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. 2020 Oct 28:11:570403.
doi: 10.3389/fgene.2020.570403. eCollection 2020.

Impact of a Gap Junction Protein Alpha 4 Variant on Clinical Disease Phenotype in F508del Homozygous Patients With Cystic Fibrosis

Tabea Horn  1 , Michael Ludwig  2 , Olaf Eickmeier  3 , Anne H Neerinex  4 , Anke H Maitland-van der Zee  4   5 , Christina Smaczny  6 , Thomas O F Wagner  6 , Ralf Schubert  3 , Stefan Zielen  3 , Christof Majoor  4 , Lieuwe D Bos  4   7 , Sabina Schmitt-Grohé  1   3
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Impact of a Gap Junction Protein Alpha 4 Variant on Clinical Disease Phenotype in F508del Homozygous Patients With Cystic Fibrosis

Tabea Horn et al. Front Genet. .

Abstract

Background: Lung disease phenotype varies widely even in the F508del (homozygous) genotype. Leukocyte-driven inflammation is important for pulmonary disease pathogenesis in cystic fibrosis (CF). Blood cytokines correlate negatively with pulmonary function in F508del homozygous patients, and gap junction proteins (GJA) might be related to the influx of blood cells into the lung and influence disease course. We aimed to assess the relationship between GJA1/GJA4 genotypes and the clinical disease phenotype.

Methods: One-hundred-and-sixteen homozygous F508del patients (mean age 27 years, m/f 66/50) were recruited from the CF centers of Bonn, Frankfurt, and Amsterdam. Sequence analysis was performed for GJA1 and GJA4. The clinical disease course was assessed over 3 years using pulmonary function tests, body mass index, Pseudomonas aeruginosa colonization, diabetes mellitus, survival to end-stage lung disease, blood and sputum inflammatory markers.

Results: Sequence analysis revealed one clinically relevant single nucleotide polymorphism. In this GJA4 variant (rs41266431), homozygous G variant carriers (n = 84/116; 72.4%) had poorer pulmonary function (FVC% pred: mean 78/86, p < 0.040) and survival to end-stage lung disease was lower (p < 0.029). The frequency of P. aeruginosa colonization was not influenced by the genotype, but in those chronically colonized, those with the G/G genotype had reduced pulmonary function (FVC% pred: mean 67/80, p < 0.049). Serum interleukin-8 (median: 12.4/6.7 pg/ml, p < 0.052) and sputum leukocytes (2305/437.5 pg/ml, p < 0.025) were higher for the G/G genotype.

Conclusions: In carriers of the A allele (27.6%) the GJA4 variant is associated with significantly better protection against end-stage lung disease and superior pulmonary function test results in F508del homozygous patients. This SNP has the potential of a modifier gene for phenotyping severity of CF lung disease, in addition to the CFTR genotype.

Clinical trial registration: The study was registered with ClinicalTrials.gov, number NCT04242420, retrospectively on January 24th, 2020.

Keywords: F508del homozygous; cystic fibrosis; gap junction protein alpha 4-genotype; inflammatory markers; lung disease phenotype; lung function; phenotype/genotype relation; precision medicine.

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Figures

FIGURE 1
FIGURE 1
Kaplan-Meier plot of survival of CF patients. Events are defined as death (n = 13) and lung transplantation (n = 2) (end stage CF). Red line indicates carriers of A allele, and blue line indicates G/G homozygous patients.
See this image and copyright information in PMC

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References

    1. Cantin A. M., Hartl D., Konstan M. W., Chmiel J. F. (2015). Inflammation in cystic fibrosis lung disease: pathogenesis and therapy. J. Cyst. Fibros. 14 419–430. 10.1016/j.jcf.2015.03.003 - DOI - PubMed
    1. Carbone A., Zefferino R., Beccia E., Casavola V., Castellani S., Di Gioia S., et al. (2018). Gap junctions are involved in the rescue of CFTR-dependent chloride efflux by amniotic mesenchymal stem cells in coculture with cystic fibrosis CFBE41o- cells. Stem Cells Int. 2018:1203717. 10.1155/2018/1203717 - DOI - PMC - PubMed
    1. Cartegni L., Wang J., Zhu Z., Zhang M., Krainer A. R. (2003). ESEfinder: a web resource to identify exonic splicing enhancers. Nucleic Acid Res. 31 3568–3571. 10.1093/nar/gkg616 - DOI - PMC - PubMed
    1. Corvol H., Blackman S. M., Boëlle P. Y., Gallins P. J., Pace R. G., Stonebraker J. R., et al. (2015). Genome-wide association meta-analysis identifies five modifier loci of lung disease severity in cystic fibrosis. Nat. Commun. 6:8382. 10.1038/ncomms9382 - DOI - PMC - PubMed
    1. Cutting G. R. (2015). Cystic fibrosis genetics: from molecular understanding to clinical application. Nat. Rev. Genet. 16 45–56. 10.1155/2018/1203717 - DOI - PMC - PubMed

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