• Natalia V Rivera, Marcus Ronninger, Klementy Shchetynsky, Andre Franke, Markus M Nöthen, Joachim Müller-Quernheim, Stefan Schreiber, Indra Adrianto, Bekir Karakaya, Coline H M van Moorsel, Zdenka Navratilova, Vitezslav Kolek, Benjamin A Rybicki, Michael C Iannuzzi, Martin Petrek, Jan C Grutters, Courtney Montgomery, Annegret Fischer, Anders Eklund, Leonid Padyukov, and Johan Grunewald.
• 1 Respiratory Unit, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
• Am. J. Respir. Crit. Care Med. 2016 May 1; 193 (9): 1008-22.

RationaleSarcoidosis is a multisystem disease of unknown cause. Löfgren's syndrome (LS) is a characteristic subgroup of sarcoidosis that is associated with a good prognosis in sarcoidosis. However, little is known about its genetic architecture or its broader phenotype, non-LS sarcoidosis.ObjectivesTo address the genetic architecture of sarcoidosis phenotypes, LS and non-LS.MethodsAn association study in a white Swedish cohort of 384 LS, 664 non-LS, and 2,086 control subjects, totaling 3,134 subjects using a fine-mapping genotyping platform was conducted. Replication was performed in four independent cohorts, three of white European descent (Germany, n = 4,975; the Netherlands, n = 613; and Czech Republic, n = 521), and one of black African descent (United States, n = 1,657), totaling 7,766 subjects.Measurements And Main ResultsA total of 727 LS-associated variants expanding throughout the extended major histocompatibility complex (MHC) region and 68 non-LS-associated variants located in the MHC class II region were identified and confirmed. A shared overlap between LS and non-LS defined by 17 variants located in the MHC class II region was found. Outside the MHC region, two LS-associated loci, in ADCY3 and between CSMD1 and MCPH1, were observed and replicated.ConclusionsComprehensive and integrative analyses of genetics, transcription, and pathway modeling on LS and non-LS indicates that these sarcoidosis phenotypes have different genetic susceptibility, genomic distributions, and cellular activities, suggesting distinct molecular mechanisms in pathways related to immune response with a common region.

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