title: CCSP G38A polymorphism environment interactions regulate CCSP levels differentially in COPD.
abstract: Impaired airway homeostasis in chronic obstructive pulmonary disease (COPD) could be partly related to club cell secretory protein (CCSP) deficiency. We hypothesize that CCSP G38A polymorphism is involved and aim to examine the influence of the CCSP G38A polymorphism on CCSP transcription levels and its regulatory mechanisms. CCSP genotype and CCSP levels in serum and sputum were assessed in 66 subjects with stable COPD included in a 1-yr observational study. Forty-nine of them had an exacerbation. In an in vitro study, the impact on the CCSP promoter of 38G wild-type or 38A variant was assessed. BEAS-2B cells were transfected by either the 38G or 38A construct, in the presence/absence of cigarette smoke extract (CSE) or lipopolysaccharides (LPS). Cotransfections with modulating transcription factors, p53 and Nkx2.1, identified by in silico analysis by using ConSite and TFSEARCH were conducted. A allele carrier COPD patients had lower serum and sputum CCSP levels, especially among active smokers, and a decreased body mass index, airflow obstruction, dyspnea, and exercise capacity (BODE) score. In vitro, baseline CCSP transcription levels were similar between the wild and variant constructs. CSE decreased more profoundly the CCSP transcription level of 38A transfected cells. The opposite effect was observed with p53 cotransfection. LPS stimulation induced CCSP repression in 38A promoter transfected cells. Cotransfection with Nkx2.1 significantly activated the CCSP promoters irrespective of the polymorphism. Circulating CCSP levels are associated with smoking and the CCSP G38A polymorphism. CSE, LPS, and the Nkx2.1 and p53 transcription factors modulated the CCSP promoter efficiency. The 38A polymorphism exaggerated the CCSP repression in response to p53 and CSE.
authors: PhyMedExp, University of Montpellier, INSERM U1046, CNRS UMR 9214, Montpellier, France; Department of Respiratory Diseases, Montpellier University Hospital, Montpellier, France.
authors: Lucie
authors: L
authors: Knabe
authors: EA7402, Montpellier University, Montpellier, France.
authors: Jessica
authors: J
authors: Varilh
authors: Molecular Genetics Laboratory-IURC, Montpellier University Hospital, Montpellier, France; and.
authors: Anne
authors: A
authors: Bergougnoux
authors: Department of Respiratory Diseases, Montpellier University Hospital, Montpellier, France.
authors: Anne-Sophie
authors: AS
authors: Gamez
authors: EA7402, Montpellier University, Montpellier, France.
authors: Jennifer
authors: J
authors: Bonini
authors: EA7402, Montpellier University, Montpellier, France.
authors: Alexandra
authors: A
authors: Pommier
authors: Department of Respiratory Diseases, Montpellier University Hospital, Montpellier, France.
authors: Aurélie
authors: A
authors: Petit
authors: IMAG U5149, Department of Medical Information, Montpellier University Hospital Montpellier, France.
authors: Nicolas
authors: N
authors: Molinari
authors: Department of Respiratory Diseases, Montpellier University Hospital, Montpellier, France.
authors: Isabelle
authors: I
authors: Vachier
authors: EA7402, Montpellier University, Montpellier, France.
authors: Magali
authors: M
authors: Taulan-Cadars
authors: PhyMedExp, University of Montpellier, INSERM U1046, CNRS UMR 9214, Montpellier, France; Department of Respiratory Diseases, Montpellier University Hospital, Montpellier, France; a-bourdin@chu-montpellier.fr.
authors: Arnaud
authors: A
authors: Bourdin
mesh_terms: D000368:Aged; D001483:Base Sequence; D002460:Cell Line; D017124:Conserved Sequence; D005260:Female; D059647:Gene-Environment Interaction; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D011446:Prospective Studies; D029424:Pulmonary Disease, Chronic Obstructive / Q000097:blood / Q000235:genetics*; D012907:Smoking / Q000009:adverse effects / Q000235:genetics; D015533:Transcriptional Activation; D014598:Uteroglobin / Q000097:blood / Q000235:genetics*
chemical_list: D008070:Lipopolysaccharides; C556389:SCGB1A1 protein, human; D014598:Uteroglobin
keywords: CC10; CCSP; COPD; CSE; G38A polymorphism