• Annegret Fischer, David Ellinghaus, Marcel Nutsua, Sylvia Hofmann, Courtney G Montgomery, Michael C Iannuzzi, Benjamin A Rybicki, Martin Petrek, Frantisek Mrazek, Stefan Pabst, Christian Grohé, Johan Grunewald, Marcus Ronninger, Anders Eklund, Leonid Padyukov, Violeta Mihailovic-Vucinic, Dragana Jovanovic, Martina Sterclova, Jiri Homolka, Markus M Nöthen, Stefan Herms, Christian Gieger, Konstantin Strauch, Juliane Winkelmann, Bernhard O Boehm, Stephan Brand, Carsten Büning, Manfred Schürmann, Eva Ellinghaus, Hansjörg Baurecht, Wolfgang Lieb, Almut Nebel, Joachim Müller-Quernheim, Andre Franke, Stefan Schreiber, and GenPhenReSa Consortium.
• 1 Institute of Clinical Molecular Biology, Kiel University and University Hospital Schleswig-Holstein, Kiel, Germany.
• Am. J. Respir. Crit. Care Med. 2015 Sep 15; 192 (6): 727736727-36.

RationaleGenetic variation plays a significant role in the etiology of sarcoidosis. However, only a small fraction of its heritability has been explained so far.ObjectivesTo define further genetic risk loci for sarcoidosis, we used the Immunochip for a candidate gene association study of immune-associated loci.MethodsAltogether 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 ResultsFour 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.ConclusionsFunctional 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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