Connexin Genotypes in Cystic Fibrosis

NCT04242420 | Unknown

• 1 other identifier: BN 178/01
• Study Type: interventional
• Target: 300
• Locations: 2 countries
• Sites: 3

Brief Summary

Background: There is wide variety in lung disease phenotype for the delta F508 (homozygous) genotype. A leukocyte driven inflammation is most important for the pathogenesis of pulmonary disease in CF. Blood cytokines correlate negatively with pulmonary function in delta F508 homozygous patients. Gap junction proteins might be of importance for the influx of blood cells into the lung and may influence the course of pulmonary inflammation. A primary analysis (Horn et al. 2020) has shown that GJA4 variants (rs41266431) are linked to more severe disease in CF. This is very similar to variants of MBL. Aims: To assess the relationship between gap junction proteins alpha 1 (GJA1/Connexin 43) and alpha 4 (GJA4/connexin 37) genotypes and clinical disease phenotype. Moreover are GJA4 variants in terms of clinical phenotype independent of MBL variants. Methods:Patients homozygous for delta F508 get recruited from the CF centres of Bonn, Frankfurt and Amsterdam. Sequence analysis is performed for connexin 43 and 37 and MBL genotypes. Clinical disease is assessed longitudinally over 3 years by pulmonary function tests (FEV1 (forced expiratory volume in one second), FVC (=(forced vital capacity), FEF75 % (Forced expiratory flow at 75% of the pulmonary volume) pred), BMI (percentiles), P. aeruginosa colonization, diabetes mellitus and survival to end-stage CF lung disease (death or lung transplantation).

Conditions

Cystic Fibrosis; Inflammation

Keywords

connexin 37+43, MBL, TGF beta; Lung function; Interleukin 8

Outcome Measures

Primary Outcomes (4)

• Survival to end stage lung disease

  End stage lung disease: Death or lung transplantation

  through study completion, on average 27 years

• Lung function parameter: FEV1

  Best FEV1 value in % predicted of the year according to German registry according to Global lung initiative (GLI)

  3 years

• Lung function parameters: FVC

  Best FVC value in % predicted of the year according to German registry according to Global lung initiative (GLI)

  3 years

• Lung function parameters: FEF75

  Best FEF75 value in % predicted of the year according to German registry according to Global lung initiative (GLI)

  3 years

Secondary Outcomes (4)

• Interleukin-8 in blood

  through study completion, an average of 3 year

• Interleukin-8 in sputum

  through study completion, an average of 3 year

• White blood cell count

  through study completion, an average of 3 year

• Inflammatory markers in sputum

  through study completion, an average of 3 year

Other Outcomes (2)

• Colonisation with Pseudomonas aeruginosa

  3 years

• CF related diabetes mellitus

  through study completion, an average of 3 year

Study Arms (1)

Connexin genotype

OTHER

Genotyping

Diagnostic Test: Genotyping; Diagnostic Test: Lung function; Diagnostic Test: Microbiology; Diagnostic Test: Blood sample; Diagnostic Test: Induced Sputum

Interventions

Genotyping DIAGNOSTIC_TEST

Genotyping for single nucleotide polymorphisms for Connexin 37\&43, Mannose binding lectin (MBL) and transforming growth factor beta (TGF beta) genotypes

Connexin genotype

Lung function DIAGNOSTIC_TEST

Spirometry,

Connexin genotype

Microbiology DIAGNOSTIC_TEST

Bacterial culture from Sputum or swab

Connexin genotype

Blood sample DIAGNOSTIC_TEST

Interleukin-8 assay (via chemiluminescence) blood cell count

Connexin genotype

Induced Sputum DIAGNOSTIC_TEST

Interleukin-8 assay (via chemiluminescence) blood cell count

Connexin genotype

Eligibility Criteria

• Age: 6 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Homozygosity for delta F 508

You may not qualify if:

• treatment with systemic steroids 14 days preceding this trial, participation in another study within the past 30 days, treatment with Orkambi or status after lung transplantation (for assessment of all parameters except survival).

Sponsors & Collaborators

• University Childrens' Hospital (Zentrum für Kinderheilkunde des Universitätsklinikum Bonn): lead
• Goethe University: collaborator
• Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA): collaborator

Study Sites (3)

University Hospital

Frankfurt, Hessia, 60590, Germany

RECRUITING

University Hospital

Bonn, Nordrhine-Westphalia, 53113, Germany

RECRUITING

University Hospital

Amsterdam, Netherlands

RECRUITING

Related Publications (14)

• Drumm ML, Konstan MW, Schluchter MD, Handler A, Pace R, Zou F, Zariwala M, Fargo D, Xu A, Dunn JM, Darrah RJ, Dorfman R, Sandford AJ, Corey M, Zielenski J, Durie P, Goddard K, Yankaskas JR, Wright FA, Knowles MR; Gene Modifier Study Group. Genetic modifiers of lung disease in cystic fibrosis. N Engl J Med. 2005 Oct 6;353(14):1443-53. doi: 10.1056/NEJMoa051469.

  PMID: 16207846 BACKGROUND

• Cystic Fibrosis Genotype-Phenotype Consortium. Correlation between genotype and phenotype in patients with cystic fibrosis. N Engl J Med. 1993 Oct 28;329(18):1308-13. doi: 10.1056/NEJM199310283291804.

  PMID: 8166795 RESULT

• McKone EF, Goss CH, Aitken ML. CFTR genotype as a predictor of prognosis in cystic fibrosis. Chest. 2006 Nov;130(5):1441-7. doi: 10.1378/chest.130.5.1441.

  PMID: 17099022 RESULT

• Schmitt-Grohe S, Naujoks C, Bargon J, Wagner TO, Schubert R, Hippe V, Zielen S. Interleukin-8 in whole blood and clinical status in cystic fibrosis. Cytokine. 2005 Jan 7;29(1):18-23. doi: 10.1016/j.cyto.2004.09.004.

  PMID: 15579374 RESULT

• Schmitt-Grohe S, Hippe V, Igel M, von Bergmann K, Posselt HG, Krahl A, Smaczny C, Wagner TO, Nikolazik W, Schubert R, Lentze MJ, Zielen S. Lipopolysaccharide binding protein, cytokine production in whole blood, and lipoproteins in cystic fibrosis. Pediatr Res. 2005 Nov;58(5):903-7. doi: 10.1203/01.PDR.0000182598.98167.24. Epub 2005 Sep 23.

  PMID: 16183806 RESULT

• Schmitt-Grohe S, Stuber F, Book M, Bargon J, Wagner TO, Naujoks C, Schubert R, Lentze MJ, Zielen S. TNF-alpha promoter polymorphism in relation to TNF-alpha production and clinical status in cystic fibrosis. Lung. 2006 Mar-Apr;184(2):99-104. doi: 10.1007/s00408-005-2568-x.

  PMID: 16622779 RESULT

• Eickmeier O, Boom Lv, Schreiner F, Lentze MJ, NGampolo D, Schubert R, Zielen S, Schmitt-Grohe S. Transforming growth factor beta1 genotypes in relation to TGFbeta1, interleukin-8, and tumor necrosis factor alpha in induced sputum and blood in cystic fibrosis. Mediators Inflamm. 2013;2013:913135. doi: 10.1155/2013/913135. Epub 2013 Aug 26.

  PMID: 24062613 RESULT

• Dempsie Y, Martin P, Upton PD. Connexin-mediated regulation of the pulmonary vasculature. Biochem Soc Trans. 2015 Jun;43(3):524-9. doi: 10.1042/BST20150030.

  PMID: 26009202 RESULT

• Chanson M, Derouette JP, Roth I, Foglia B, Scerri I, Dudez T, Kwak BR. Gap junctional communication in tissue inflammation and repair. Biochim Biophys Acta. 2005 Jun 10;1711(2):197-207. doi: 10.1016/j.bbamem.2004.10.005. Epub 2004 Oct 30.

  PMID: 15955304 RESULT

• Kwak BR, Mulhaupt F, Veillard N, Gros DB, Mach F. Altered pattern of vascular connexin expression in atherosclerotic plaques. Arterioscler Thromb Vasc Biol. 2002 Feb 1;22(2):225-30. doi: 10.1161/hq0102.104125.

  PMID: 11834520 RESULT

• Zahler S, Hoffmann A, Gloe T, Pohl U. Gap-junctional coupling between neutrophils and endothelial cells: a novel modulator of transendothelial migration. J Leukoc Biol. 2003 Jan;73(1):118-26. doi: 10.1189/jlb.0402184.

  PMID: 12525569 RESULT

• Saez PJ, Shoji KF, Aguirre A, Saez JC. Regulation of hemichannels and gap junction channels by cytokines in antigen-presenting cells. Mediators Inflamm. 2014;2014:742734. doi: 10.1155/2014/742734. Epub 2014 Sep 9.

  PMID: 25301274 RESULT

• Horn T, Ludwig M, Eickmeier O, Neerinex AH, Maitland-van der Zee AH, Smaczny C, Wagner TOF, Schubert R, Zielen S, Majoor C, Bos LD, Schmitt-Grohe S. Impact of a Gap Junction Protein Alpha 4 Variant on Clinical Disease Phenotype in F508del Homozygous Patients With Cystic Fibrosis. Front Genet. 2020 Oct 28;11:570403. doi: 10.3389/fgene.2020.570403. eCollection 2020.

  PMID: 33193670 RESULT

• Laubach JP, Ludwig M, Horn T, Eickmeier O, Smaczny C, Schubert R, Zielen S, Majoor C, Aydin M, Schnell A, Schmitt-Grohe S. Transforming Growth Factor ss1 and Gap Junction Protein Alpha 4 Gene Heterogeneity in Relation to the Severity of Clinical Disease in Cystic Fibrosis. Front Biosci (Landmark Ed). 2023 Jul 19;28(7):138. doi: 10.31083/j.fbl2807138.

  PMID: 37525914 DERIVED

MeSH Terms

Conditions

Cystic Fibrosis; Inflammation; Camurati-Engelmann Syndrome

Interventions

Genotype; Respiration; Attachment Sites, Microbiological; Blood Specimen Collection

Condition Hierarchy (Ancestors)

Pancreatic Diseases; Digestive System Diseases; Lung Diseases; Respiratory Tract Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Infant, Newborn, Diseases; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Osteochondrodysplasias; Bone Diseases, Developmental; Bone Diseases; Musculoskeletal Diseases

Intervention Hierarchy (Ancestors)

Genetic Phenomena; Respiratory Physiological Phenomena; Circulatory and Respiratory Physiological Phenomena; Genome Components; Genome; Genetic Structures; Specimen Handling; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Punctures; Surgical Procedures, Operative; Investigative Techniques

Study Officials

• Sabina Schmitt-Grohe, MD

  University Hospital, Bonn

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Sabina Schmitt-Grohe, MD

CONTACT

004915254568942; s.schmitt-grohe@ukbonn.de

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NA
• Masking: NONE
• Purpose: DIAGNOSTIC
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal investigator

Model Details: Evaluation of clinical parameters by genotype

Study Record Dates

• First Submitted: December 20, 2019
• First Posted: January 27, 2020
• Study Start: April 1, 2002
• Primary Completion: December 31, 2023
• Study Completion: December 31, 2024
• Last Updated: August 16, 2021

Record last verified: 2021-08

Data Sharing

• IPD Sharing: Will not share

Locations

DE (2); NL (1)