RATIONALE: Sarcoidosis is a multisystem disease of unknown cause. Löfgren's syndrome (LS) is a characteristic subgroup of sarcoidosis that is associated with a good prognosis in sarcoidosis. However, little is known about its genetic architecture or its broader phenotype, non-LS sarcoidosis. OBJECTIVES: To address the genetic architecture of sarcoidosis phenotypes, LS and non-LS. METHODS: An association study in a white Swedish cohort of 384 LS, 664 non-LS, and 2,086 control subjects, totaling 3,134 subjects using a fine-mapping genotyping platform was conducted. Replication was performed in four independent cohorts, three of white European descent (Germany, n = 4,975; the Netherlands, n = 613; and Czech Republic, n = 521), and one of black African descent (United States, n = 1,657), totaling 7,766 subjects. MEASUREMENTS AND MAIN RESULTS: A total of 727 LS-associated variants expanding throughout the extended major histocompatibility complex (MHC) region and 68 non-LS-associated variants located in the MHC class II region were identified and confirmed. A shared overlap between LS and non-LS defined by 17 variants located in the MHC class II region was found. Outside the MHC region, two LS-associated loci, in ADCY3 and between CSMD1 and MCPH1, were observed and replicated. CONCLUSIONS: Comprehensive and integrative analyses of genetics, transcription, and pathway modeling on LS and non-LS indicates that these sarcoidosis phenotypes have different genetic susceptibility, genomic distributions, and cellular activities, suggesting distinct molecular mechanisms in pathways related to immune response with a common region.

Arthritis and Clinical Immunology Research Program Oklahoma Medical Research Foundation Oklahoma City Oklahoma

Center for Molecular Medicine and

Center of Interstitial Lung Diseases St Antonius Hospital Nieuwegein the Netherlands

Clinic of Internal Medicine 1 University Hospital Schleswig Holstein Kiel Germany

Department of Genomics Life and Brain Center University of Bonn Bonn Germany

Department of Pathological Physiology and

Department of Pneumology University of Freiburg Freiburg Germany

Department of Public Health Sciences Henry Ford Health Systems Detroit Michigan; and

Department of Respiratory Medicine Faculty of Medicine and Dentistry Palacky University Olomouc Olomouc Czech Republic

Division of Heart and Lungs University Medical Center Utrecht Utrecht the Netherlands

Institute of Clinical Molecular Biology University Hospital Schleswig Holstein Campus Kiel and Kiel University Kiel Germany

Institute of Human Genetics and

Popgen Biobank and

Respiratory Unit Department of Medicine Karolinska Institutet Karolinska University Hospital Stockholm Sweden

Rheumatology Unit Department of Medicine Karolinska Institutet Stockholm Sweden

State University of New York Upstate Medical University Syracuse Syracuse New York

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Am J Respir Crit Care Med. 2016 May 1;193(9):942-3. doi: 10.1164/rccm.201512-2358ED. PubMed

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Iannuzzi MC, Rybicki BA, Teirstein AS. Sarcoidosis. N Engl J Med. 2007;357:2153–2165. PubMed

Bauer HJ, Löfgren S. International study of pulmonary sarcoidosis in mass chest radiography. Acta Med Scand Suppl. 1964;425:103–105. PubMed

Grunewald J, Eklund A. Löfgren’s syndrome: human leukocyte antigen strongly influences the disease course. Am J Respir Crit Care Med. 2009;179:307–312. PubMed

De Vries J, Van Heck GL, Drent M. Gender differences in sarcoidosis: symptoms, quality of life, and medical consumption. Women Health. 1999;30:99–114. PubMed

Drent M, Marcellis R, Lenssen A, De Vries J. Association between physical functions and quality of life in sarcoidosis. Sarcoidosis. 2014;31:117–128. PubMed

Belfer MH, Stevens RW. Sarcoidosis: a primary care review. Am Fam Physician. 1998;58:2041–2050, 55–6. PubMed

Bauer HJ, Löfgren S. International study of pulmonary sarcoidosis in mass chest radiography. Acta Med Scand Suppl. 1964;425:103–105. PubMed

Trynka G, Hunt KA, Bockett NA, Romanos J, Mistry V, Szperl A, Bakker SF, Bardella MT, Bhaw-Rosun L, Castillejo G, et al. Spanish Consortium on the Genetics of Coeliac Disease (CEGEC); PreventCD Study Group; Wellcome Trust Case Control Consortium (WTCCC) Dense genotyping identifies and localizes multiple common and rare variant association signals in celiac disease. Nat Genet. 2011;43:1193–1201. PubMed PMC

Eyre S, Bowes J, Diogo D, Lee A, Barton A, Martin P, Zhernakova A, Stahl E, Viatte S, McAllister K, et al. Biologics in Rheumatoid Arthritis Genetics and Genomics Study Syndicate; Wellcome Trust Case Control Consortium. High-density genetic mapping identifies new susceptibility loci for rheumatoid arthritis. Nat Genet. 2012;44:1336–1340. PubMed PMC

Tsoi LC, Spain SL, Knight J, Ellinghaus E, Stuart PE, Capon F, Ding J, Li Y, Tejasvi T, Gudjonsson JE, et al. Collaborative Association Study of Psoriasis (CASP); Genetic Analysis of Psoriasis Consortium; Psoriasis Association Genetics Extension; Wellcome Trust Case Control Consortium 2. Identification of 15 new psoriasis susceptibility loci highlights the role of innate immunity. Nat Genet. 2012;44:1341–1348. PubMed PMC

Beecham AH, Patsopoulos NA, Xifara DK, Davis MF, Kemppinen A, Cotsapas C, Shah TS, Spencer C, Booth D, Goris A, et al. International Multiple Sclerosis Genetics Consortium (IMSGC); Wellcome Trust Case Control Consortium 2 (WTCCC2); International IBD Genetics Consortium (IIBDGC) Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis. Nat Genet. 2013;45:1353–1360. PubMed PMC

Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, Maller J, Sklar P, de Bakker PI, Daly MJ, et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet. 2007;81:559–575. PubMed PMC

Ellinghaus D, Baurecht H, Esparza-Gordillo J, Rodríguez E, Matanovic A, Marenholz I, Hübner N, Schaarschmidt H, Novak N, Michel S, et al. High-density genotyping study identifies four new susceptibility loci for atopic dermatitis. Nat Genet. 2013;45:808–812. PubMed PMC

Viechtbauer W.Conducting meta-analyses in R with the Metafor package J Stat Softw 2010363:1–48

Liu JZ, McRae AF, Nyholt DR, Medland SE, Wray NR, Brown KM, Hayward NK, Montgomery GW, Visscher PM, Martin NG, et al. AMFS Investigators. A versatile gene-based test for genome-wide association studies. Am J Hum Genet. 2010;87:139–145. PubMed PMC

Westra HJ, Peters MJ, Esko T, Yaghootkar H, Schurmann C, Kettunen J, Christiansen MW, Fairfax BP, Schramm K, Powell JE, et al. Systematic identification of trans eQTLs as putative drivers of known disease associations. Nat Genet. 2013;45:1238–1243. PubMed PMC

Dimas AS, Deutsch S, Stranger BE, Montgomery SB, Borel C, Attar-Cohen H, Ingle C, Beazley C, Gutierrez Arcelus M, Sekowska M, et al. Common regulatory variation impacts gene expression in a cell type-dependent manner. Science. 2009;325:1246–1250. PubMed PMC

Dixon AL, Liang L, Moffatt MF, Chen W, Heath S, Wong KC, Taylor J, Burnett E, Gut I, Farrall M, et al. A genome-wide association study of global gene expression. Nat Genet. 2007;39:1202–1207. PubMed

Gaffney DJ, Veyrieras JB, Degner JF, Pique-Regi R, Pai AA, Crawford GE, Stephens M, Gilad Y, Pritchard JK. Dissecting the regulatory architecture of gene expression QTLs. Genome Biol. 2012;13:R7. PubMed PMC

Montgomery SB, Sammeth M, Gutierrez-Arcelus M, Lach RP, Ingle C, Nisbett J, Guigo R, Dermitzakis ET. Transcriptome genetics using second generation sequencing in a caucasian population. Nature. 2010;464:773–777. PubMed PMC

Nica AC, Parts L, Glass D, Nisbet J, Barrett A, Sekowska M, Travers M, Potter S, Grundberg E, Small K, et al. MuTHER Consortium. The architecture of gene regulatory variation across multiple human tissues: the MuTHER study. PLoS Genet. 2011;7:e1002003. PubMed PMC

Pickrell JK, Marioni JC, Pai AA, Degner JF, Engelhardt BE, Nkadori E, Veyrieras JB, Stephens M, Gilad Y, Pritchard JK. Understanding mechanisms underlying human gene expression variation with RNA sequencing. Nature. 2010;464:768–772. PubMed PMC

Stranger BE, Nica AC, Forrest MS, Dimas A, Bird CP, Beazley C, Ingle CE, Dunning M, Flicek P, Koller D, et al. Population genomics of human gene expression. Nat Genet. 2007;39:1217–1224. PubMed PMC

Veyrieras JB, Kudaravalli S, Kim SY, Dermitzakis ET, Gilad Y, Stephens M, Pritchard JK. High-resolution mapping of expression-QTLs yields insight into human gene regulation. PLoS Genet. 2008;4:e1000214. PubMed PMC

Zeller T, Wild P, Szymczak S, Rotival M, Schillert A, Castagne R, Maouche S, Germain M, Lackner K, Rossmann H, et al. Genetics and beyond: the transcriptome of human monocytes and disease susceptibility. PLoS One. 2010;5:e10693. PubMed PMC

Boyle APHE, Hong EL, Hariharan M, Cheng Y, Schaub MA, Kasowski M, Karczewski KJ, Park J, Hitz BC, Weng S, et al. Annotation of functional variation in personal genomes using RegulomeDB. Genome Res. 2012;22:1790–1797. PubMed PMC

Ward LD, Kellis M. HaploReg: a resource for exploring chromatin states, conservation, and regulatory motif alterations within sets of genetically linked variants. Nucleic Acids Res. 2012;40:D930–D934. PubMed PMC

Sharma SM, Choi D, Planck SR, Harrington CA, Austin CR, Lewis JA, Diebel TN, Martin TM, Smith JR, Rosenbaum JT. Insights in to the pathogenesis of axial spondyloarthropathy based on gene expression profiles. Arthritis Res Ther. 2009;11:R168. PubMed PMC

Koth LL, Solberg OD, Peng JC, Bhakta NR, Nguyen CP, Woodruff PG. Sarcoidosis blood transcriptome reflects lung inflammation and overlaps with tuberculosis. Am J Respir Crit Care Med. 2011;184:1153–1163. PubMed PMC

Judson MA, Marchell RM, Mascelli M, Piantone A, Barnathan ES, Petty KJ, Chen D, Fan H, Grund H, Ma K, et al. Molecular profiling and gene expression analysis in cutaneous sarcoidosis: the role of interleukin-12, interleukin-23, and the T-helper 17 pathway. J Am Acad Dermatol. 2012;66:901–910. PubMed

Horton R, Wilming L, Rand V, Lovering RC, Bruford EA, Khodiyar VK, Lush MJ, Povey S, Talbot CC, Jr, Wright MW, et al. Gene map of the extended human MHC. Nat Rev Genet. 2004;5:889–899. PubMed

Ferreira MA, Mangino M, Brumme CJ, Zhao ZZ, Medland SE, Wright MJ, Nyholt DR, Gordon S, Campbell M, McEvoy BP, et al. International HIV Controllers Study. Quantitative trait loci for CD4:CD8 lymphocyte ratio are associated with risk of type 1 diabetes and HIV-1 immune control. Am J Hum Genet. 2010;86:88–92. PubMed PMC

Manolio TA, Collins FS, Cox NJ, Goldstein DB, Hindorff LA, Hunter DJ, McCarthy MI, Ramos EM, Cardon LR, Chakravarti A, et al. Finding the missing heritability of complex diseases. Nature. 2009;461:747–753. PubMed PMC

Small KS, Hedman AK, Grundberg E, Nica AC, Thorleifsson G, Kong A, Thorsteindottir U, Shin SY, Richards HB, Soranzo N, et al. GIANT Consortium; MAGIC Investigators; DIAGRAM Consortium; MuTHER Consortium. Identification of an imprinted master trans regulator at the KLF14 locus related to multiple metabolic phenotypes. Nat Genet. 2011;43:561–564. PubMed PMC

Wei G, Wei L, Zhu J, Zang C, Hu-Li J, Yao Z, Cui K, Kanno Y, Roh TY, Watford WT, et al. Global mapping of H3K4me3 and H3K27me3 reveals specificity and plasticity in lineage fate determination of differentiating CD4+ T cells. Immunity. 2009;30:155–167. PubMed PMC

Ansel KM, Lee DU, Rao A. An epigenetic view of helper T cell differentiation. Nat Immunol. 2003;4:616–623. PubMed

Merkenschlager M, Wilson CB. RNAi and chromatin in T cell development and function. Curr Opin Immunol. 2008;20:131–138. PubMed

Zhou L, Chong MM, Littman DR. Plasticity of CD4+ T cell lineage differentiation. Immunity. 2009;30:646–655. PubMed

Wilson CB, Rowell E, Sekimata M. Epigenetic control of T-helper-cell differentiation. Nat Rev Immunol. 2009;9:91–105. PubMed

Ostadkarampour M, Eklund A, Moller D, Glader P, Olgart Höglund C, Lindén A, Grunewald J, Wahlström J. Higher levels of interleukin IL-17 and antigen-specific IL-17 responses in pulmonary sarcoidosis patients with Löfgren’s syndrome. Clin Exp Immunol. 2014;178:342–352. PubMed PMC

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