Publikation

Identification of Immune-Relevant Factors Conferring Sarcoidosis Genetic Risk

Wissenschaftlicher Artikel/Review - 15.09.2015

Bereiche
PubMed
DOI

Zitation
Fischer A, Nöthen M, Herms S, Gieger C, Strauch K, Winkelmann J, Boehm B, Brand S, Büning C, Schürmann M, Ellinghaus E, Baurecht H, Lieb W, Nebel A, Müller-Quernheim J, Franke A, Schreiber S, Homolka J, Sterclova M, Ellinghaus D, Nutsua M, Hofmann S, Montgomery C, Iannuzzi M, Rybicki B, Petrek M, Mrazek F, Pabst S, Grohé C, Grunewald J, Ronninger M, Eklund A, Padyukov L, Mihailovic-Vucinic V, Jovanovic D. Identification of Immune-Relevant Factors Conferring Sarcoidosis Genetic Risk. Am J Respir Crit Care Med 2015; 192:727-36.
Art
Wissenschaftlicher Artikel/Review (Englisch)
Zeitschrift
Am J Respir Crit Care Med 2015; 192
Veröffentlichungsdatum
15.09.2015
eISSN (Online)
1535-4970
Seiten
727-36
Kurzbeschreibung/Zielsetzung

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.