Identification of Immune-Relevant Factors Conferring Sarcoidosis Genetic Risk

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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References

Wijnen P, Cremers J, Nelemans P, Erckens R, Hoitsma E, Jansen T . Association of the TNF-α G-308A polymorphism with TNF-inhibitor response in sarcoidosis. Eur Respir J. 2014; 43(6):1730-9. DOI: 10.1183/09031936.00169413. View

Levin A, Iannuzzi M, Montgomery C, Trudeau S, Datta I, McKeigue P . Association of ANXA11 genetic variation with sarcoidosis in African Americans and European Americans. Genes Immun. 2012; 14(1):13-8. PMC: 3595044. DOI: 10.1038/gene.2012.48. View

Ellinghaus D, Baurecht H, Esparza-Gordillo J, Rodriguez E, Matanovic A, Marenholz I . High-density genotyping study identifies four new susceptibility loci for atopic dermatitis. Nat Genet. 2013; 45(7):808-12. PMC: 3797441. DOI: 10.1038/ng.2642. View

Maliarik M, Chen K, Major M, Sheffer R, Popovich Jr J, Rybicki B . Analysis of HLA-DPB1 polymorphisms in African-Americans with sarcoidosis. Am J Respir Crit Care Med. 1998; 158(1):111-4. DOI: 10.1164/ajrccm.158.1.9708111. View

Spagnolo P, Sato H, Grutters J, Renzoni E, Marshall S, Ruven H . Analysis of BTNL2 genetic polymorphisms in British and Dutch patients with sarcoidosis. Tissue Antigens. 2007; 70(3):219-27. DOI: 10.1111/j.1399-0039.2007.00879.x. View

Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira M, Bender D . PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet. 2007; 81(3):559-75. PMC: 1950838. DOI: 10.1086/519795. View

Duerr R, Taylor K, Brant S, Rioux J, Silverberg M, Daly M . A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science. 2006; 314(5804):1461-3. PMC: 4410764. DOI: 10.1126/science.1135245. View

Jensen L, Kuhn M, Stark M, Chaffron S, Creevey C, Muller J . STRING 8--a global view on proteins and their functional interactions in 630 organisms. Nucleic Acids Res. 2008; 37(Database issue):D412-6. PMC: 2686466. DOI: 10.1093/nar/gkn760. View

Fischer A, Nothnagel M, Franke A, Jacobs G, Saadati H, Gaede K . Association of inflammatory bowel disease risk loci with sarcoidosis, and its acute and chronic subphenotypes. Eur Respir J. 2010; 37(3):610-6. DOI: 10.1183/09031936.00049410. View

10.

Cozier Y, Ruiz-Narvaez E, McKinnon C, Berman J, Rosenberg L, Palmer J . Replication of genetic loci for sarcoidosis in US black women: data from the Black Women's Health Study. Hum Genet. 2013; 132(7):803-10. PMC: 3746966. DOI: 10.1007/s00439-013-1292-5. View

11.

Ellinghaus D, Ellinghaus E, Nair R, Stuart P, Esko T, Metspalu A . Combined analysis of genome-wide association studies for Crohn disease and psoriasis identifies seven shared susceptibility loci. Am J Hum Genet. 2012; 90(4):636-47. PMC: 3322238. DOI: 10.1016/j.ajhg.2012.02.020. View

12.

Jostins L, Ripke S, Weersma R, Duerr R, McGovern D, Hui K . Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature. 2012; 491(7422):119-24. PMC: 3491803. DOI: 10.1038/nature11582. View

13.

Kopylov U, Afif W, Cohen A, Bitton A, Wild G, Bessissow T . Subcutaneous ustekinumab for the treatment of anti-TNF resistant Crohn's disease--the McGill experience. J Crohns Colitis. 2014; 8(11):1516-22. DOI: 10.1016/j.crohns.2014.06.005. View

14.

Judson M, Baughman R, Costabel U, Drent M, Gibson K, Raghu G . Safety and efficacy of ustekinumab or golimumab in patients with chronic sarcoidosis. Eur Respir J. 2014; 44(5):1296-307. DOI: 10.1183/09031936.00000914. View

15.

Rossman M, Thompson B, Frederick M, Maliarik M, Iannuzzi M, Rybicki B . HLA-DRB1*1101: a significant risk factor for sarcoidosis in blacks and whites. Am J Hum Genet. 2003; 73(4):720-35. PMC: 1180597. DOI: 10.1086/378097. View

16.

Li Y, Pabst S, Kubisch C, Grohe C, Wollnik B . First independent replication study confirms the strong genetic association of ANXA11 with sarcoidosis. Thorax. 2010; 65(10):939-40. DOI: 10.1136/thx.2010.138743. View

17.

Valentonyte R, Hampe J, Huse K, Rosenstiel P, Albrecht M, Stenzel A . Sarcoidosis is associated with a truncating splice site mutation in BTNL2. Nat Genet. 2005; 37(4):357-64. DOI: 10.1038/ng1519. View

18.

Schurmann M, Bein G, Kirsten D, Schlaak M, Muller-Quernheim J, Schwinger E . HLA-DQB1 and HLA-DPB1 genotypes in familial sarcoidosis. Respir Med. 1998; 92(4):649-52. DOI: 10.1016/s0954-6111(98)90512-1. View

19.

Tsoi L, Spain S, Knight J, Ellinghaus E, Stuart P, Capon F . Identification of 15 new psoriasis susceptibility loci highlights the role of innate immunity. Nat Genet. 2012; 44(12):1341-8. PMC: 3510312. DOI: 10.1038/ng.2467. View

20.

Richeldi L, Sorrentino R, Saltini C . HLA-DPB1 glutamate 69: a genetic marker of beryllium disease. Science. 1993; 262(5131):242-4. DOI: 10.1126/science.8105536. View