High-Density Genetic Mapping Identifies New Susceptibility Variants in Sarcoidosis Phenotypes and Shows Genomic-driven Phenotypic Differences.
Am J Respir Crit Care Med
; 193(9): 1008-22, 2016 05 01.
Article
em En
| MEDLINE
| ID: mdl-26651848
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 MAINRESULTS:
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.Palavras-chave
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Base de dados:
MEDLINE
Assunto principal:
Fenótipo
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Sarcoidose Pulmonar
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Predisposição Genética para Doença
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Genômica
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Genótipo
Tipo de estudo:
Prognostic_studies
Limite:
Female
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Humans
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Male
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Middle aged
País como assunto:
America do norte
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Europa
Idioma:
En
Ano de publicação:
2016
Tipo de documento:
Article