Identification of Immune-Relevant Factors Conferring Sarcoidosis Genetic Risk

Publication

Identification of Immune-Relevant Factors Conferring Sarcoidosis Genetic Risk

Journal Paper/Review - Sep 15, 2015

Fischer Annegret, Nöthen Markus M, Herms Stefan, Gieger Christian, Strauch Konstantin, Winkelmann Juliane, Boehm Bernhard O, Brand Stephan, Büning Carsten, Schürmann Manfred, Ellinghaus Eva, Baurecht Hansjörg, Lieb Wolfgang, Nebel Almut, Müller-Quernheim Joachim, Franke Andre, Schreiber Stefan, Homolka Jiri, Sterclova Martina, Ellinghaus David, Nutsua Marcel, Hofmann Sylvia, Montgomery Courtney G, Iannuzzi Michael C, Rybicki Benjamin A, Petrek Martin, Mrazek Frantisek, Pabst Stefan, Grohé Christian, Grunewald Johan, Ronninger Marcus, Eklund Anders, Padyukov Leonid, Mihailovic-Vucinic Violeta, Jovanovic Dragana

Citation

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.

Type

Journal Paper/Review (English)

Journal

Am J Respir Crit Care Med 2015; 192

Publication Date

Sep 15, 2015

Issn Electronic

1535-4970

Pages

727-36

Brief description/objective

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.