Mutations that permit residual CFTR function delay acquisition of multiple respiratory pathogens in CF patients

Abstract

BackgroundLung infection by various organisms is a characteristic feature of cystic fibrosis (CF). CFTR genotype effects acquisition of Pseudomonas aeruginosa (Pa), however the effect on acquisition of other infectious organisms that frequently precede Pa is relatively unknown. Understanding the role of CFTR in the acquisition of organisms first detected in patients may help guide symptomatic and molecular-based treatment for CF.MethodsLung infection, defined as a single positive respiratory tract culture, was assessed for 13 organisms in 1,381 individuals with CF. Subjects were divided by predicted CFTR function: 'Residual': carrying at least one partial function CFTR mutation (class IV or V) and 'Minimal' those who do not carry a partial function mutation. Kaplan-Meier estimates were created to assess CFTR effect on age of acquisition for each organism. Cox proportional hazard models were performed to control for possible cofactors. A separate Cox regression was used to determine whether defining infection with Pa, mucoid Pa or Aspergillus (Asp) using alternative criteria affected the results. The influence of severity of lung disease at the time of acquisition was evaluated using stratified Cox regression methods by lung disease categories.ResultsSubjects with 'Minimal' CFTR function had a higher hazard than patients with 'Residual' function for acquisition of 9 of 13 organisms studied (HR ranging from 1.7 to 3.78 based on the organism studied). Subjects with minimal CFTR function acquired infection at a younger age than those with residual function for 12 of 13 organisms (p-values ranging: < 0.001 to 0.017). Minimal CFTR function also associated with younger age of infection when 3 alternative definitions of infection with Pa, mucoid Pa or Asp were employed. Risk of infection is correlated with CFTR function for 8 of 9 organisms in patients with good lung function (>90%ile) but only 1 of 9 organisms in those with poorer lung function (<50%ile).ConclusionsResidual CFTR function correlates with later onset of respiratory tract infection by a wide spectrum of organisms frequently cultured from CF patients. The protective effect conferred by residual CFTR function is diminished in CF patients with more advanced lung disease.

Progressive ventilation inhomogeneity in infants with cystic fibrosis after pulmonary infection

“…CF transmembrane conductance regulator (CFTR) genotype was classified as severe (at least one class I, II or III mutation) or mild (class IV or V), as previously described [39][40][41][42].…”

Assessing the Disease-Liability of Mutations in CFTR

“…In general, mutations in class I to III are associated with complete or near complete loss of CFTR function (,3% of wild-type CFTR function) . Mutations in these classes are primarily associated with pancreatic insufficiency, higher rates of pulmonary infection, and higher mortality (Kubesch et al 1993;Koch et al 2001;Ahmed et al 2003;McKone et al 2003;Green et al 2010). On the other hand, residual CFTR function tends to be higher (3% -10%) in class IV and V mutations.…”

“…On the other hand, residual CFTR function tends to be higher (3% -10%) in class IV and V mutations. Consequently, patients with these mutations tend to have higher rates of pancreatic sufficiency and less elevated sweat chloride levels (Koch et al 2001;Ahmed et al 2003;McKone et al 2003;Green et al 2010). As residual CFTR function is increased, such as in the case of the R117H mutation bearing the 7T variant, lung function is improved sufficiently such that a CF diagnosis may not be evident.…”

Preliminary study of haplotypes linked to the rare cystic fibrosis E1104X mutation

“…The E1104X mutation was later described in Germany by Reiss in 1993 (21), in France (4,23,24), and in US (10).…”

“…The most common defect is observed to be the F508 del mutation, deletion of 3 base pair in exon 10. In Tunisian population, 12 different CFTR mutations, accounting for 90% of CF alleles, have been found.…”