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 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, < 0.035) and a lower survival to ESLD ( < 0.029). For the TGBβ1 variant: 509 carriers of the C variant ( genotype, n = 105, 91.3%) had better LFTs (Forced expiratory flow at 75% of the FVC (FEF75% predicted: median 40/29.5, < 0.015), although a similar outcome to ESLD. A gene-gene interaction was not observed between TGBβ1 and GJA4 variants for any clinical measure.
Conclusions: GJA4 variants are independent of TGBβ1 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.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.31083/j.fbl2807138 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
GNA14 and GNAQ somatic mutations cause spinal and intracranial extra-axial cavernous hemangiomas.
Am J Hum Genet
July 2024
Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, China International Neuroscience Institute, National Center for Neurological Disorders, Beijing, China; Department of Neurosurgery, Xiongan Xuanwu Hospital, Xiong'an New Area, China. Electronic address:
Article Synopsis
- Extra-axial cavernous hemangiomas (ECHs) are vascular lesions primarily found in the spine and cavernous sinus, posing risks during removal due to their complex nature and unclear genetic basis.
- Genetic analyses of 31 ECH tissue samples revealed that 77.4% had mutations in specific genes (GNA14, GNAQ, GJA4), which were linked to significant changes in various cellular pathways, particularly those involved in angiogenesis.
- Treatment with rapamycin in a 14-year-old patient with a specific GNAQ mutation showed promising results, with reduced hemangiomas and improved strength, indicating potential for targeted therapy in ECH treatment.
Transforming Growth Factor ß1 and Gap Junction Protein Alpha 4 Gene Heterogeneity in Relation to the Severity of Clinical Disease in Cystic Fibrosis.
Front Biosci (Landmark Ed)
July 2023
Department of General Pediatrics, University Children's Hospital, 53127 Bonn, Germany.
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.
View Article and Find Full Text PDFA clinicopathological reappraisal of orbital vascular malformations and distinctive GJA4 mutation in cavernous venous malformations.
Hum Pathol
December 2022
Department of Anatomic Pathology, Linkou Chang Gung Memorial Hospital, Chang Gung University, College of Medicine, Taoyuan, 333 Taiwan; Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, 333 Taiwan. Electronic address:
Vascular anomalies are common orbital lesions, while variations in previous nomenclature might hamper robust characterization of their clinicopathological and genetic features. We reviewed and reclassified 92 orbital vascular lesions by the modified International Society for the Study of Vascular Anomalies (ISSVA) classification with reappraising clinicopathological parameters of 4 main types of vascular malformations, including orbital venous malformation 1 (OVM1, cavernous venous malformation), OVM2 (varix), OVM3 (infiltrating venous malformation), and arteriovenous malformation (AVM). GJA4, BRAF, and KRAS mutations were assessed by Sanger sequencing.
View Article and Find Full Text PDFMannose-Binding Lectin (MBL) and Gap Junction Protein Alpha 4 (GJA4) Gene Heterogeneity in Relation to Severity of Clinical Disease in Cystic Fibrosis.
Front Biosci (Landmark Ed)
May 2022
University Children's Hospital Bonn, 53127 Bonn, Germany.
Background: Recently, we provided evidence that a single nucleotide polymorphism (SNP), rs41266431, on the gap junction protein alpha 4 (GJA4) gene, acts as a modifier for clinical disease severity in patients with cystic fibrosis (CF). These features are very similar to those of variants of the mannose-binding lectin (MBL). This study aimed to clarify whether the clinical disease phenotype associated with GJA4 variants is independent of MBL variants.
View Article and Find Full Text PDFImpact of a Variant on Clinical Disease Phenotype in Homozygous Patients With Cystic Fibrosis.
Front Genet
October 2020
Abt. Allgemeine Pädiatrie, Zentrum für Kinderheilkunde des Universitätsklinikums Bonn, Bonn, Germany.
Background: Lung disease phenotype varies widely even in the (homozygous) genotype. Leukocyte-driven inflammation is important for pulmonary disease pathogenesis in cystic fibrosis (CF). Blood cytokines correlate negatively with pulmonary function homozygous patients, and gap junction proteins (GJA) might be related to the influx of blood cells into the lung and influence disease course.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!