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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.

Impact of a Gap Junction Protein Alpha 4 Variant on Clinical Disease Phenotype in F508del Homozygous Patients With Cystic Fibrosis