Biomedical Engineering Reference
In-Depth Information
individual's mucocilliary clearance rate. This may have important implica-
tions for an individual's cumulative exposure to the compounds found in
cigarette smoke.
Cystic Fibrosis Transmembrane Regulator:
The cystic fibrosis trans-
membrane conductance regulator (CFTR) forms a chloride channel at the
apical surface of airway epithelial cells and is involved in the control of air-
way secretions. In 1989, mutations in the CFTR gene were identified as the
cause of CF. The CF carriers may also be predisposed to respiratory disease.
The CF heterozygotes had increased bronchial reactivity to methacholine
(156) and increased incidence of wheeze accompanied by decreased FEV
1
and FEF
25-75
(157).
The most frequent CF-causing variant is DF508 and heterozygosity for
this mutation was increased in patients who had disseminated bronchiectasis
(158,159) and in patients who had ''bronchial hypersecretion'' (160). The
prevalence of DF508 was not increased in patients who had chronic bronchi-
tis (159). Other CFTR mutations were increased in patients who had disse-
minated bronchiectasis and normal sweat chloride levels (161,162). One of
these mutations is a variable length thymine repeat in intron 8 of the CFTR
gene (IVS8). The IVS8-5T allele results in reduced CFTR gene expression.
Studies of IVS8-5T as a risk factor for COPD have yielded conflicting
results (161,162). In another study, patients with obstructive lung diseases
were screened for variants in the whole CFTR coding region (163). The
study compared 12 COPD patients with 52 controls, both groups from
the Greek population. There was no significant increase in CF-causing
mutations in the patients vs. the controls. However, the frequency of the
methionine allele of the Met470Val polymorphism was increased in the
patients (71%) compared with the controls (36%). However, the Met470 var-
iant is associated with increased CFTR chloride channel activity compared
with the Val variant (164), and therefore the reason for the association with
COPD is unclear. A recent study performed in a Korean population found a
different CFTR polymorphism pattern from that in Caucasian populations
(165). These authors also found several polymorphisms and their corre-
sponding haplotypes were associated with bronchiectasis and chronic
pancreatitis. In a functional study, the E2I7G and Q1352H polymor-
phisms were shown to significantly affect CFTR chloride activity in the
presence of Met470Val polymorphism (165). These data suggest that
interactions between multiple genetic variants affect the final phenotype of
the CFTR gene.
In summary, CFTR variants have been consistently associated with
disseminated bronchiectasis. This may be due to the effect of these variants
on the rate of mucociliary clearance. However, it is not clear whether the
patients who have disseminated bronchiectasis represent a clinically distinct
group or have mild, undiagnosed CF with an unknown CFTR mutation on
