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

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 (Pr0.01), the specific effective airway resistance (Pr0.005) and the forced expiratory volume in 1 s (Pr0.005). 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.

Whole-Exome Sequencing and Whole-Genome Sequencing in Critically Ill Neonates Suspected to Have Single-Gene Disorders

“…In the future, more extensive data analysis and more mature knowledge will be necessary to identify pathology resulting from mutations in multiple genes. In its simplest form, this involves identification of epistatic modifiers of monogenetic disease genes, such as variants that influence progression in cystic fibrosis (Gisler et al 2013). In common complex diseases with multifactorial inheritance, this will necessitate integration of information about genic and structural mutations with environmental exposures.…”

A Genotypic-Oriented View of CFTR Genetics Highlights Specific Mutational Patterns Underlying Clinical Macrocategories of Cystic Fibrosis

“…The second step may be defined as the transition from the CFTR protein residual function to clinical phenotype (residual functionality → clinical step). This transition is more likely to be influenced by extragenic variability due to genes other than CFTR, such as the socalled modifier genes (9,47) and the CFTR interactome (48,49). Significant differences emerged in the average sweat test values, which may be considered an in vivo measurement of the CFTR protein residual function between the populations analyzed.…”

SpliceAid-F: a database of human splicing factors and their RNA-binding sites

“…These tools are being used by researchers studying functional effects of gene polymorphisms (32) or mutations (33), as they predict whether these variations can affect the splicing process by altering the binding between SFs and pre-mRNA. SpliceAid-F is instead a different resource, consisting of a database collecting information about SFs, such as their expression, their orthologous genes and proteins, the associated diseases, interacting proteins and chemicals, RNA-binding domains and interacting and not-interacting RNAs.…”