TY  - JOUR
A1  - Horn, Tabea
A1  - Ludwig, Michael
A1  - Eickmeier, Olaf
A1  - Neerinex, Anne H.
A1  - Maitland-van der Zee, Anke Hilse
A1  - Smaczny, Christina
A1  - Wagner, Thomas O. F.
A1  - Schubert, Ralf
A1  - Zielen, Stefan
A1  - Majoor, Christof
A1  - Bos, Lieuwe D.
A1  - Schmitt-Grohé, Sabina
T1  - Impact of a gap junction protein alpha 4 variant on clinical disease phenotype in F508del homozygous patients with cystic fibrosis
T2  - Frontiers in genetics
N2  - 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.
KW  - cystic fibrosis
KW  - F508del homozygous
KW  - lung disease phenotype
KW  - lung function
KW  - inflammatory markers
KW  - phenotype/genotype relation
KW  - precision medicine
KW  - gap junction protein alpha 4-genotype
Y1  - 2020
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/56630
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-566306
SN  - 1664-8021
N1  - This work was funded by the heritage of Juliana Gerner, Germany, and the Netherlands Lung Foundation (Longfonds, grant #5.2.16.126JO). The open access publication fee will be paid by the Department of Pediatric Pulmonology of the University Hospital Frankfurt.
VL  - 11
IS  - art. 570403
SP  - 1
EP  - 8
PB  - Frontiers Media
CY  - Lausanne
ER  -