Importin-13 genetic variation is associated with improved airway responsiveness in childhood asthma

<p>Abstract</p> <p>Background</p> <p>Glucocorticoid function is dependent on efficient translocation of the glucocorticoid receptor (GR) from the cytoplasm to the nucleus of cells. Importin-13 (IPO13) is a nuclear transport receptor that mediates nuclear entry of GR. In airway epithelial cells, inhibition of IPO13 expression prevents nuclear entry of GR and abrogates anti-inflammatory effects of glucocorticoids. Impaired nuclear entry of GR has been documented in steroid-non-responsive asthmatics. We hypothesize that common IPO13 genetic variation influences the anti-inflammatory effects of inhaled corticosteroids for the treatment of asthma, as measured by change in methacholine airway hyperresponsiveness (AHR-PC₂₀).</p> <p>Methods</p> <p>10 polymorphisms were evaluated in 654 children with mild-to-moderate asthma participating in the Childhood Asthma Management Program (CAMP), a clinical trial of inhaled anti-inflammatory medications (budesonide and nedocromil). Population-based association tests with repeated measures of PC₂₀were performed using mixed models and confirmed using family-based tests of association.</p> <p>Results</p> <p>Among participants randomized to placebo or nedocromil, IPO13 polymorphisms were associated with improved PC₂₀(i.e. less AHR), with subjects harboring minor alleles demonstrating an average 1.51–2.17 fold increase in mean PC₂₀at 8-months post-randomization that persisted over four years of observation (p = 0.01–0.005). This improvement was similar to that among children treated with long-term inhaled corticosteroids. There was no additional improvement in PC₂₀by IPO13 variants among children treated with inhaled corticosteroids.</p> <p>Conclusion</p> <p>IPO13 variation is associated with improved AHR in asthmatic children. The degree of this improvement is similar to that observed with long-term inhaled corticosteroid treatment, suggesting that IPO13 variation may improve nuclear bioavailability of endogenous glucocorticoids.</p

REMISSION OF CHILDHOOD ASTHMA AFTER LONG-TERM TREATMENT WITH AN INHALED CORTICOSTEROID (BUDESONIDE) - CAN IT BE ACHIEVED

This study was undertaken in order to determine whether long-term treatment with inhaled corticosteroid can induce a remission in childhood asthma, and to decide when stabilization of airway responsiveness occurred. We therefore carried out, an extended follow-up of 28-36 months in one of two groups of children who participated in a long-term intervention study. This former study had shown that long-term (median follow-up 22 months) treatment with inhaled corticosteroid plus beta(2)-agonist improves symptoms, airway calibre and airway responsiveness in children with asthma, compared with beta(2)-agonist alone. On treatment with inhaled corticosteroid plus beta(2)-agonist, airway calibre did not further improve after 4 months, whereas the provocative dose of histamine which causes a 20% fall in forced expiratory volume in one second (PD20) histamine showed gradual improvement without reaching an apparent plateau. Remission was defined as being symptom free during any 8 month period. Of the 58 children originally randomized to receive 0.2 mg salbutamol, plus 0.2 mg budesonide, Lid, five children withdrew: three due to lack of motivation, one for psychological reasons, and one due to a deterioration of asthma One patient was hospitalized because of an asthma exacerbation. Airway calibre showed no improvement after 4 months up to 36 months. Mean PD,histamine stabilized after 20 months at 2.1 doubling doses above baseline, but at a subnormal level of 80 mu g. Symptoms improved during the first 18 months, and may have been improving further, but slowly, during the period between 18 and 36 months. Thirty five patients (60%) achieved a period of remission at some time during the 28-36 months of treatment, However, 23 (66%) of these had a relapse. We conclude that long-term treatment with inhaled corticosteroid improves clinical signs, airway calibre and airway responsiveness, although in most patients only up to a subnormal level Only a minority of the patients achieve a long-lasting remission