Background: High TGFβ1-producing variants cause severe clinical
disease in F508del homozygous patients. Lately, we showed that a single
nucleotide polymorphism (SNP), rs41266431, in the GJA4 gene modifies the disease
severity of cystic fibrosis (CF). Our aim was to investigate whether the clinical
phenotype associated with GJA4 variants was independent of TGFβ1
variants. Methods: Homozygous F508del patients (n = 115, mean age 27.2
years, m/f (65/50)) were included in this study. A deep sequence analysis was
performed for GJA4 and TGBβ1, and disease severity was assessed over 3
years using lung function tests (LFTs), body mass index, diabetes mellitus,
colonization with Pseudomonas aeruginosa, survival to end-stage lung
disease (ESLD), as well as distinct inflammatory biomarkers. Results:
The analyses revealed that one SNP (rs41266431) in GJA4 may be clinically
relevant. Carriers homozygous for the G variant (n = 84; 73%) presented with
worse LFTs (forced vital capacity (FVC) % predicted: mean 80/86.6, p
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Open Access
Original Research
Transforming Growth Factor ß1 and Gap Junction Protein Alpha 4 Gene Heterogeneity in Relation to the Severity of Clinical Disease in Cystic Fibrosis
Joern Pascal Laubach1, Michael Ludwig2, Tabea Horn1, Olaf Eickmeier3, Christina Smaczny4, Ralf Schubert3, Stefan Zielen3, Christof Majoor5, Malik Aydin6,7, Alexander Schnell8, Sabina Schmitt-Grohé1,3,*
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1
Department of General Pediatrics, University Children’s Hospital, 53127 Bonn, Germany
2
Department of Genetics, Institut für Klinische Chemie und Klinische Pharmakologie des Universitätsklinikums, 53127 Bonn, Germany
3
Department for Children and Adolescents, Division of Allergology, Pulmonology, and Cystic Fibrosis, Goethe-University, 60590 Frankfurt, Germany
4
Christiane-Herzog CF-Ambulanz, Department of Internal Medicine, Goethe-University, 60590 Frankfurt, Germany
5
Department of Respiratory Medicine, Amsterdam University Medical Centers (UMC), University of Amsterdam, 1100 AZ Amsterdam, The Netherlands
6
Center for Child and Adolescent Medicine, Children’s Hospital, Center for Clinical and Translational Research (CCTR), Helios University Hospital Wuppertal, Witten/Herdecke University, 42283 Wuppertal, Germany
7
Laboratory of Experimental Pediatric Pneumology and Allergology, Center for Biomedical Education and Research, School of Life Sciences (ZBAF), Faculty of Health, Witten/Herdecke University, 58455 Witten, Germany
8
Department of Pediatrics and Adolescent Medicine, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, 91054 Erlangen, Germany
*Correspondence: sabina.schmitt-grohe@kgu.de (Sabina Schmitt-Grohé)
Front. Biosci. (Landmark Ed) 2023, 28(7), 138;
https://doi.org/10.31083/j.fbl2807138
Submitted: 18 October 2022 | Revised: 20 February 2023 | Accepted: 17 May 2023 | Published: 19 July 2023
Copyright: © 2023 The Author(s). Published by IMR Press.
This is an open access article under the CC BY 4.0 license.
Abstract
Keywords
cystic fibrosis
transforming growth factor beta1
gap junction protein alpha 4
bronchial inflammation
F508del homozygous
gene–gene interaction
geno-/phenotype relation
precision medicine
Funding
heritage of Juliana Gerner
Figures
Fig. 1.