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Identification of Immune-Relevant Factors Conferring Sarcoidosis Genetic Risk
A. Fischer, D. Ellinghaus, M. Nutsua, S. Hofmann, CG. Montgomery, MC. Iannuzzi, BA. Rybicki, M. Petrek, F. Mrazek, S. Pabst, C. Grohé, J. Grunewald, M. Ronninger, A. Eklund, L. Padyukov, V. Mihailovic-Vucinic, D. Jovanovic, M. Sterclova, J....
Language English Country United States
Document type Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't
NLK
Free Medical Journals
from 1997-07-01 to 1 year ago
Freely Accessible Science Journals
from 1997 to 1 year ago
ProQuest Central
from 2003-02-01 to 2019-09-15
Open Access Digital Library
from 1998-01-01
Nursing & Allied Health Database (ProQuest)
from 2003-02-01 to 2019-09-15
Health & Medicine (ProQuest)
from 2003-02-01 to 2019-09-15
Public Health Database (ProQuest)
from 2003-02-01 to 2019-09-15
- MeSH
- White People genetics MeSH
- Genome-Wide Association Study * MeSH
- Black or African American genetics MeSH
- Adult MeSH
- Genetic Predisposition to Disease * MeSH
- Genetic Markers MeSH
- Genotype MeSH
- Polymorphism, Single Nucleotide * MeSH
- Middle Aged MeSH
- Humans MeSH
- Sarcoidosis ethnology genetics immunology MeSH
- Aged MeSH
- Case-Control Studies MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Research Support, N.I.H., Extramural MeSH
- Geographicals
- Europe MeSH
RATIONALE: Genetic variation plays a significant role in the etiology of sarcoidosis. However, only a small fraction of its heritability has been explained so far. 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, 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. 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.
1st Lung Department Prague General Hospital Charles University Prague Czech Republic
Department of Gastroenterology Hepatology and Endocrinology Charité Campus Mitte Berlin Germany
Department of Medicine 2 Grosshadern Ludwig Maximilians University Munich Germany
Department of Medicine Upstate Medical University Syracuse New York
Department of Pneumology University of Freiburg Freiburg Germany
Department of Public Health Sciences Henry Ford Hospital Detroit Michigan
Department of Respiratory Medicine Evangelische Lungenklinik Berlin Buch Berlin Germany
Department of Respiratory Medicine Thomayer Hospital and 1 Medical Faculty and
Department of Sarcoidosis and Other Granulomatous Diseases and
Faculty of Medicine and Dentistry Palacky University Olomouc Czech Republic
Institute of Epidemiology and Popgen Biobank Kiel University Kiel Germany
Institute of Human Genetics University of Lübeck Lübeck Germany
Pneumologische Praxis Bonn Germany
Rheumatology Unit Department of Medicine Karolinska Institutet Stockholm Sweden
References provided by Crossref.org
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- $a Identification of Immune-Relevant Factors Conferring Sarcoidosis Genetic Risk / $c A. Fischer, D. Ellinghaus, M. Nutsua, S. Hofmann, CG. Montgomery, MC. Iannuzzi, BA. Rybicki, M. Petrek, F. Mrazek, S. Pabst, C. Grohé, J. Grunewald, M. Ronninger, A. Eklund, L. Padyukov, V. Mihailovic-Vucinic, D. Jovanovic, M. Sterclova, J. Homolka, MM. Nöthen, S. Herms, C. Gieger, K. Strauch, J. Winkelmann, BO. Boehm, S. Brand, C. Büning, M. Schürmann, E. Ellinghaus, H. Baurecht, W. Lieb, A. Nebel, J. Müller-Quernheim, A. Franke, S. Schreiber, . ,
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- $a RATIONALE: Genetic variation plays a significant role in the etiology of sarcoidosis. However, only a small fraction of its heritability has been explained so far. 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, 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. 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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