To the Editor,
Folliculin, a protein expressed in various types of cells including
airway epithelial cells, encoded by the FLCN gene, is associated
with the 5′ AMP-activated protein kinase (AMPK) and mammalian target of
rapamycin complex 1 (mTORC1) signaling pathways and, it is thought to
alter cell-to-cell adhesion and contribute to the pathogenesis of cystic
lung disease in Birt-Hogg-Dubé syndrome (1-5). In addition, the geneFLCN regulates the E-cadherin-LKB1-AMPK axis, which controls lung
epithelial cell survival and alveoli size (2).
In a recent study, serum
folliculin levels were found to be higher in patients with asthma than
in healthy control groups and high
folliculin levels were associated with increased airway
hyperresponsiveness in patients with asthma. In vitro data demonstrated
the eosinophil-induced release of folliculin from epithelial cells.
These clinical and in vitro observations suggest that folliculin may
play some role in the interaction between the eosinophils and airway
epithelium (6).
To investigate the relationship between clinical characteristics and the
level of folliculin in asthmatics, the data of a total of 404 patients
with asthma and 94 of controls were enrolled and retrospectively
reviewed. To correct for the heavily skewed distributions of the serum
folliculin levels, values were log-transformed. Study methods, design
and definitions used can be found in the online supplement (Study
S1).
The proportions of males and smokers were significantly higher among the
patients with asthma than in the controls, and the mean serum folliculin
level in asthmatics was significantly higher than that in controls (4.80
pg/mL versus 4.13 ng/mL; P < 0.001) (Table S1). As the
control group was comprised only of males and a significant difference
in smoking history was noted, adjusting for sex and smoking history was
performed and significantly higher serum folliculin levels were still
observed (P < 0.001).
We
compared the serum folliculin levels between asthmatics and controls
subdivided by sex and smoking status. In these subgroups,
the serum folliculin levels were
still significantly higher in asthmatics than in the control
group (Table S2). ROC curve
analysis revealed a significant difference in serum folliculin levels
between asthmatics and controls (area under the curve = 0.846,
confidence interval [CI] 0.80–0.89, P < 0.001);
the optimal cut-off value of serum folliculin level that distinguished
asthma patients from controls was 4.31 pg/mL after log-transformation,
correlating with 83.91%
sensitivity and 77.66% specificity (Figure 1).
When we perform ROC curve analysis
with only the males, the optimal cut-off value of serum folliculin level
was 4.33 pg/mL (Figure S1).
We compared folliculin levels
among the four groups divided by pre- pre-bronchodilator (BD) predicted
FEV1 (%) and found a significant difference in serum folliculin level
(P < 0.001, Figure
S2).
Simple
and multiple linear regression analysis was performed to determine the
correlation between serum folliculin level and lung function in patients
with asthma. In simple linear regression analysis, serum folliculin
level were significantly correlated with pre-BD FEV1% predicted
(β-coefficient = −4.848, P = 0.013),
however significance was only
marginal after adjusting for age and sex (β-coefficient = −3.199,P = 0.096) in multiple linear regression analysis. This is
because, firstly, there was collinearity of folliculin level and age in
our data, and secondly, the rate of smokers (85.22%) among males was
higher than among females (14.91%), so it seems that lung function in
females is higher.
Patients with asthma were divided into two groups using the mean value
of the logarithmic serum folliculin levels (4.80 pg/mL). Patients in the
high-folliculin group were older at the onset of symptoms,
heavier smokers and had a
significantly lower lung function. The number of acute exacerbations
occurring per year was more
frequent in the high folliculin group than in the low folliculin group,
but no statistical significance was noted (Table
1).
When patients with asthma were divided into the upper
quartile of folliculin levels
and the lower three quartiles
combined, those from the high folliculin group in the upper 25
percentile were found to be older and had lower atopy and lung function
than the lower folliculin group with the lower 75 percentile combined.
(Table S3). Likewise, we also divided the patients into 4 quantile
groups according to serum folliculin levels and identified differences
in each group in lung function and age (Table S4).
A previous in vitro study showed that human airway epithelial cells
(HAECs) exposed to leukotriene E4 and peripheral blood eosinophils
released folliculin and interleukin (IL)-8, which resulted in the
destruction of the integrity of the epithelial cells. The knockdown of
folliculin expression resulted in a decrease in IL-8 release and
suppression of epithelial cell activation, which restored the epithelial
integrity in HAECs. In their study, folliculin was suggested to be
associated with a higher serum
transforming growth factor-β1 level, which was associated with worsening
of airway inflammation and remodeling (6,7). Consistent with theses
result, a higher serum folliculin level in patients with asthma than in
healthy controls was also observed in our study, in addition, we showed
that an increase in serum folliculin level was associated with a
decrease in basal lung function. As folliculin is released from
bronchial epithelial cells in response to compressive stress that mimics
a bronchospasm (8, 9), we postulate that chronic airway inflammation
produces mechanical stress on the airway epithelium, thereby inducing
oxidative damage and release of folliculin with changes in the
epithelial cell structure. Therefore, we assume that folliculin is
associated with the airway inflammation and remodeling pathway in
patients with asthma. In our study, serum folliculin level showed no
association with serum laboratory variables, suggesting that the
increase in folliculin level following mechanical stress is independent
of other serum inflammatory markers.
In conclusion, our study
demonstrates for the first time that serum folliculin concentration is
higher in patients with asthma, and it is associated with worse lung
function independent to other serum inflammatory markers.
Thus, folliculin may represent a
novel biomarker related to lower pulmonary function in patients with
asthma and further studies are warranted to evaluate the mechanism and
test our hypothesis.
Keywords: asthma; folliculin; biomarker