Connexin Genotypes in Cystic Fibrosis

August 8, 2021 updated by: Sabina Schmitt-Grohe, University Childrens' Hospital (Zentrum für Kinderheilkunde des Universitätsklinikum Bonn)

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

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).

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed 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.

Study Type

Interventional

Enrollment (Anticipated)

300

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

6 years and older (Child, Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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).

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Diagnostic
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Survival to end stage lung disease
Time Frame: through study completion, on average 27 years
End stage lung disease: Death or lung transplantation
through study completion, on average 27 years
Lung function parameter: FEV1
Time Frame: 3 years
Best FEV1 value in % predicted of the year according to German registry according to Global lung initiative (GLI)
3 years
Lung function parameters: FVC
Time Frame: 3 years
Best FVC value in % predicted of the year according to German registry according to Global lung initiative (GLI)
3 years
Lung function parameters: FEF75
Time Frame: 3 years
Best FEF75 value in % predicted of the year according to German registry according to Global lung initiative (GLI)
3 years

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Interleukin-8 in blood
Time Frame: through study completion, an average of 3 year
single spot value (cross-sectional)
through study completion, an average of 3 year
Interleukin-8 in sputum
Time Frame: through study completion, an average of 3 year
single spot value (cross-sectional)
through study completion, an average of 3 year
White blood cell count
Time Frame: through study completion, an average of 3 year
Leukocytes (single spot value (cross-sectional))
through study completion, an average of 3 year
Inflammatory markers in sputum
Time Frame: through study completion, an average of 3 year
Leukocyte count in sputum (single spot value (cross-sectional))
through study completion, an average of 3 year

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Colonisation with Pseudomonas aeruginosa
Time Frame: 3 years
Never, Intermittent or chronic according to Leeds criteria
3 years
CF related diabetes mellitus
Time Frame: through study completion, an average of 3 year
Assessment via patient charts/ registry
through study completion, an average of 3 year

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University Childrens' Hospital (Zentrum für Kinderheilkunde des Universitätsklinikum Bonn)

Collaborators

Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
University Hospital Frankfurt

Investigators

  • Principal Investigator: Sabina Schmitt-Grohe, MD, University Hospital, Bonn

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

April 1, 2002

Primary Completion (Anticipated)

December 31, 2023

Study Completion (Anticipated)

December 31, 2024

Study Registration Dates

First Submitted

December 20, 2019

First Submitted That Met QC Criteria

January 24, 2020

First Posted (Actual)

January 27, 2020

Study Record Updates

Last Update Posted (Actual)

August 16, 2021

Last Update Submitted That Met QC Criteria

August 8, 2021

Last Verified

August 1, 2021

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • BN 178/01

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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