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 

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

JOURNAL=Frontiers in Genetics

VOLUME=11

YEAR=2020

URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2020.570403

DOI=10.3389/fgene.2020.570403

ISSN=1664-8021

ABSTRACT=<sec><title>Background</title><p>Lung disease phenotype varies widely even in the <italic>F508del</italic> (homozygous) genotype. Leukocyte-driven inflammation is important for pulmonary disease pathogenesis in cystic fibrosis (CF). Blood cytokines correlate negatively with pulmonary function <italic>in F508del</italic> 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 <italic>GJA1/GJA4</italic> genotypes and the clinical disease phenotype.</p></sec><sec><title>Methods</title><p>One-hundred-and-sixteen homozygous <italic>F508del</italic> 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 <italic>GJA1</italic> and <italic>GJA4</italic>. The clinical disease course was assessed over 3 years using pulmonary function tests, body mass index, <italic>Pseudomonas aeruginosa</italic> colonization, diabetes mellitus, survival to end-stage lung disease, blood and sputum inflammatory markers.</p></sec><sec><title>Results</title><p>Sequence analysis revealed one clinically relevant single nucleotide polymorphism. In this <italic>GJA4</italic> variant (rs41266431), homozygous G variant carriers (<italic>n</italic> = 84/116; 72.4%) had poorer pulmonary function (FVC% pred: mean 78/86, <italic>p</italic> &lt; 0.040) and survival to end-stage lung disease was lower (<italic>p</italic> &lt; 0.029). The frequency of <italic>P. aeruginosa</italic> 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, <italic>p</italic> &lt; 0.049). Serum interleukin-8 (median: 12.4/6.7 pg/ml, <italic>p</italic> &lt; 0.052) and sputum leukocytes (2305/437.5 pg/ml, <italic>p</italic> &lt; 0.025) were higher for the G/G genotype.</p></sec><sec><title>Conclusions</title><p>In carriers of the A allele (27.6%) the <italic>GJA4</italic> variant is associated with significantly better protection against end-stage lung disease and superior pulmonary function test results in <italic>F508del</italic> homozygous patients. This SNP has the potential of a modifier gene for phenotyping severity of CF lung disease, in addition to the <italic>CFTR</italic> genotype.</p></sec><sec><title>Clinical Trial Registration</title><p>The study was registered with <ext-link ext-link-type="uri" xlink:href="https://clinicaltrials.gov" xmlns:xlink="http://www.w3.org/1999/xlink">ClinicalTrials.gov</ext-link>, number NCT04242420, retrospectively on January 24th, 2020.</p></sec>