Exome sequencing and pathogenicity-network analysis of 5 French families implicate mTOR signalling and autophagy in familial sarcoidosis

Sarcoidosis is a complex disease characterised by the presence of epithelioid non-caseating granulomatous inflammation affecting multiple organs and whose aetiology has been related to microbial, environmental and genetic factors [1, 2]. However, no single antigenic trigger has been identified, although associations with Propionibacterium acnes and mycobacteria pathogen-associated molecular pattern (PAMP), deposition of serum amyloid A (SAA), and exposure to inorganic particles and insecticides have been suggested [3–5]. Occurrence of familial cases suggests that genetic variation contributes to disease pathogenesis with a heritability of about 39% [6]. Despite intensive genome-wide association studies (GWAS), no single nucleotide polymorphism (SNP) is as yet able to explain the “missing heritability” in the disease, especially for non-resolving, non-Lofgren's syndrome (non-LS) sarcoidosis [5–7]. Footnotes This manuscript has recently been accepted for publication in the European Respiratory Journal . It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article. Conflict of interest: Dr. CALENDER has nothing to disclose. Conflict of interest: Dr. LIM has nothing to disclose. Conflict of interest: Dr. Weichhart has nothing to disclose. Conflict of interest: Dr. BUISSON has nothing to disclose. Conflict of interest: Dr. Besnard has nothing to disclose. Conflict of interest: Dr. Rollat-Farnier has nothing to disclose. Conflict of interest: Dr. Bardel has nothing to disclose. Conflict of interest: Dr. ROY has nothing to disclose. Conflict of interest: Dr. Cottin reports personal fees and non-financial support from Actelion, grants, personal fees and non-financial support from Boehringer Ingelheim, personal fees from Bayer/MSD, personal fees from Gilead, personal fees from GSK, personal fees from Novartis, grants, personal fees and non-financial support from Roche, grants from Sanofi, personal fees from Promedior, personal fees from Celgene, personal fees from Galapagos, outside the submitted work. Conflict of interest: Dr. DEVOUASSOUX has nothing to disclose. Conflict of interest: Dr. FINAT has nothing to disclose. Conflict of interest: Dr. PINSON has nothing to disclose. Conflict of interest: Dr. lebecque has nothing to disclose. Conflict of interest: Dr. Nunes reports grants and personal fees from Roche/Genentech, grants and personal fees from Boehringer Ingelheim, other from Sanofi, other from Gilead, outside the submitted work. Conflict of interest: Dr. ISRAEL-BIET has nothing to disclose. Conflict of interest: Dr. Bentaher has nothing to disclose. Conflict of interest: Dr. VALEYRE reports personal fees from Boehringer Ingelheim, personal fees from Roche, personal fees from Astra Zenecca, personal fees from Boehringer Ingelheim & Roche, outside the submitted work. Conflict of interest: Dr. PACHECO has nothing to disclose.