boehm, B.O.* ; Brand, S.* ; Büning, C.* ; Schürmann, M.* ; Ellinghaus, E.* ; Baurecht, H.* ; Lieb, W.* ; Nebel, A.* ; Müller-Quernheim, J.* ; Franke, A.* ; Schreiber, S.*

Identification of immune-relevant factors conferring sarcoidosis genetic risk.

Am. J. Respir. Crit. Care Med. 192, 727-736 (2015)
Postprint DOI PMC
Open Access Green
RATIONALE AND 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, 1726 German sarcoidosis cases and 5482 controls were genotyped for 128,705 SNPs using the Illumina Immunochip for the screening step. The remaining 3955 cases, 7514 controls and 684 parents of affected offspring were used for validation and replication of 44 candidate and 2 established risk SNPs. 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.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Btnl2 ; Hla ; Il23 ; Immunochip ; Association
ISSN (print) / ISBN 1073-449X
e-ISSN 1535-4970
Journal American Journal of Respiratory and Critical Care Medicine
Quellenangaben Volume: 192, Issue: 6, Pages: 727-736 Article Number: , Supplement: ,
Publisher American Thoracic Society
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Genetic Epidemiology (IGE)
Institute of Epidemiology II (EPI2)
Institute of Human Genetics (IHG)
Institute of Neurogenomics (ING)