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Am J Respir Crit Care Med. 2016 May 1;193(9):1008-22. doi: 10.1164/rccm.201507-1372OC.

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

Author information

1
1 Respiratory Unit, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
2
2 Center for Molecular Medicine, and.
3
3 Rheumatology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
4
4 Institute of Clinical Molecular Biology, University Hospital Schleswig-Holstein, Campus Kiel and Kiel University, Kiel, Germany.
5
5 Institute of Human Genetics, and.
6
6 Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany.
7
7 Department of Pneumology, University of Freiburg, Freiburg, Germany.
8
8 Popgen Biobank and.
9
9 Clinic of Internal Medicine I, University Hospital Schleswig-Holstein, Kiel, Germany.
10
10 Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma.
11
11 Center of Interstitial Lung Diseases, St. Antonius Hospital, Nieuwegein, the Netherlands.
12
12 Division of Heart & Lungs, University Medical Center Utrecht, Utrecht, the Netherlands.
13
13 Department of Pathological Physiology and.
14
14 Department of Respiratory Medicine, Faculty of Medicine and Dentistry, Palacky University Olomouc, Olomouc, Czech Republic.
15
15 Department of Public Health Sciences, Henry Ford Health Systems, Detroit, Michigan; and.
16
16 State University of New York Upstate Medical University Syracuse, Syracuse, New York.

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.

KEYWORDS:

Immunochip; Löfgren’s syndrome; genetic epidemiology of sarcoidosis; genome-wide associations; non-Löfgren’s syndrome

Comment in

PMID:
26651848
PMCID:
PMC4872654
DOI:
10.1164/rccm.201507-1372OC
[Indexed for MEDLINE]
Free PMC Article

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