{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T15:40:01Z","timestamp":1753890001774,"version":"3.41.2"},"reference-count":31,"publisher":"IMR Press","issue":"7","license":[{"start":{"date-parts":[[2023,7,19]],"date-time":"2023-07-19T00:00:00Z","timestamp":1689724800000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"heritage of Juliana Gerner"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Front. Biosci. (Landmark Ed)"],"abstract":"<jats:p>Background: High TGF\u03b21-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 TGF\u03b21 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 TGB\u03b21, 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 &lt; 0.035) and a lower survival to ESLD (p &lt; 0.029). For the TGB\u03b21 variant: 509 carriers of the C variant (CT + CC genotype, n = 105, 91.3%) had better LFTs (Forced expiratory flow at 75% of the FVC (FEF75% predicted: median 40\/29.5, p &lt; 0.015), although a similar outcome to ESLD. A gene\u2013gene interaction was not observed between TGB\u03b21 and GJA4 variants for any clinical measure. Conclusions: GJA4 variants are independent of TGB\u03b21 variants. Both variants had an impact on the LFTs, although only GJA4 variants were associated with an improved outcome for ESLD. Clinical Trial Registration: The study was registered with ClinicalTrials.gov, number NCT04242420, retrospectively on January 24th, 2020.<\/jats:p>","DOI":"10.31083\/j.fbl2807138","type":"journal-article","created":{"date-parts":[[2023,7,21]],"date-time":"2023-07-21T08:24:20Z","timestamp":1689927860000},"source":"Crossref","is-referenced-by-count":1,"title":["Transforming Growth Factor \u00df1 and Gap Junction Protein Alpha 4 Gene Heterogeneity in Relation to the Severity of Clinical Disease in Cystic Fibrosis"],"prefix":"10.31083","volume":"28","author":[{"given":"Joern Pascal","family":"Laubach","sequence":"first","affiliation":[{"name":"Department of General Pediatrics, University Children\u2019s Hospital, 53127 Bonn, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Ludwig","sequence":"first","affiliation":[{"name":"Department of Genetics, Institut f\u00fcr Klinische Chemie und Klinische Pharmakologie des Universit\u00e4tsklinikums, 53127 Bonn, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tabea","family":"Horn","sequence":"first","affiliation":[{"name":"Department of General Pediatrics, University Children\u2019s Hospital, 53127 Bonn, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Olaf","family":"Eickmeier","sequence":"first","affiliation":[{"name":"Department for Children and Adolescents, Division of Allergology, Pulmonology, and Cystic Fibrosis, Goethe-University, 60590 Frankfurt, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christina","family":"Smaczny","sequence":"first","affiliation":[{"name":"Christiane-Herzog CF-Ambulanz, Department of Internal Medicine, Goethe-University, 60590 Frankfurt, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ralf","family":"Schubert","sequence":"first","affiliation":[{"name":"Department for Children and Adolescents, Division of Allergology, Pulmonology, and Cystic Fibrosis, Goethe-University, 60590 Frankfurt, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stefan","family":"Zielen","sequence":"first","affiliation":[{"name":"Department for Children and Adolescents, Division of Allergology, Pulmonology, and Cystic Fibrosis, Goethe-University, 60590 Frankfurt, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christof","family":"Majoor","sequence":"first","affiliation":[{"name":"Department of Respiratory Medicine, Amsterdam University Medical Centers (UMC), University of Amsterdam, 1100 AZ Amsterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Malik","family":"Aydin","sequence":"first","affiliation":[{"name":"Center for Child and Adolescent Medicine, Children\u2019s Hospital, Center for Clinical and Translational Research (CCTR), Helios University Hospital Wuppertal, Witten\/Herdecke University, 42283 Wuppertal, Germany"},{"name":"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"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexander","family":"Schnell","sequence":"first","affiliation":[{"name":"Department of Pediatrics and Adolescent Medicine, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, 91054 Erlangen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sabina","family":"Schmitt-Groh\u00e9","sequence":"first","affiliation":[{"name":"Department of General Pediatrics, University Children\u2019s Hospital, 53127 Bonn, Germany"},{"name":"Department for Children and Adolescents, Division of Allergology, Pulmonology, and Cystic Fibrosis, Goethe-University, 60590 Frankfurt, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"16242","published-online":{"date-parts":[[2023,7,19]]},"reference":[{"key":"ref1","doi-asserted-by":"crossref","unstructured":"Elborn JS. 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