Rivera, N. V., Ronninger, M., Shchetynsky, K., Franke, A., Nothen, M. M., Muller-Quernheim, J., Schreiber, Stefan, Adrianto, I., Karakaya, B., van Moorsel, C. H. M., Navratilova, Z., Kolek, V., Rybicki, B. A., Iannuzzi, M. C., Petrek, M., Grutters, J. C., Montgomery, C., Fischer, A., Eklund, A., Padyukov, L. and Grunewald, J. (2016) High-Density Genetic Mapping Identifies New Susceptibility Variants in Sarcoidosis Phenotypes and Shows Genomic-driven Phenotypic Differences. American Journal of Respiratory and Critical Care Medicine, 193 (9). pp. 1008-1022. DOI 10.1164/rccm.201507-1372OC.

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Abstract

Rationale: Sarcoidosis is a multisystem disease of unknown cause. Lofgren'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. Objectives: To address the genetic architecture of sarcoidosis phenotypes, LS and non-LS. Methods: 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. Measurements and Main Results: 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. Conclusions: 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.

Document Type:	Article
Additional Information:	Times Cited: 6 Rivera, Natalia V. Ronninger, Marcus Shchetynsky, Klementy Franke, Andre Noethen, Markus M. Mueller-Quernheim, Joachim Schreiber, Stefan Adrianto, Indra Karakaya, Bekir van Moorsel, Coline H. M. Navratilova, Zdenka Kolek, Vitezslav Rybicki, Benjamin A. Iannuzzi, Michael C. Petrek, Martin Grutters, Jan C. Montgomery, Courtney Fischer, Annegret Eklund, Anders Padyukov, Leonid Grunewald, Johan
Keywords:	genetic epidemiology of sarcoidosis; Löfgren’s syndrome; non-Löfgren’s syndrome; genome-wide associations; Immunochip
Research affiliation:	OceanRep > The Future Ocean - Cluster of Excellence Kiel University
Refereed:	Yes
Open Access Journal?:	No
Publisher:	American Thoracic Society
Projects:	Future Ocean
Date Deposited:	07 Mar 2017 10:06
Last Modified:	13 Jun 2019 13:51
URI:	https://oceanrep.geomar.de/id/eprint/36288

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