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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 junc...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7655539/ https://www.ncbi.nlm.nih.gov/pubmed/33193670 http://dx.doi.org/10.3389/fgene.2020.570403 |
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author | Horn, Tabea Ludwig, Michael Eickmeier, Olaf Neerinex, Anne H. Maitland-van der Zee, Anke H. Smaczny, Christina Wagner, Thomas O. F. Schubert, Ralf Zielen, Stefan Majoor, Christof Bos, Lieuwe D. Schmitt-Grohé, Sabina |
author_facet | Horn, Tabea Ludwig, Michael Eickmeier, Olaf Neerinex, Anne H. Maitland-van der Zee, Anke H. Smaczny, Christina Wagner, Thomas O. F. Schubert, Ralf Zielen, Stefan Majoor, Christof Bos, Lieuwe D. Schmitt-Grohé, Sabina |
author_sort | Horn, Tabea |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-7655539 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-76555392020-11-13 Impact of a Gap Junction Protein Alpha 4 Variant on Clinical Disease Phenotype in F508del Homozygous Patients With Cystic Fibrosis Horn, Tabea Ludwig, Michael Eickmeier, Olaf Neerinex, Anne H. Maitland-van der Zee, Anke H. Smaczny, Christina Wagner, Thomas O. F. Schubert, Ralf Zielen, Stefan Majoor, Christof Bos, Lieuwe D. Schmitt-Grohé, Sabina Front Genet Genetics 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. Frontiers Media S.A. 2020-10-28 /pmc/articles/PMC7655539/ /pubmed/33193670 http://dx.doi.org/10.3389/fgene.2020.570403 Text en Copyright © 2020 Horn, Ludwig, Eickmeier, Neerinex, Maitland-van der Zee, Smaczny, Wagner, Schubert, Zielen, Majoor, Bos and Schmitt-Grohé. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Genetics Horn, Tabea Ludwig, Michael Eickmeier, Olaf Neerinex, Anne H. Maitland-van der Zee, Anke H. Smaczny, Christina Wagner, Thomas O. F. Schubert, Ralf Zielen, Stefan Majoor, Christof Bos, Lieuwe D. Schmitt-Grohé, Sabina Impact of a Gap Junction Protein Alpha 4 Variant on Clinical Disease Phenotype in F508del Homozygous Patients With Cystic Fibrosis |
title | Impact of a Gap Junction Protein Alpha 4 Variant on Clinical Disease Phenotype in F508del Homozygous Patients With Cystic Fibrosis |
title_full | Impact of a Gap Junction Protein Alpha 4 Variant on Clinical Disease Phenotype in F508del Homozygous Patients With Cystic Fibrosis |
title_fullStr | Impact of a Gap Junction Protein Alpha 4 Variant on Clinical Disease Phenotype in F508del Homozygous Patients With Cystic Fibrosis |
title_full_unstemmed | Impact of a Gap Junction Protein Alpha 4 Variant on Clinical Disease Phenotype in F508del Homozygous Patients With Cystic Fibrosis |
title_short | Impact of a Gap Junction Protein Alpha 4 Variant on Clinical Disease Phenotype in F508del Homozygous Patients With Cystic Fibrosis |
title_sort | impact of a gap junction protein alpha 4 variant on clinical disease phenotype in f508del homozygous patients with cystic fibrosis |
topic | Genetics |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7655539/ https://www.ncbi.nlm.nih.gov/pubmed/33193670 http://dx.doi.org/10.3389/fgene.2020.570403 |
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