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Familial Vs. Sporadic Sarcoidosis: BTNL2 Polymorphisms, Clinical

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Familial Vs. Sporadic Sarcoidosis: BTNL2 Polymorphisms, Clinical Familial vs. sporadic sarcoidosis: BTNL2 polymorphisms, clinical presentations, and outcomes in a French cohort Yves Pacheco, Alain Calender, Dominique Israël-Biet, Pascal Roy, Serge Lebecque, Vincent Cottin, Diane Bouvry, Hilario Nunes, Pascal Sève, Laurent Pérard, et al. To cite this version: Yves Pacheco, Alain Calender, Dominique Israël-Biet, Pascal Roy, Serge Lebecque, et al.. Familial vs. sporadic sarcoidosis: BTNL2 polymorphisms, clinical presentations, and outcomes in a French cohort. Orphanet Journal of Rare Diseases, BioMed Central, 2016, 11 (1), 10.1186/s13023-016-0546-4. hal- 01595465 HAL Id: hal-01595465 https://hal.archives-ouvertes.fr/hal-01595465 Submitted on 26 Sep 2017 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Distributed under a Creative Commons Attribution - ShareAlike| 4.0 International License Pacheco et al. Orphanet Journal of Rare Diseases (2016) 11:165 DOI 10.1186/s13023-016-0546-4 RESEARCH Open Access Familial vs. sporadic sarcoidosis: BTNL2 polymorphisms, clinical presentations, and outcomes in a French cohort Yves Pacheco1,11*, Alain Calender2, Dominique Israël-Biet3, Pascal Roy4, Serge Lebecque5, Vincent Cottin6, Diane Bouvry7, Hilario Nunes7, Pascal Sève8, Laurent Pérard9, Gilles Devouassoux8, Nathalie Freymond1, Chahira Khouatra6, Benoît Wallaert10, Raphaelle Lamy2, Mad-Hélénie Elsensohn4, Claire Bardel4, Dominique Valeyre7 and GSF group Abstract Background: The occurrence of familial forms of sarcoidosis (OMIM 181100) suggests a genetic predisposition. The involvement of butyrophilin-like 2 (BTNL2) gene (rs2076530 variant) has to be investigated. Results: The study performed independent analyses of BTNL2 polymorphism, clinical phenotypes, and outcomes in familial vs. sporadic presentations in 256 sporadic and 207 familial cases from 140 families. The logistic multivariate model showed that a young age at diagnosis and the combination of lung and skin involvement at diagnosis may distinguish sporadic from familial sarcoidosis (p = 0.016 and p = 0.041). We observed also that Sarcoid Clinical Activity Classification (SCAC) profiles were significantly different between familial and sporadic cases (p = 0.0497). Variant rs2076530 was more frequent in patients than in controls (OR = 2.02; 95% CI: [1.32–3.09]) but showed no difference between sporadic and familial cases and no difference according to the clinical phenotype or the outcome. Conclusion: Despite a significant difference in BTNL2 polymorphism between sarcoid patients and controls, there was no such difference between familial and sporadic sarcoidosis cases and no correlation between BTNL2 polymorphism and disease severity or outcome. Thus, BTNL2 difference cannot be considered as a key marker for disease classification or patient management. Keywords: Sarcoidosis, Medical genetics, Human BTNL2 protein, Candidate gene association study, Classification Background investigate the clinical phenotypes and outcomes of sar- Sarcoidosis is a rare multisystemic granulomatous dis- coidosis in search for genotype-phenotype correlations. order of still unknown origin. It has various presenta- Nevertheless, interesting suggestions about classical radio- tions, severities, treatments, and outcomes [1]. Genetic graphic staging [3], factor analysis [4, 5], SCAC (Sarcoid studies have searched for polymorphisms associated with Clinical Activity Classification) [6], and WASOG (World the risk of developing the disease and for genotype- Association for Sarcoidosis and Other Granulomatous phenotype correlations. Among several candidate genes, Disorders) clinical outcome status classification [7] are BTNL2 (butyrophylin-like 2) has been intensively stud- available. ied. A recent meta-analysis has confirmed that BTNL2 We investigated BTNL2 gene in familial forms of sar- rs2076530 polymorphism contributes to the risk of coidosis to assess the role of this gene as a major indica- sarcoidosis [2]. Meanwhile, it has been difficult to tor of hereditary predisposition to the disease [8–10] and find out whether it can be a useful genetic marker * Correspondence: [email protected] for clinical management and prognosis. 1Hospices Civils de Lyon, Centre Hospitalier Lyon Sud, Université Claude Bernard – Lyon 1, EA-7426, Lyon, France 11Université Claude Bernard Lyon 1 - EA-7426, 165 Chemin du Grand Revoyet, F-69495 Pierre Benite, France Full list of author information is available at the end of the article © The Author(s). 2016 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Pacheco et al. Orphanet Journal of Rare Diseases (2016) 11:165 Page 2 of 9 Methods The disease outcome was examined using SCAC with Participant inclusion six progression patterns [6] and, whenever possible, a SARCFAM (a national project on familial sarcoidosis) is classification of outcome in four categories: 1) recovery a prospective observational cohort study started in 2008. within 3 years; 2) recovery between 3 and 5 years; 3) no It involves 28 French university departments of internal recovery at 5 years; 4) death. medicine or pulmonology that care for sarcoidosis patients. Genetic study Three inclusion criteria were: i) clinical and paraclinical Blood DNAs were obtained from nearly all patients and features consistent with sarcoidosis; ii) histopathological tested for BTNL2 gene rs2076530 polymorphism. Primer evidence of non-caseating granuloma, except Löfgren syn- oligonucleotides for polymerase chain reaction and DNA drome; and, iii) exclusion of any other chronic disease. sequencing were located within the reference sequence The evidence for non-caseating granulomatous lesions surrounding rs2076530, the major single-nucleotide was obtained by mediastinoscopy (26.4%), or bronchial/ polymorphisms (SNPs) that induce truncation of the pulmonary (34.9%), accessory salivary gland (12.3%), per- BTNL2 protein [8]. A 490-bp amplicon was produced ipheral lymph node (10.4%), skin (9.8%), conjunctiva and sequenced using primers 5′-AATGCACAGAGC (2.5%), kidney (1.2%) or other (2.5%) biopsies. ATGGAGGTGAG-3′ and 5′-GAAGATACTGGAAAAG All 463 cases included were diagnosed according to ATACAAG-3′. the Joint Statement of the American Thoracic Society The quality control of PCR products was performed on (ATS), the European Respiratory Society (ERS), and the a LabChipGX system (PERKIN ELMER™) and the prod- (WASOG) [11]. The disease type (familial vs. sporadic) ucts purified by NucleoFast® 96 PCR Clean-up Kit from was determined by structured interview. MACHEREY-NAGEL™. The sequencing was performed The control population for the genetic investigation by Big Dye terminator v1.1 after purification with BigDye® consisted of 430 DNA samples from a single genetic XTerminator™ Purification Kit. Sequence delineation and database of healthy human reference population. The base calling used an automated fluorescent DNA sequen- mean age (41.5 ± 17.5 years) and geographic origins cer (Applied Biosystems™, model 3130xl). [European: n = 324 (75.3%) and Sub-Saharan African plus Caribbean: n = 106 (24.7%)] were quite similar to Statistical analysis those of the study sarcoid patients. Familial and sporadic cases were compared using a gen- eralized linear mixed model. To allow for family links, the model included correlations between patients’ ran- Clinical assessment dom effects [12]. All patients with sporadic sarcoidosis or index cases with In a first application of the model, univariate submo- familial sarcoidosis were diagnosed and followed-up in dels were constructed and compared with a null model the 28 clinical centers. A specific case report form was (model with intercept only) using a likelihood ratio test filled in with demographic data, medical history, disease to test the effects of the main variables (Table 1). The onset (symptomatic or asymptomatic), detailed organ in- clinical characteristics of BTNL2 G/G vs. BTNL2 A/A volvement, treatments, and outcome. A detailed familial plus BTNL2 A/G genotypes were compared with the history of sarcoidosis was also examined to assess gen- same method (Table 2). Because the study was mainly etic predisposition. Familial cases were offered a DNA exploratory, only raw p-values are shown; however, a sampling and the related forms were filled in the center Bonferroni correction for multiple testing was applied and where the index case was diagnosed. when raw p-values were significant, adjusted p-values Clinical, biological, and imaging data were also collected were also calculated [13]. at diagnosis and each follow-up visit until December 2012. In
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