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

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.