title: Identification of Immune-Relevant Factors Conferring Sarcoidosis Genetic Risk.
abstract: BACKGROUND
  Genetic variation plays a significant role in the etiology of sarcoidosis. However, only a small fraction of its heritability has been explained so far.
  
  
  OBJECTIVE
  To define further genetic risk loci for sarcoidosis, we used the Immunochip for a candidate gene association study of immune-associated loci.
  
  
  METHODS
  Altogether the study population comprised over 19,000 individuals. In a two-stage design, 1,726 German sarcoidosis cases and 5,482 control subjects were genotyped for 128,705 single-nucleotide polymorphisms using the Illumina Immunochip for the screening step. The remaining 3,955 cases, 7,514 control subjects, and 684 parents of affected offspring were used for validation and replication of 44 candidate and two established risk single-nucleotide polymorphisms.
  
  
  RESULTS
  Four novel susceptibility loci were identified with genome-wide significance in the European case-control populations, located on chromosomes 12q24.12 (rs653178; ATXN2/SH2B3), 5q33.3 (rs4921492; IL12B), 4q24 (rs223498; MANBA/NFKB1), and 2q33.2 (rs6748088; FAM117B). We further defined three independent association signals in the HLA region with genome-wide significance, peaking in the BTNL2 promoter region (rs5007259), at HLA-B (rs4143332/HLA-B*0801) and at HLA-DPB1 (rs9277542), and found another novel independent signal near IL23R (rs12069782) on chromosome 1p31.3.
  
  
  CONCLUSIONS
  Functional predictions and protein network analyses suggest a prominent role of the drug-targetable IL23/Th17 signaling pathway in the genetic etiology of sarcoidosis. Our findings reveal a substantial genetic overlap of sarcoidosis with diverse immune-mediated inflammatory disorders, which could be of relevance for the clinical application of modern therapeutics.
authors.affiliation: 1 Institute of Clinical Molecular Biology, Kiel University and University Hospital Schleswig-Holstein, Kiel, Germany.
authors.forename: Annegret
authors.initials: A
authors.lastname: Fischer
authors.affiliation: 1 Institute of Clinical Molecular Biology, Kiel University and University Hospital Schleswig-Holstein, Kiel, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Ellinghaus
authors.affiliation: 1 Institute of Clinical Molecular Biology, Kiel University and University Hospital Schleswig-Holstein, Kiel, Germany.
authors.forename: Marcel
authors.initials: M
authors.lastname: Nutsua
authors.affiliation: 1 Institute of Clinical Molecular Biology, Kiel University and University Hospital Schleswig-Holstein, Kiel, Germany.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Hofmann
authors.affiliation: 2 Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma.
authors.forename: Courtney G
authors.initials: CG
authors.lastname: Montgomery
authors.affiliation: 3 Department of Medicine, Upstate Medical University, Syracuse, New York.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Iannuzzi
authors.affiliation: 4 Department of Public Health Sciences, Henry Ford Hospital, Detroit, Michigan.
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Rybicki
authors.affiliation: 5 Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic.
authors.forename: Martin
authors.initials: M
authors.lastname: Petrek
authors.affiliation: 5 Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic.
authors.forename: Frantisek
authors.initials: F
authors.lastname: Mrazek
authors.affiliation: 6 Pneumologische Praxis, Bonn, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Pabst
authors.affiliation: 7 Department of Respiratory Medicine, Evangelische Lungenklinik Berlin-Buch, Berlin, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Grohé
authors.affiliation: 8 Respiratory Medicine Unit, Department of Medicine and CMM, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Grunewald
authors.affiliation: 8 Respiratory Medicine Unit, Department of Medicine and CMM, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Marcus
authors.initials: M
authors.lastname: Ronninger
authors.affiliation: 8 Respiratory Medicine Unit, Department of Medicine and CMM, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Eklund
authors.affiliation: 9 Rheumatology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Leonid
authors.initials: L
authors.lastname: Padyukov
authors.affiliation: 10 Department of Sarcoidosis and Other Granulomatous Diseases and.
authors.forename: Violeta
authors.initials: V
authors.lastname: Mihailovic-Vucinic
authors.affiliation: 11 Thoracic Oncology and ILD Department, University Hospital of Pulmonology, Clinical Center of Serbia, Belgrade, Serbia.
authors.forename: Dragana
authors.initials: D
authors.lastname: Jovanovic
authors.affiliation: 12 Department of Respiratory Medicine, Thomayer Hospital and 1 Medical Faculty and.
authors.forename: Martina
authors.initials: M
authors.lastname: Sterclova
authors.affiliation: 13 1st Lung Department, Prague General Hospital, Charles University, Prague, Czech Republic.
authors.forename: Jiri
authors.initials: J
authors.lastname: Homolka
authors.affiliation: 14 Institute of Human Genetics and.|15 Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany.
authors.forename: Markus M
authors.initials: MM
authors.lastname: Nöthen
authors.affiliation: 14 Institute of Human Genetics and.|15 Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany.|16 Genomics Group, Medical Genetics, Department of Biomedicine, University of Basel, Basel, Switzerland.
authors.forename: Stefan
authors.initials: S
authors.lastname: Herms
authors.affiliation: 17 Institute of Epidemiology II and.|18 Research Unit of Molecular Epidemiology, Helmholtz Center Munich, Munich, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Gieger
authors.affiliation: 19 Institute of Genetic Epidemiology and.|20 Institute of Medical Informatics, Biometry and Epidemiology and.
authors.forename: Konstantin
authors.initials: K
authors.lastname: Strauch
authors.affiliation: 21 Institute of Human Genetics, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany.|22 Institute of Human Genetics, MRI.|23 Department of Neurology, MRI, and.
authors.forename: Juliane
authors.initials: J
authors.lastname: Winkelmann
authors.affiliation: 24 Department of Internal Medicine I, Ulm University Medical Centre, Ulm, Germany.|25 LKCMedicine, Nanyang Technological University, Singapore.|26 Imperial College London, London, United Kingdom.
authors.forename: Bernhard O
authors.initials: BO
authors.lastname: Boehm
authors.affiliation: 27 Department of Medicine II-Grosshadern, Ludwig-Maximilians-University, Munich, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Brand
authors.affiliation: 28 Department of Gastroenterology, Hepatology and Endocrinology, Charité, Campus Mitte, Berlin, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Büning
authors.affiliation: 29 Institute of Human Genetics, University of Lübeck, Lübeck, Germany.
authors.forename: Manfred
authors.initials: M
authors.lastname: Schürmann
authors.affiliation: 1 Institute of Clinical Molecular Biology, Kiel University and University Hospital Schleswig-Holstein, Kiel, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Ellinghaus
authors.affiliation: 31 Graduate School of Information Science in Health, Technische Universität München, Munich, Germany.|30 Department of Dermatology, Allergology, and Venerology, and.
authors.forename: Hansjörg
authors.initials: H
authors.lastname: Baurecht
authors.affiliation: 32 Institute of Epidemiology and Popgen Biobank, Kiel University, Kiel, Germany; and.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Lieb
authors.affiliation: 1 Institute of Clinical Molecular Biology, Kiel University and University Hospital Schleswig-Holstein, Kiel, Germany.
authors.forename: Almut
authors.initials: A
authors.lastname: Nebel
authors.affiliation: 33 Department of Pneumology, University of Freiburg, Freiburg, Germany.
authors.forename: Joachim
authors.initials: J
authors.lastname: Müller-Quernheim
authors.affiliation: 1 Institute of Clinical Molecular Biology, Kiel University and University Hospital Schleswig-Holstein, Kiel, Germany.
authors.forename: Andre
authors.initials: A
authors.lastname: Franke
authors.affiliation: 1 Institute of Clinical Molecular Biology, Kiel University and University Hospital Schleswig-Holstein, Kiel, Germany.|34 Clinic of Internal Medicine I, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Schreiber
mesh_terms: D000328:Adult; D001741:Black or African American / Q000235:genetics; D000368:Aged; D016022:Case-Control Studies; D005060:Europe; D005260:Female; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012507:Sarcoidosis / Q000208:ethnology / Q000235:genetics* / Q000276:immunology; D044465:White People / Q000235:genetics
chemical_list: D005819:Genetic Markers
keywords: BTNL2; HLA; IL23; Immunochip; association