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Fischer, A.* ; Ellinghaus, D.* ; Nutsua, M.* ; Hofmann, S.* ; Montgomery, C.G.* ; Iannuzzi, M.C.* ; Rybicki, B.A.* ; Petrek, M.* ; Mrazek, F.* ; Pabst, S.* ; Grohe, C.* ; Grunewald, J.* ; Ronninger, M.* ; Eklund, A.* ; Padyukov, L.* ; Mihailovic-Vucinic, V.* ; Jovanovic, D.L.* ; Sterclova, M.* ; Homolka, J.* ; Nöthen, M.M.* ; Herms, S.* ; Gieger, C. ; Strauch, K. ; Winkelmann, J. ; Boehm, B.O.* ; Brand, S.* ; Büning, C.* ; Schürmann, M.* ; Ellinghaus, E.* ; Baurecht, H.* ; Lieb, W.* ; Nebel, A.* ; Müller-Quernheim, J.* ; Franke, A.* ; Schreiber, S.*

Identification of immune-relevant factors conferring sarcoidosis genetic risk.

Am. J. Respir. Crit. Care Med. 192, 727-736 (2015)
Verlagsversion Postprint DOI PMC
Open Access Green
RATIONALE AND OBJECTIVES: 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, 1726 German sarcoidosis cases and 5482 controls were genotyped for 128,705 SNPs using the Illumina Immunochip for the screening step. The remaining 3955 cases, 7514 controls and 684 parents of affected offspring were used for validation and replication of 44 candidate and 2 established risk SNPs. MEASUREMENTS AND MAIN 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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Btnl2 ; Hla ; Il23 ; Immunochip ; Association
Sprache englisch
Veröffentlichungsjahr 2015
HGF-Berichtsjahr 2015
ISSN (print) / ISBN 1073-449X
e-ISSN 1535-4970
Zeitschrift American Journal of Respiratory and Critical Care Medicine
Quellenangaben Band: 192, Heft: 6, Seiten: 727-736 Artikelnummer: , Supplement: ,
Verlag American Thoracic Society
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Genetic Epidemiology (IGE)
Institute of Epidemiology (EPI)
Institute of Human Genetics (IHG)
Institute of Neurogenomics (ING)
POF Topic(s) 30501 - Systemic Analysis of Genetic and Environmental Factors that Impact Health
30202 - Environmental Health
30205 - Bioengineering and Digital Health
Forschungsfeld(er) Genetics and Epidemiology
PSP-Element(e) G-504100-001
G-504091-004
G-500700-001
G-503200-002
PubMed ID 26051272
DOI 10.1164/rccm.201503-0418OC
WOS ID WOS:000361420400015
Scopus ID 84942245587
Erfassungsdatum 2015-06-10
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