title: High-Density Genetic Mapping Identifies New Susceptibility Variants in Sarcoidosis Phenotypes and Shows Genomic-driven Phenotypic Differences.
abstract: 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.
  
  
  
  To address the genetic architecture of sarcoidosis phenotypes, LS and non-LS.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: 1 Respiratory Unit, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.|2 Center for Molecular Medicine, and.
authors.forename: Natalia V
authors.initials: NV
authors.lastname: Rivera
authors.affiliation: 1 Respiratory Unit, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.|2 Center for Molecular Medicine, and.
authors.forename: Marcus
authors.initials: M
authors.lastname: Ronninger
authors.affiliation: 2 Center for Molecular Medicine, and.|3 Rheumatology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Klementy
authors.initials: K
authors.lastname: Shchetynsky
authors.affiliation: 4 Institute of Clinical Molecular Biology, University Hospital Schleswig-Holstein, Campus Kiel and Kiel University, Kiel, Germany.
authors.forename: Andre
authors.initials: A
authors.lastname: Franke
authors.affiliation: 5 Institute of Human Genetics, and.|6 Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany.
authors.forename: Markus M
authors.initials: MM
authors.lastname: Nöthen
authors.affiliation: 7 Department of Pneumology, University of Freiburg, Freiburg, Germany.
authors.forename: Joachim
authors.initials: J
authors.lastname: Müller-Quernheim
authors.affiliation: 4 Institute of Clinical Molecular Biology, University Hospital Schleswig-Holstein, Campus Kiel and Kiel University, Kiel, Germany.|8 Popgen Biobank and.|9 Clinic of Internal Medicine I, University Hospital Schleswig-Holstein, Kiel, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Schreiber
authors.affiliation: 10 Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma.
authors.forename: Indra
authors.initials: I
authors.lastname: Adrianto
authors.affiliation: 11 Center of Interstitial Lung Diseases, St. Antonius Hospital, Nieuwegein, the Netherlands.
authors.forename: Bekir
authors.initials: B
authors.lastname: Karakaya
authors.affiliation: 11 Center of Interstitial Lung Diseases, St. Antonius Hospital, Nieuwegein, the Netherlands.|12 Division of Heart & Lungs, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Coline H M
authors.initials: CH
authors.lastname: van Moorsel
authors.affiliation: 13 Department of Pathological Physiology and.
authors.forename: Zdenka
authors.initials: Z
authors.lastname: Navratilova
authors.affiliation: 14 Department of Respiratory Medicine, Faculty of Medicine and Dentistry, Palacky University Olomouc, Olomouc, Czech Republic.
authors.forename: Vitezslav
authors.initials: V
authors.lastname: Kolek
authors.affiliation: 15 Department of Public Health Sciences, Henry Ford Health Systems, Detroit, Michigan; and.
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Rybicki
authors.affiliation: 16 State University of New York Upstate Medical University Syracuse, Syracuse, New York.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Iannuzzi
authors.affiliation: 13 Department of Pathological Physiology and.
authors.forename: Martin
authors.initials: M
authors.lastname: Petrek
authors.affiliation: 11 Center of Interstitial Lung Diseases, St. Antonius Hospital, Nieuwegein, the Netherlands.|12 Division of Heart & Lungs, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Jan C
authors.initials: JC
authors.lastname: Grutters
authors.affiliation: 10 Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma.
authors.forename: Courtney
authors.initials: C
authors.lastname: Montgomery
authors.affiliation: 4 Institute of Clinical Molecular Biology, University Hospital Schleswig-Holstein, Campus Kiel and Kiel University, Kiel, Germany.
authors.forename: Annegret
authors.initials: A
authors.lastname: Fischer
authors.affiliation: 1 Respiratory Unit, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Eklund
authors.affiliation: 2 Center for Molecular Medicine, and.|3 Rheumatology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Leonid
authors.initials: L
authors.lastname: Padyukov
authors.affiliation: 2 Center for Molecular Medicine, and.|3 Rheumatology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Grunewald
mesh_terms: D018153:Czech Republic; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D023281:Genomics / Q000379:methods*; D005838:Genotype; D005858:Germany; D006801:Humans; D008297:Male; D008875:Middle Aged; D009426:Netherlands; D010641:Phenotype; D017565:Sarcoidosis, Pulmonary / Q000235:genetics*; D013548:Sweden; D014481:United States
keywords: Immunochip; Löfgren’s syndrome; genetic epidemiology of sarcoidosis; genome-wide associations; non-Löfgren’s syndrome