Cystic fibrosis mutations for p.F508del compound heterozygotes predict sweat chloride levels and pancreatic sufficiency

Abstract

Cystic fibrosis (CF) is a monogenetic disease with a complex phenotype. Over 1500 mutations in the CFTR gene have been identified; however, the p.F508del mutation is most common. There has been limited correlation between the CFTR mutation genotype and the disease phenotypes. We evaluated the non-p.F508del mutation of 108 p.F508del compound heterozygotes using the biological classification method, Grantham and Sorting Intolerant from Tolerant (SIFT) scores to assess whether these scoring systems correlated with sweat chloride levels, pancreatic sufficiency, predicted FEV1, and risk of infection with Pseudomonas aeruginosa in the last year. Mutations predicted to be ‘mild’ by the biological classification method are associated with more normal sweat chloride levels (p < 0.001), pancreatic sufficiency (p < 0.001) and decreased risk of infection with Pseudomonas in the last year (p = 0.014). Lower Grantham scores are associated with more normal sweat chloride levels (p < 0.001), and pancreatic sufficiency (p = 0.014). Higher SIFT scores are associated with more normal sweat chloride levels (p < 0.001) and pancreatic sufficiency (p = 0.011). There was no association between pulmonary function measured by predicted FEV1 and the biological classification (p = 0.98), Grantham (p = 0.28) or SIFT scores (p = 0.62), which suggests the pulmonary disease related to CF may involve other modifier genes and environmental factors.

Cigarette Smoke Induces Systemic Defects in Cystic Fibrosis Transmembrane Conductance Regulator Function

“…Sweat chloride was significantly increased in healthy smokers, smokers with COPD, and former smokers with COPD, indicative of reduced CFTR activity in the sweat gland, a site remote from the airway ( Figure 1A). Increased sweat chloride was not accounted for by differences in serum chloride, sodium, or aldosterone (Table 1), and sweat chloride in normal control subjects was similar to that in prior publications (see Figure 1B) (19)(20)(21). Based on the genotypephenotype correlation in CF relating CFTR activity measured by NPD and sweat chloride analysis (22) (Figure 1B), the increase in sweat chloride in COPD subjects is equivalent to a 42% decrement in CFTR function ( Figure 1C) and similar to that observed in the airway (11).…”

Prevalence of malnutrition and obesity among cystic fibrosis patients

“…They also showed that patients with a severe CFTR genotype or who were F508del homozygous had higher percentages of malnutrition in comparison to patients with mild genotypes . The finding that a milder genotype is associated with less Pseudomonas colonization lends support to an association between genotype and overweight/obesity. Pedreira et al .…”

Association of sweat chloride concentration at time of diagnosis and CFTR genotype with mortality and cystic fibrosis phenotype

“…More severe CFTR mutations were found to be associated with higher sweat chloride levels, pancreatic insufficiency, and increased risk of Pseudomonas infection, but neither CFTR genotype nor sweat chloride concentration were significant predictors of FEV 1 % predicted [17,18].…”

“…Sweat chloride concentration has been proposed as a measure of the level of CFTR expression, although attempts to directly correlate sweat chloride concentration with clinical phenotypes have not shown consistent results [15][16][17][18]. The reasons for these differing results may be due to study design and varying degrees of power to detect a true association in different studies.…”