High-density Genetic Mapping Identifies New Susceptibility Variants in Sarcoidosis Phenotypes and Shows Genomic-driven Phenotypic Differences.

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, Johan Grunewald
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American journal of respiratory and critical care medicine
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Sarcoidosis is a multisystem disease of unknown cause(s). 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.To address the genetic architecture of sarcoidosis phenotypes, LS and non-LS.An association study in a Swedish Caucasian cohort of 384 LS, 664 non-LS and 2,086 controls, totaling 3,134 subjects employing a fine-mapping genotyping platform was conducted. Replication was performed in four independent cohorts, three of white European decent, Germany (N = 4,975), The Netherlands (N = 613), and Czech Republic (N =521), and one of black African descent, USA (N = 1,657), totaling altogether 7,766 subjects.A 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. Noteworthy, 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.Comprehensive 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.