DCTN4 as a modifier of chronic Pseudomonas aeruginosa infection in cystic fibrosis Marion Viel 1 , Dominique Hubert 2 , Pierre-Regis Burgel 2 , Emmanuelle Génin 3 , Isabelle Honoré 2 , Brigitte Martinez 1 , Natacha Gaitch 1 , Jeanne Chapron 2 , Reem Kanaan 2 , Daniel Dusser 2 , Emmanuelle Girodon 1 and Thierry Bienvenu 1,4 1 AP-HP, Laboratoire de Biochimie et Génétique Moléculaire, Groupe Universitaire Paris Centre, Paris, France 2 Service de Pneumologie, GH Cochin-Broca-Hôtel Dieu, Université Paris Descartes, Paris, France 3 Inserm U1078, Génétique, Génomique fonctionnelle et Biotechnologies, Brest, France 4 Institut Cochin, INSERM U1016, Université Paris Descartes, Paris, France Abstract Background and Aims: Pseudomonas aeruginosa (Pa) infection in cystic fibrosis (CF) patients is associated with worse long-term pulmonary disease and shorter survival, and chronic Pa infection (CPA) is associated with reduced lung function, faster rate of lung decline, increased rates of exacerbations and shorter survival. By using exome sequencing and extreme phenotype design, it was recently shown that isoforms of dynactin 4 (DCTN4) may influence Pa infection in CF, leading to worse respiratory disease. The purpose of this study was to investigate the role of DCTN4 missense variants on Pa infection incidence, age at first Pa infection and chronic Pa infection incidence in a cohort of adult CF patients from a single centre. Methods: Polymerase chain reaction and direct sequencing were used to screen DNA samples for DCTN4 variants. Results: A total of 121 adult CF patients from the Cochin Hospital CF centre have been included, all of them carrying two CFTR defects: 103 developed at least 1 pulmonary infection with Pa, and 68 patients of them had CPA. DCTN4 variants were identified in 24% (29/121) CF patients with Pa infection and in only 17% (3/18) CF patients with no Pa infection. Of the patients with CPA, 29% (20/68) had DCTN4 missense variants vs 23% (8/35) in patients without CPA. Interestingly, p.Tyr263Cys tend to be more frequently observed in CF patients with CPA than in patients without CPA (4/68 vs 0/35), and DCTN4 missense variants tend to be more frequent in male CF patients with CPA bearing two class II mutations than in male CF patients without CPA bearing two class II mutations (P = 0.06). Conclusions: Our observations reinforce that DCTN4 missense variants, especially p.Tyr263Cys,may be involved in the pathogenesis of CPA in male CF. Please cite this paper as: Viel M, Hubert D, Burgel P-R, Génin E, Honoré I, Martinez B, Gaitch N, Chapron J, Kanaan R, Dusser D, Girodon E and Bienvenu T. DCTN4 as a modifier of chronic Pseudomonas aeruginosa infection in cystic fibrosis. Clin Respir J 2015; ••: ••–••. DOI:10.1111/crj.12288. Key words cystic fibrosis – DCTN4 – dynactin 4 – modifier gene – Pseudomonas aeruginosa infection Correspondence Thierry Bienvenu, PhD, Laboratoire de Biochimie et Génétique Moléculaire, Hôpital Cochin, 27 Rue du Faubourg Saint Jacques, 75014 Paris, France. Tel: 33 1 44 41 24 79/33 1 58 41 16 17 Fax: 33 1 44 41 24 21/33 1 58 41 15 80 email: thierry.bienvenu@inserm.fr Received: 01 August 2014 Accepted: 28 February 2015 DOI:10.1111/crj.12288 Authorship and contributorship Thierry Bienvenu and Emmanuelle Girodon designed the study and wrote the first draft of the paper. Dominique Hubert, Pierre-Regis Burgel, Isabelle Honoré, Jeanne Chapron, Reem Kanaan and Daniel Dusser included the CF patients. Marion Viel, Brigitte Martinez and Natacha Gaitch performed the genetic analyses. Thierry Bienvenu, Emmanuelle Girodon and Emmanuelle Génon collected the samples and analysed the data. All authors interpreted the data, contributed to the subsequent versions of the article and approved the final report. Ethics The human study has been reviewed by the appropriate ethics committee and has been performed in accordance with the ethical standards laid down in an appropriate version of the 2000 Declaration of Helsinki. All persons gave their informed consent prior to their inclusion in the study. Conflict of interest The authors have stated explicitly that there are no conflicts of interest in connection with this article. The Clinical Respiratory Journal ORIGINAL ARTICLE 1 The Clinical Respiratory Journal (2015) • ISSN 1752-6981 © 2015 John Wiley & Sons Ltd