Identification of SNPs in the cystic fibrosis interactome influencing pulmonary
progression in cystic fibrosis |
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Authors: | Franziska M Gisler Thomas von Kanel Richard Kraemer André Schaller Sabina Gallati |
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Institution: | 1.Division of Human Genetics, Departments of
Pediatrics and Clinical Research, University of Bern, Bern, Switzerland;2.Division of Pediatric Respiratory Medicine,
Department of Pediatrics, Inselspital, University of Bern, Bern, Switzerland |
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Abstract: | There is growing evidence that the great phenotypic variability in patients with cystic
fibrosis (CF) not only depends on the genotype, but apart from a combination of
environmental and stochastic factors predominantly also on modifier gene effects. It has
been proposed that genes interacting with CF transmembrane conductance regulator (CFTR)
and epithelial sodium channel (ENaC) are potential modifiers. Therefore, we assessed the
impact of single-nucleotide polymorphisms (SNPs) of several of these interacters on CF
disease outcome. SNPs that potentially alter gene function were genotyped in 95
well-characterized p.Phe508del homozygous CF patients. Linear mixed-effect model analysis
was used to assess the relationship between sequence variants and the repeated
measurements of lung function parameters. In total, we genotyped 72 SNPs in 10 genes.
Twenty-five SNPs were used for statistical analysis, where we found strong associations
for one SNP in PPP2R4 with the lung clearance index (P≤0.01), the
specific effective airway resistance (P≤0.005) and the forced expiratory
volume in 1 s (P≤0.005). In addition, we identified one SNP in
SNAP23 to be significantly associated with three lung function parameters as
well as one SNP in PPP2R1A and three in KRT19 to show a significant
influence on one lung function parameter each. Our findings indicate that direct
interacters with CFTR, such as SNAP23, PPP2R4 and PPP2R1A, may modify the residual
function of p.Phe508del-CFTR while variants in KRT19 may modulate the amount of
p.Phe508del-CFTR at the apical membrane and consequently modify CF disease. |
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Keywords: | cystic fibrosis interactome modifier genes |
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