TY - JOUR
T1 - High-density genetic mapping identifies new susceptibility variants in sarcoidosis phenotypes and shows genomic-driven phenotypic differences
AU - Rivera, Natalia V.
AU - Ronninger, Marcus
AU - Shchetynsky, Klementy
AU - Franke, Andre
AU - Nöthen, Markus M.
AU - Müller-Quernheim, Joachim
AU - Schreiber, Stefan
AU - Adrianto, Indra
AU - Karakaya, Bekir
AU - Van Moorsel, Coline H.M.
AU - Navratilova, Zdenka
AU - Kolek, Vitezslav
AU - Rybicki, Benjamin A.
AU - Iannuzzi, Michael C.
AU - Petrek, Martin
AU - Grutters, Jan C.
AU - Montgomery, Courtney
AU - Fischer, Annegret
AU - Eklund, Anders
AU - Padyukov, Leonid
AU - Grunewald, Johan
N1 - Publisher Copyright:
© 2016 by the American Thoracic Society.
PY - 2016/5/1
Y1 - 2016/5/1
N2 - Rationale: 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. 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.
AB - Rationale: 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. 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.
KW - Genetic epidemiology of sarcoidosis
KW - Genome-wide associations
KW - Immunochip
KW - Löfgren's syndrome
KW - Non-Löfgren's syndrome
UR - http://www.scopus.com/inward/record.url?scp=84971606006&partnerID=8YFLogxK
U2 - 10.1164/rccm.201507-1372OC
DO - 10.1164/rccm.201507-1372OC
M3 - Article
C2 - 26651848
AN - SCOPUS:84971606006
SN - 1073-449X
VL - 193
SP - 1008
EP - 1022
JO - American Journal of Respiratory and Critical Care Medicine
JF - American Journal of Respiratory and Critical Care Medicine
IS - 9
ER -