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Am J Respir Crit Care Med. 2015 Sep 15;192(6):727-36. doi: 10.1164/rccm.201503-0418OC.

Identification of Immune-Relevant Factors Conferring Sarcoidosis Genetic Risk.

Author information

1
1 Institute of Clinical Molecular Biology, Kiel University and University Hospital Schleswig-Holstein, Kiel, Germany.
2
2 Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma.
3
3 Department of Medicine, Upstate Medical University, Syracuse, New York.
4
4 Department of Public Health Sciences, Henry Ford Hospital, Detroit, Michigan.
5
5 Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic.
6
6 Pneumologische Praxis, Bonn, Germany.
7
7 Department of Respiratory Medicine, Evangelische Lungenklinik Berlin-Buch, Berlin, Germany.
8
8 Respiratory Medicine Unit, Department of Medicine and CMM, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
9
9 Rheumatology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
10
10 Department of Sarcoidosis and Other Granulomatous Diseases and.
11
11 Thoracic Oncology and ILD Department, University Hospital of Pulmonology, Clinical Center of Serbia, Belgrade, Serbia.
12
12 Department of Respiratory Medicine, Thomayer Hospital and 1 Medical Faculty and.
13
13 1st Lung Department, Prague General Hospital, Charles University, Prague, Czech Republic.
14
14 Institute of Human Genetics and.
15
15 Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany.
16
16 Genomics Group, Medical Genetics, Department of Biomedicine, University of Basel, Basel, Switzerland.
17
17 Institute of Epidemiology II and.
18
18 Research Unit of Molecular Epidemiology, Helmholtz Center Munich, Munich, Germany.
19
19 Institute of Genetic Epidemiology and.
20
20 Institute of Medical Informatics, Biometry and Epidemiology and.
21
21 Institute of Human Genetics, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany.
22
22 Institute of Human Genetics, MRI.
23
23 Department of Neurology, MRI, and.
24
24 Department of Internal Medicine I, Ulm University Medical Centre, Ulm, Germany.
25
25 LKCMedicine, Nanyang Technological University, Singapore.
26
26 Imperial College London, London, United Kingdom.
27
27 Department of Medicine II-Grosshadern, Ludwig-Maximilians-University, Munich, Germany.
28
28 Department of Gastroenterology, Hepatology and Endocrinology, Charité, Campus Mitte, Berlin, Germany.
29
29 Institute of Human Genetics, University of Lübeck, Lübeck, Germany.
30
31 Graduate School of Information Science in Health, Technische Universität München, Munich, Germany.
31
30 Department of Dermatology, Allergology, and Venerology, and.
32
32 Institute of Epidemiology and Popgen Biobank, Kiel University, Kiel, Germany; and.
33
33 Department of Pneumology, University of Freiburg, Freiburg, Germany.
34
34 Clinic of Internal Medicine I, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.

Abstract

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.

KEYWORDS:

BTNL2; HLA; IL23; Immunochip; association

Comment in

PMID:
26051272
PMCID:
PMC4595678
DOI:
10.1164/rccm.201503-0418OC
[Indexed for MEDLINE]
Free PMC Article

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