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

2015; American Thoracic Society; Volume: 193; Issue: 9 Linguagem: Inglês

10.1164/rccm.201507-1372oc

1535-4970

Natalia V. Rivera, Marcus Ronninger, Klementy Shchetynsky, André Franke, Markus M. Nöthen, Joachim Müller‐Quernheim, Stefan Schreiber, Indra Adrianto, Bekir Karakaya, Coline H.M. van Moorsel, Zdeňka Navrátilová, Vı́tězslav Kolek, Benjamin A. Rybicki, Michael C. Iannuzzi, Martin Petřek, Jan C. Grutters, Courtney G. Montgomery, Annegret Fischer, Anders Eklúnd, Leonid Padyukov, Johan Grünewald,

Immunodeficiency and Autoimmune Disorders

Sarcoidosis 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.To address the genetic architecture of sarcoidosis phenotypes, LS and non-LS.An 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.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. 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.