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

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. We aimed to assess the relationship between genotypes and the clinical disease phenotype. One-hundred-and-sixteen homozygous 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 and . The clinical disease course was assessed over 3 years using pulmonary function tests, body mass index, colonization, diabetes mellitus, survival to end-stage lung disease, blood and sputum inflammatory markers. Sequence analysis revealed one clinically relevant single nucleotide polymorphism. In this variant (rs41266431), homozygous G variant carriers ( = 84/116; 72.4%) had poorer pulmonary function (FVC% pred: mean 78/86, < 0.040) and survival to end-stage lung disease was lower ( < 0.029). The frequency of 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, < 0.049). Serum interleukin-8 (median: 12.4/6.7 pg/ml, < 0.052) and sputum leukocytes (2305/437.5 pg/ml, < 0.025) were higher for the G/G genotype. In carriers of the A allele (27.6%) the variant is associated with significantly better protection against end-stage lung disease and superior pulmonary function test results in homozygous patients. This SNP has the potential of a modifier gene for phenotyping severity of CF lung disease, in addition to the genotype. The study was registered with ClinicalTrials.gov, number NCT04242420, retrospectively on January 24th, 2020.