Connexin Genotypes in Cystic Fibrosis

Cystic Fibrosis Clinical Trial

Official title:

Impact of Connexin 37, Connexin 43 on Clinical Disease Phenotype in Delta F508 Homozygous Patients With Cystic Fibrosis (CF) (CF-Modifier)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04242420
• Other study ID #: BN 178/01
• Status: Recruiting
• Phase: N/A
• Start date: April 2002
• Est. completion date: December 31, 2024

Study information

• Verified date: August 2021
• Source: University Childrens' Hospital (Zentrum für Kinderheilkunde des Universitätsklinikum Bonn)
• Contact: Sabina Schmitt-Grohe, MD
• Phone: 004915254568942
• Email: s.schmitt-grohe[@]ukbonn.de
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

Description:

Progressive pulmonary destruction is the major cause of morbidity and mortality in human subjects with cystic fibrosis. Many studies could not find an association between delta F 508 and severity of pulmonary disease . The most important factor in CF lung disease is an inflammation driven by leukocytes and cytokines. The investigators have provided evidence in former studies that cytokines (Interleukin-8 (IL-8), tumour necrosis factor (TNF) alpha, Lipopolysaccahride binding protein (LBP), transforming growth factor (TGF) ß)measured in blood correlate negatively with lung function in delta 508 homozygous patients.

The question arises, what other factors influence recruitment of proinflammatory leukocytes from blood capillaries into the lung .

Connexins are a family of transmembrane proteins, which oligomerize into hexameric structures to form a hemichannel (connexon) and ultimately pair with a partner hemichannel in an adjacent cell to form gap junction intercellular communication channels (GJIC) . There is evidence of expression of connexin 37 (=gap junction protein A4 (GJA4)) on macrophages in humans. Moreover there is evidence of expression of connexin 37 on vascular endothelia in humans . Connexin 37 is expressed on human neutrophils . Pulmonary disease in CF is dominated by a leukocyte driven inflammation. GAP junction proteins might be of importance for the influx of blood cells into the lung. In this regard, the hypothesis was that Cx37 or Cx43 genotypes have an impact on clinical disease phenotype in CF patients homozygous for delta F508. The first analysis (Horn et al 2020) has shown a clinical phenotype linked to the GJA4 genotype is very similar to MBL variants. In this regard the question arises whether there is a link between the MBL variant alleles and the GJA4 variants. Moreover some TGFbeta genotypes are linked to certain pulmonary phenotypes. So we are looking for interactions between Cx37 and TGFbeta genotypes and their impact on the clinical phenotype as well.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 300
• Est. completion date: December 31, 2024
• Est. primary completion date: December 31, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 6 Years and older

Eligibility

Inclusion Criteria:

Homozygosity for delta F 508

Exclusion Criteria:

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).

Related Conditions & MeSH terms

• Cystic Fibrosis
• Fibrosis
• Inflammation

Intervention

Diagnostic Test:
• Genotyping
Genotyping for single nucleotide polymorphisms for Connexin 37&43, Mannose binding lectin (MBL) and transforming growth factor beta (TGF beta) genotypes
• Lung function
Spirometry,
• Microbiology
Bacterial culture from Sputum or swab
• Blood sample
Interleukin-8 assay (via chemiluminescence) blood cell count
• Induced Sputum
Interleukin-8 assay (via chemiluminescence) blood cell count

Locations

Country	Name	City	State
Germany	University Hospital	Bonn	Nordrhine-Westphalia
Germany	University Hospital	Frankfurt	Hessia
Netherlands	University Hospital	Amsterdam

Sponsors (3)

Lead Sponsor	Collaborator
University Childrens' Hospital (Zentrum für Kinderheilkunde des Universitätsklinikum Bonn)	Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA), University Hospital, Frankfurt

Countries where clinical trial is conducted

Germany,  Netherlands, 

References & Publications (13)

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. Epub 2004 Oct 30. Review. — View Citation

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. — View Citation

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. Review. — View Citation

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. — View Citation

Eickmeier O, Boom Lv, Schreiner F, Lentze MJ, NGampolo D, Schubert R, Zielen S, Schmitt-Grohé S. Transforming growth factor ß1 genotypes in relation to TGFß1, interleukin-8, and tumor necrosis factor alpha in induced sputum and blood in cystic fibrosis. M — View Citation

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-Grohé S. Impact of a Gap Junction Protein Alpha 4 Variant on Clinical Disease Phenotype in F508del Homozygous Patie — View Citation

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. — View Citation

McKone EF, Goss CH, Aitken ML. CFTR genotype as a predictor of prognosis in cystic fibrosis. Chest. 2006 Nov;130(5):1441-7. — View Citation

Sáez PJ, Shoji KF, Aguirre A, Sáez 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. Review. — View Citation

Schmitt-Grohé 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 — View Citation

Schmitt-Grohé 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. — View Citation

Schmitt-Grohé S, Stüber 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. — View Citation

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. — View Citation

* Note: There are 13 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Colonisation with Pseudomonas aeruginosa	Never, Intermittent or chronic according to Leeds criteria	3 years
Other	CF related diabetes mellitus	Assessment via patient charts/ registry	through study completion, an average of 3 year
Primary	Survival to end stage lung disease	End stage lung disease: Death or lung transplantation	through study completion, on average 27 years
Primary	Lung function parameter: FEV1	Best FEV1 value in % predicted of the year according to German registry according to Global lung initiative (GLI)	3 years
Primary	Lung function parameters: FVC	Best FVC value in % predicted of the year according to German registry according to Global lung initiative (GLI)	3 years
Primary	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	Interleukin-8 in blood	single spot value (cross-sectional)	through study completion, an average of 3 year
Secondary	Interleukin-8 in sputum	single spot value (cross-sectional)	through study completion, an average of 3 year
Secondary	White blood cell count	Leukocytes (single spot value (cross-sectional))	through study completion, an average of 3 year
Secondary	Inflammatory markers in sputum	Leukocyte count in sputum (single spot value (cross-sectional))	through study completion, an average of 3 year