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

Calender, Alain; Lim, Clarice X.; Weichhart, Thomas; Buisson, Adrien; Besnard, Valérie; Rollat‐Farnier, Pierre Antoine; Bardel, Claire; Roy, Pascal; Cottin, Vincent; Devouassoux, Gilles; Finat, Amélie; Pinson, Stéphane; Lebecque, Serge; Nunès, Hilario; Israël‐Biet, Dominique; Bentaher, Abderrazzak; Valeyre, Dominique; Pachéco, Yves

doi:10.1183/13993003.00430-2019

Cited by 45 publications

(45 citation statements)

References 17 publications

(20 reference statements)

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“…This region has also been found to associate with familial sarcoidosis in a recent WES study in German patients (20). However, in French WES study of familial sarcoidosis, no association with this region was found (21). In our study, variations in these genes were associated with disease resolution independent of the HLA markers DRB1 * 03:01 and DRB1 * 04:01.…”

Section: Discussionsupporting

confidence: 54%

Exome Sequencing Identifies Susceptibility Loci for Sarcoidosis Prognosis

et al. 2019

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Many sarcoidosis-associating immunological genes have been shown to be shared between other immune-mediated diseases. In Finnish sarcoidosis patients, good prognosis subjects more commonly have HLA-DRB1 * 03:01 and/or HLA-DRB1 * 04:01-DPB1 * 04:01 haplotype, but no marker for persistent disease have been found. The objective was to further pinpoint genetic differences between prognosis subgroups in relation to the HLA markers. Whole-exome sequencing was conducted for 72 patients selected based on disease activity (resolved disease, n = 36; persistent disease, n = 36). Both groups were further divided by the HLA markers (one/both markers, n = 18; neither of the markers, n = 18). The Finnish exome data from the Genome Aggregation Database was used as a control population in the WES sample. Statistical analyses included single-variant analysis for common variants and gene level analysis for rare variants. We attempted to replicate associated variants in 181 Finnish sarcoidosis patients and 150 controls. An association was found in chromosome 1p36.21 (AADACL3 and C1orf158), which has recently been associated with sarcoidosis in another WES study. In our study, variations in these genes were associated with resolved disease (AADACL3, p = 0.0001 and p = 0.0003; C1orf158, p = 7.03E-05). Another interesting chromosomal region also peaked, Leucocyte Receptor Complex in 19q13.42, but the association diminished in the replication sample. In conclusion, this WES study supports the previously found association in the region 1p36.21. Furthermore, a novel to sarcoidosis region was found, but additional studies are warranted to verify this association.

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Section: Discussionsupporting

confidence: 54%

Exome Sequencing Identifies Susceptibility Loci for Sarcoidosis Prognosis

et al. 2019

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“…Recently, Calender et al showed that mTOR signaling and autophagy signaling are overexpressed in sarcoidosis. 16 This was consistent with previously published data in mice. 136 In 2011, Manzia et al described a case of a liver transplant recipient with sarcoid-like granulomatosis which improved on introduction of rapamycin 137 after CisA failure.…”

Section: Mtor Inhibitorssupporting

confidence: 93%

“…Indeed, several polymorphisms in genes implicated in autophagy were also shown to be linked with sarcoidosis. 16 The lack of clearance of certain antigens may represent one possible explanation for the granulomatous reaction linked to autophagy failure.…”

Section: Pathophysiology Of Sarcoidosis and Granuloma Formationmentioning

confidence: 99%

<p>Refractory Sarcoidosis: A Review</p>

Jammal

Jamilloux

Gerfaud‐Valentin

et al. 2020

TCRM

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Sarcoidosis is a multi-system disease of unknown etiology characterized by granuloma formation in various organs (especially lung and mediastinohilar lymph nodes). In more than half of patients, the disease resolves spontaneously. When indicated, it usually responds to corticosteroids, the first-line treatment, but some patients may not respond or tolerate them. An absence of treatment response is rare and urges for verifying the absence of a diagnosis error, the good adherence of the treatment, the presence of active lesions susceptible to respond since fibrotic lesions are irreversible. That is when second-line treatments, immunosuppressants (methotrexate, leflunomide, azathioprine, mycophenolate mofetil, hydroxychloroquine), should be considered. Methotrexate is the only first-line immunosuppressant validated by a randomized controlled trial. Refractory sarcoidosis is not yet a well-defined condition, but it remains a real challenge for the physicians. Herein, we considered refractory sarcoidosis as a disease in which second-line treatments are not sufficient to achieve satisfying disease control or satisfying corticosteroids tapering. Tumor necrosis alpha inhibitors, third-line treatments, have been validated through randomized controlled trials. There are currently no guidelines or recommendations regarding refractory sarcoidosis. Moreover, criteria defining non-response to treatment need to be clearly specified. The delay to achieve response to organ involvement and drugs also should be defined. In the past ten years, the efficacy of several immunosuppressants beforehand used in other autoimmune or inflammatory diseases was reported in refractory cases series. Among them, anti-CD20 antibodies (rituximab), repository corticotrophin injection, and anti-JAK therapy anti-interleukin-6 receptor monoclonal antibody (tocilizumab) were the main reported. Unfortunately, no clinical trial is available to validate their use in the case of sarcoidosis. Currently, other immunosuppressants such as JAK inhibitors are on trial to assess their efficacy in sarcoidosis. In this review, we propose to summarize the state of the art regarding the use of immunosuppressants and their management in the case of refractory or multidrugresistant sarcoidosis.

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“…In addition, the authors identified activated mTORC1 signalling in one third of granulomas obtained from 27 biopsies from patients. These results were confirmed by CALENDER et al [11] in genetic studies on five French families, which led to the identification of genes enriched in the regulation of mTOR signalling pathway and autophagy. As a consequence, a clinical trial targeting mTOR in a pilot study of sirolimus inhibitors in sarcoidosis with cutaneous affection is ongoing (EudraCT Number: 2017-004930-27).…”

supporting

confidence: 68%

“…Multiple pathways have been described in the pathogenesis of sarcoidosis, including autophagy/mTOR [7,11] and JAK/STAT [8,9,12] signalling pathways and future investigations are required to provide important leads toward the development of effective therapeutic strategies. Targeting the inflammasome using MCC950 [22] or other molecules is currently under deep investigation in multiple conditions [17], such as cardiac sarcoidosis (MAGiC-ART; ClinicalTrials.gov Identifier: NCT04017936).…”

mentioning

confidence: 99%

In addition to mTOR and JAK/STAT, NLRP3 inflammasome is another key pathway activated in sarcoidosis

Riteau

Bernaudin

2020

Eur Respir J

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The study of Huppertz and co-workers addresses the role of the NLRP3 inflammasome in sarcoidosis. Employing both mouse model and human samples, they provide evidence of NLPR3 inflammasome activation and increased IL-1β production in lung granulomas. http://bit.ly/32a4GsI Cite this article as: Riteau N, Bernaudin J-F. In addition to mTOR and JAK/STAT, NLRP3 inflammasome is another key pathway activated in sarcoidosis.

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

Cited by 45 publications

References 17 publications

Exome Sequencing Identifies Susceptibility Loci for Sarcoidosis Prognosis

Exome Sequencing Identifies Susceptibility Loci for Sarcoidosis Prognosis

<p>Refractory Sarcoidosis: A Review</p>

In addition to mTOR and JAK/STAT, NLRP3 inflammasome is another key pathway activated in sarcoidosis

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