Identification of SNPs in the cystic fibrosis interactome influencing pulmonary progression in cystic fibrosis

There is growing evidence that the great phenotypic variability in patients with cysticfibrosis (CF) not only depends on the genotype, but apart from a combination ofenvironmental and stochastic factors predominantly also on modifier gene effects. It hasbeen proposed that genes interacting with CF transmembrane conductance regulator (CFTR)and epithelial sodium channel (ENaC) are potential modifiers. Therefore, we assessed theimpact of single-nucleotide polymorphisms (SNPs) of several of these interacters on CFdisease outcome. SNPs that potentially alter gene function were genotyped in 95well-characterized p.Phe508del homozygous CF patients. Linear mixed-effect model analysiswas used to assess the relationship between sequence variants and the repeatedmeasurements 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 associationsfor one SNP in PPP2R4 with the lung clearance index (P≤0.01), thespecific effective airway resistance (P≤0.005) and the forced expiratoryvolume in 1 s (P≤0.005). In addition, we identified one SNP inSNAP23 to be significantly associated with three lung function parameters aswell as one SNP in PPP2R1A and three in KRT19 to show a significantinfluence on one lung function parameter each. Our findings indicate that directinteracters with CFTR, such as SNAP23, PPP2R4 and PPP2R1A, may modify the residualfunction of p.Phe508del-CFTR while variants in KRT19 may modulate the amount ofp.Phe508del-CFTR at the apical membrane and consequently modify CF disease.