High-Density Genetic Mapping Identifies New Susceptibility Variants in Sarcoidosis Phenotypes and Shows Genomic-driven Phenotypic Differences
Recommended Citation
Rivera NV, Ronninger M, Shchetynsky K, Franke A, Nothen MM, Muller-Quernheim J, Schreiber S, Adrianto I, Karakaya B, van Moorsel CH, Navratilova Z, Kolek V, Rybicki BA, Iannuzzi MC, Petrek M, Grutters JC, Montgomery C, Fischer A, Eklund A, Padyukov L, and Grunewald J. High-density genetic mapping identifies new susceptibility variants in sarcoidosis phenotypes and shows genomic-driven phenotypic differences. Am J Respir Crit Care Med 2015;193(9):1008-22.
Document Type
Article
Publication Date
5-1-2016
Publication Title
American journal of respiratory and critical care medicine
Abstract
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.
Medical Subject Headings
Czech Republic; Female; Genetic Predisposition to Disease; Genomics; Genotype; Germany; Humans; Male; Middle Aged; Netherlands; Phenotype; Sarcoidosis, Pulmonary; Sweden; United States
PubMed ID
26651848
Volume
193
Issue
9
First Page
1008
Last Page
1022
