Impact of a gap junction protein alpha 4 variant on clinical disease phenotype in F508del homozygous patients with cystic fibrosis

  • 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, number NCT04242420, retrospectively on January 24th, 2020.

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Author:Tabea Horn, Michael Ludwig, Olaf EickmeierORCiDGND, Anne H. Neerinex, Anke Hilse Maitland-van der Zee, Christina Smaczny, Thomas O. F. WagnerORCiDGND, Ralf SchubertORCiDGND, Stefan ZielenORCiDGND, Christof Majoor, Lieuwe D. Bos, Sabina Schmitt-Grohé
Parent Title (English):Frontiers in genetics
Publisher:Frontiers Media
Place of publication:Lausanne
Document Type:Article
Date of Publication (online):2020/10/28
Date of first Publication:2020/10/28
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2020/10/28
Tag:F508del homozygous; cystic fibrosis; gap junction protein alpha 4-genotype; inflammatory markers; lung disease phenotype; lung function; phenotype/genotype relation; precision medicine
Issue:art. 570403
Page Number:8
First Page:1
Last Page:8
This work was funded by the heritage of Juliana Gerner, Germany, and the Netherlands Lung Foundation (Longfonds, grant # The open access publication fee will be paid by the Department of Pediatric Pulmonology of the University Hospital Frankfurt.
Institutes:Medizin / Medizin
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Licence (German):License LogoCreative Commons - Namensnennung 4.0