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. 2018 Mar 20;19(1):44.
doi: 10.1186/s12931-018-0748-5.

G908R NOD2 variant in a family with sarcoidosis

Valérie Besnard  1 , Alain Calender  2 , Diane Bouvry  3   4 , Yves Pacheco  5   6 , Catherine Chapelon-Abric  7 , Florence Jeny  3   4 , Hilario Nunes  3   4 , Carole Planès  3   4 , Dominique Valeyre  3   4
Affiliations

G908R NOD2 variant in a family with sarcoidosis

Valérie Besnard et al. Respir Res. .

Abstract

Background: Sarcoidosis is a systemic disease characterized by the formation of immune granulomas in various organs, mainly the lungs and the lymphatic system. Exaggerated granulomatous reaction might be triggered in response to unidentified antigens in individuals with genetic susceptibility. The present study aimed to determine the genetic variants implicated in a familial case of sarcoidosis.

Methods: Sarcoidosis presentation and history, NOD2 profile, NF-κB and cytokine production in blood monocytes/macrophages were evaluated in individuals from a family with late appearance of sarcoidosis.

Results: In the present study, we report a case of familial sarcoidosis with typical thoracic sarcoidosis and carrying the NOD2 2722G > C variant. This variant is associated with the presence of three additional SNPs for the IL17RA, KALRN and EPHA2 genes, which discriminate patients expressing the disease from others. Despite a decrease in NF-κB activity, IL-8 and TNF-A mRNA levels were increased at baseline and in stimulated conditions.

Conclusions: Combination of polymorphisms in the NOD2, IL17RA, EPHA2 and KALRN genes could play a significant role in the development of sarcoidosis by maintaining a chronic pro-inflammatory status in macrophages.

Keywords: Familial sarcoidosis; Genetic susceptibility; NOD2.

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Conflict of interest statement

Ethics approval and consent to participate

The study received institutional review board approval (CPP IRN number 00009118) according to French legislation. Written informed consent for all participants was obtained for genetic and biological investigations.

Consent for publication

Not applicable

Competing interests

The authors declare that they have no competing interests.

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Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Pedigree of Family X with cases of pulmonary sarcoidosis. Circles represent females; squares represent males. Slashed symbol indicate deceased subjects. Individuals with confirmed sarcoidosis are indicated in black symbols. Relatives in grey symbols underwent a workup diagnosis (clinical examination, blood tests and chest X ray) that allowed to exclude sarcoidosis. The current age is indicated below each symbol. Numbers beside each symbol correspond to the individuals described in Table 1. The directional arrow indicates the index case. His maternal grand-mother died in 1958. She was known to have recurrent asthma attacks. No medical file is available for this woman
Fig. 2
Fig. 2
NF-κB activation is decreased in untreated NOD2 G208R sarcoidosis patient. NFκB activation (p50 (a), p65 (b), p52 (c), RelB (d), cRel (e)) (measured as OD450 nm) was assessed by TransAM NFκB kit (Active Motif) in control (C) and family X (F) monocytes (Mono) or monocytes derived macrophages (MФ) in basal condition (Ctrl) or treated with MDP or LPS for 1 h
Fig. 3
Fig. 3
Up-regulation of IL-8 and TNF-A expression in untreated NOD2 G208R sarcoidosis patient. IL-8 (a), TNF-A (b), IL-6  (c), NOD2 (d) and IL17RA (e) mRNA levels were assessed by RT-qPCR in control (C) and family X (F) monocytes (Mono) or monocytes derived macrophages (MФ) in basal condition (Ctrl) or treated with MDP or LPS for 24 h
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