Connexin Genotypes in Cystic Fibrosis

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

Interventions

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

Sponsors & Collaborators

• Goethe University

  collaborator OTHER

• Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

  collaborator OTHER

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

  lead OTHER

Principal Investigators

• Sabina Schmitt-Grohe, MD · University Hospital, Bonn

Study Design

Allocation

NA

Purpose

DIAGNOSTIC

Masking

NONE

Model

SINGLE_GROUP

Eligibility

Min Age

6 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2002-04-30

Primary Completion

2023-12-31

Completion

2024-12-31

Countries

• Germany
• Netherlands

Study Locations