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 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.
Division of Human Genetics, Department of Pediatrics and Clinical Research, University of Bern, Bern, Switzerland.
Franziska M
FM
Gisler
Thomas
T
von Kanel
Richard
R
Kraemer
André
A
Schaller
Sabina
S
Gallati
D000293:Adolescent; D000328:Adult; D002648:Child; D003550:Cystic Fibrosis / Q000175:diagnosis / Q000235:genetics*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics* / Q000378:metabolism; D018450:Disease Progression; D004843:Epistasis, Genetic; D005260:Female; D015870:Gene Expression; D006720:Homozygote; D006801:Humans; D053539:Keratin-19 / Q000235:genetics / Q000378:metabolism; D008168:Lung / Q000473:pathology / Q000503:physiopathology*; D008176:Lung Volume Measurements; D008297:Male; D008957:Models, Genetic; D010749:Phosphoprotein Phosphatases / Q000235:genetics / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D054648:Protein Phosphatase 2 / Q000235:genetics / Q000378:metabolism; D050766:Qb-SNARE Proteins / Q000235:genetics / Q000378:metabolism; D050767:Qc-SNARE Proteins / Q000235:genetics / Q000378:metabolism
C505032:CFTR protein, human; D053539:Keratin-19; C517191:PPP2R1A protein, human; D050766:Qb-SNARE Proteins; D050767:Qc-SNARE Proteins; C100493:SNAP23 protein, human; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D010749:Phosphoprotein Phosphatases; D054648:Protein Phosphatase 2; C087440:PTPA protein, human